Next Article in Journal
Amyotrophic Lateral Sclerosis and Serum Lipid Level Association: A Systematic Review and Meta-Analytic Study
Previous Article in Journal
Identification of Potential Biomarkers for Diagnosis of Patients with Methamphetamine Use Disorder
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 24
Issue 10
10.3390/ijms24108665
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Preventive Role of the Vitamin D Endocrine System in Cervical Cancer

by
Euclides Avila
1,*,
Bryan Javier Noriega-Mejía
1,
Jocelyn González-Macías
1,
Ulises Cortes-Hernández
1,
Janice García-Quiroz
1,
Rocío García-Becerra
2 and
Lorenza Díaz
1
1
Departamento de Biología de la Reproducción Dr. Carlos Gual Castro, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco de Quiroga No. 15, Col. Belisario Domínguez Sección XVI, Tlalpan, Ciudad de México 14080, Mexico
2
Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Av. Universidad 3000, Coyoacán, Ciudad de México 04510, Mexico
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(10), 8665; https://doi.org/10.3390/ijms24108665
Submission received: 29 March 2023 / Revised: 8 May 2023 / Accepted: 10 May 2023 / Published: 12 May 2023
(This article belongs to the Special Issue Molecular Biology of Gynecological Cancers: From Bench to Bedside)
Browse Figures
Versions Notes

Abstract

:
Vitamin D along with its active metabolite calcitriol and its metabolic and signaling system, known as the vitamin D endocrine system, have been widely recognized as a pivotal regulator of calcium homeostasis in addition to non-calcemic antitumoral effects in a variety of human cancers, including cervical cancer. Several studies have found an inverse relationship between the incidence of cervical neoplasia and vitamin D levels. This narrative review updates the current evidence supporting the notion that the vitamin D endocrine system has a preventive role on cervical cancer, mainly in the early phases of the disease, acting at the level of suppressing cell proliferation, promoting apoptosis, modulating inflammatory responses, and probably favoring the clearance of human papillomavirus-dependent cervical lesions. Although an optimal vitamin D status helps in the prevention and regression of low-grade squamous intraepithelial lesions of the cervix, it appears that vitamin D alone or combined with chemotherapeutic agents has little effectivity once advanced cervical cancer is established. These observations suggest that an optimal vitamin D status might exert beneficial actions in the early phases of cervical cancer by preventing its onset and progression.

1. Introduction

Cervical cancer remains a major health issue affecting middle-aged women in low-income countries. Worldwide, cervical cancer is the fourth most common neoplasia in women, ranking only after breast cancer, colorectal cancer and lung cancer [1]. An estimated 604,000 new cases of cervical cancer were diagnosed globally in 2020, and about 342,000 women died of metastatic advanced cervical cancer [2]. The prevalence of invasive cervical cancer is the highest in sub-Saharan Africa, which is attributable to a combination of factors including deprivation, lower socioeconomic status and higher gender inequality, among others [3]. Fortunately, cervical cancer is highly preventable via prophylactic vaccination against the high-risk Human Papillomavirus (HPV) subtypes [4], whose chronic infection is recognized as the causal factor for the development of pre-malignant and malignant lesions of the cervix [5]. Moreover, precancerous lesions can be identified and treated using early detection screening tests based on cytologic analysis, colposcopic examination of the cervix and HPV tests [6]. These early detection programs explain why western countries have a very low incidence of invasive cervical cancer [3]. Current treatments for advanced cervical cancer have improved notably and include surgery, immunotherapy, poly (ADP-ribose) polymerase-targeted therapy, radiotherapy and standard chemotherapy [7,8].
Chronic infection with high-risk HPV subtypes is the most important risk factor for developing cervical cancer. Among the high-risk HPV subtypes, HPV16 and HPV18 account for 75% of all cases of advanced cervical cancer [5]. Of note, only a reduced percentage of chronic HPV infection cases progress to invasive cervical cancer through a very slow process, estimated to take up to 20 years or even longer. The HPV-infected cervical epithelium is first transformed to cervical intraepithelial neoplasia grade 1 (CIN1, also known as low-grade squamous intraepithelial lesion or LSIL) and later to CIN2/3 (also known as high-grade squamous intraepithelial lesion or HSIL) before developing into invasive cervical cancer [9].
In addition to high-risk chronic HPV infection, several factors contribute to cervical cancer progression and development. Some of these risk factors are related to the sexual personal history, since the chances of HPV infection increases with a younger age of sexual activity, having multiple sexual partners and full-term pregnancies, as well as young age at first full-term pregnancy [10,11,12,13]. Inflammation of the cervix caused by Chlamydia trachomatis and Neisseria gonorrhoeae infection [14] and other sexually transmitted infections as Herpes Simplex Virus type 2 infection [15] also contribute to cervical cancer progression. Chronic inflammation of the cervix by seminal prostaglandin E2 also increases the risk of cervical cancer [16]. Other risk factors for cervical cancer onset are immunosuppression by Human Immunodeficiency Virus infection [17], long-term use of oral contraceptives [18], smoking tobacco products [19], low educational levels [20], eating few vegetables and fruits [21,22], family history of this kind of cancer [23] and obesity [24,25]. In addition to these genetic, infectious, environmental, and lifestyle factors, there are some studies that associate vitamin D deficiency with a higher risk for cervical cancer [26,27,28,29,30,31,32]. Herein, we review the clinical, epidemiological and laboratory research evidence linking vitamin D and cervical cancer development.

2. The Vitamin D Endocrine System

The vitamin D endocrine system comprises a complex regulatory system formed by lipidic precursors, mitochondrial hydroxylases, one transporter protein, and one receptor with intrinsic activity of transcription factor, which are located in several organs including the skin, liver, kidneys, intestines, and bones (Figure 1). Considering that the major source of vitamin D in human beings is provided by vitamin D3 photosynthesis, in this work, we will focus only on vitamin D3; however, the vitamin D pool in the body refers to the sum of vitamin D2 (from vegetal sources) and vitamin D3 (from animal sources, including dairy products, oily fishes, eggs, and vitamin D3-fortified products).
Vitamin D3 is mainly formed in the skin via an ultraviolet light-dependent process from 7-dehydrocholesterol, whose 9–10 bond in the B-ring is cleaved, followed by a thermal isomerization of the molecule [33]. In this manner, fat-soluble vitamin D3, also named cholecalciferol, retains the 27 atoms of carbon from its precursor 7-dehydrocholesterol, but presents an opened B-ring, which is why it is considered a secosteroid.
Vitamin D3 is biologically inactive and requires two enzymatic hydroxylations to gain activity (Figure 1). The first hydroxylation of vitamin D3 takes place in the liver, where several proteins with 25-hydroxylase activity (CYP27A1, CYP3A4, and CYP2R1) produce 25-hydroxyvitamin D3 (25OHD3), the major circulating metabolite used to evaluate the nutritional vitamin D status [34]. Once transported to the kidneys by the vitamin D-binding protein (DBP), 25OHD3 undergoes a hydroxylation on position 1 by the 25OHD3 1α-hydroxylase (CYP27B1) to form 1,25-dihydroxyvitamin D3 (calcitriol or 1,25-dihydroxycholecalciferol) [35]. Calcitriol is a potent lipidic molecule considered the hormonal form of the vitamin D endocrine system. Calcitriol activates the intracellular vitamin D receptor (VDR), and through this interaction, exerts many genomic and non-genomic biological responses not only restricted to the preservation of skeleton integrity and mineral balance of calcium and phosphate [36]. According to its classic function as a transcription factor, VDR interacts with many transcriptional modulators, including retinoid X receptor (RXR) subtypes. As a heterodimer with RXR, VDR controls the gene expression patterns of calcitriol-responsive genes by recruitment to specific DNA sequences called vitamin D-response elements (VDREs) located in the promoter regions of target genes (Figure 2) [37]. The last major component of the vitamin D endocrine system is 25OHD3 24-hydroxylase (CYP24A1), the enzyme that catabolizes calcitriol as well as 25OHD3. This mitochondrial enzyme, highly induced by calcitriol, converts the active hormone calcitriol into inactive 24-hydroxylated products that are further oxidized to polar products that are excreted in the bile [38].
VDR expression has been detected in more than 30 different cell types [39], including the female reproductive tract [40], where uterine hypoplasia with impaired folliculogenesis was observed in VDR null mutant mice [41], highlighting the importance of this hormonal system in female fertility.
The vitamin D endocrine system action is essential for the physiology of many organs in the body, and impairment of this regulatory axis has been observed in several medical conditions such as osteoporosis, rickets, infection susceptibility, autoimmune diseases, diabetes, cardiovascular diseases, and cancer [42]. It is well established that the vitamin D endocrine system has preventive and therapeutic effects against many types of human neoplasias through a variety of mechanisms that included suppression of cell proliferation, increased apoptosis, and reduced angiogenesis, among others. These general mechanisms have been recently reviewed elsewhere [43,44]. Moreover, the roles of the vitamin D and VDR in breast, endometrial, ovarian, cervical, vulvar and vaginal neoplasias have been previously reviewed [40,45]. In this review, we updated the current knowledge of the overall vitamin D3 biosynthetic pathway and the new contributions made to the vitamin D3 actions in both in vitro and in vivo models of cervical cancer, with the aim to support the preventive role of this hormonal system in a significant global health issue in women.
Women with impaired immunity whose cervical epithelium is infected with high-risk HPVs may develop a chronic viral infection that results in genital warts, CIN1/2/3, and cervical cancer. Moreover, immune function is impaired, and inflammation markers are increased in cervical cancer patients [46]. Recently, it has been described that DBP levels are significantly decreased in the serum from cervical cancer patients compared with healthy controls, highlighting the participation of the vitamin D endocrine system in cervical cancer physiopathology [47].

3. The Vitamin D Endocrine System in Cervical Cancer: Preclinical Studies

It has been demonstrated that CYP27A1, CYP27B1, CYP24A1, and VDR are expressed in both normal and tumoral cervical tissue [48,49,50], which suggests local actions of this hormonal system in the cervix. Studies in HeLa cervical cancer cells demonstrated that calcitriol increased the gene expression of both CYP27A1 and CYP24A1, without affecting CYP27B1, whose mRNA was reduced by 25OHD3 [51]. In addition, we have reported that CYP27B1 expression and activity are detected in SiHa cervical cancer cells, which correlated with local calcitriol production from its precursor 25OHD3 [52]. In these cells, basal expression of CYP24A1 is detected, which is induced in the presence of calcitriol, as occurs in the vast majority of VDR-expressing cells [52]. VDR expression and activity are also detected in SiHa, and HeLa cell lines but not in C33A cells [52,53,54], where the induction of CYP24A1 gene by calcitriol is not observed [53]. It is not known why C33A lacks VDR; however, these cells might be used as negative controls to validate calcitriol-mediated effects in cervical cancer.
Although VDR is highly expressed in cervical cancer tissue compared with healthy tissue [48,49], VDR immunoreactivity is not a prognostic factor for this neoplasia, since it does not correlate with tumor stage, lymph node status, grading, histological tumor type, or the expression of the Ki-67 proliferation marker [55]. Interestingly, recent studies found that Fok1 and TaqI VDR polymorphisms are associated with a high risk of HPV16-dependent CIN2 and cervical cancer [56,57]. Fok1 and TaqI, among other VDR single-nucleotide polymorphisms, are restriction fragment length polymorphisms associated with a higher risk of gynecological neoplasias such as ovarian cancer [58]. The mechanisms by which these VDR polymorphisms promote cancer include changes in receptor affinity, DNA binding, and transcription and translation efficiency [58].
A great number of in vitro and in vivo studies have concluded that the vitamin D endocrine system has a protective role on human carcinogenesis [44]. This concept is supported by the regulatory role of vitamin D on fundamental cancer-related processes, such as cell proliferation, apoptosis, cell differentiation, angiogenesis, autophagy, inflammation, oxidative and energy metabolism, as well as immune response modulation [59]. These general mechanisms of vitamin D action have been obtained mainly from studies in different tumors, including melanoma and from colorectal, prostate and breast cancer models. In comparison, studies on the association between vitamin D and cervical cancer are scarce, and beneficial anti-cancer in vitro results have been observed only with elevated concentrations of calcitriol or its precursor 25OHD3, which could result in hypercalcemia in vivo. In this regard, calcitriol suppressed the proliferation of SiHa and HeLa cervical cancer cells [52,60]. In SiHa cells treated with vitamin D3, proliferation also is suppressed, and apoptosis is induced [61]. Thus, cell proliferation inhibition is one of the most important anti-cancer effects of the vitamin D3 endocrine system in cervical cancer.
Previously, we have demonstrated that the oncogenic potassium channel ether a go-go-1 (EAG1) is down-regulated by calcitriol both in HeLa and SiHa cervical cancer cell lines [52], by a mechanism involving the repressive function of a negative VDRE in the EAG1 promoter [53]. EAG1 is a membrane protein whose normal distribution is mainly confined to the central nervous system; however, its ectopic expression is considered a carcinogenic hallmark [62]. In cervical cancer, EAG1 expression is an early marker of the disease [63], since its protein expression is detected in early CIN stages [64]. In addition, EAG1 expression is increased by estradiol in estrogen α receptor-transfected HeLa cells and also in human keratinocytes transformed by both HPV16-E6 and HPV16-E7 oncogenes [65], which highlights that EAG1 expression is up-regulated by cervical cancer-promoting factors.
Moreover, calcitriol suppresses the proliferation of HeLa cervical cells in part by a mechanism involving the down-regulation of the human cervical cancer oncogene (HCCR-1, LETM1 domain containing 1) [60], which encodes a mitochondrial outer membrane protein highly expressed in cervical cancer tissue [66]. Calcitriol-mediated suppression of HCCR-1 synthesis correlated with increased expression of the cyclin–dependent kinase inhibitor p21, a robust cell cycle inhibitor involved in tumorigenesis [60]. In addition, it has been demonstrated in HeLa cells that calcitriol shuts down mitochondrial homeostasis by activating the PI3K-AKT-mTOR pathway, leading to autophagy inhibition [67]. Moreover, by inducing apoptosis, vitamin D3 and 25OHD3 inhibit CaSki and SiHa cell proliferation, respectively [68,69]. These effects are the result of endogenously calcitriol produced in these cervical cells by the action of calcitriol-activating hydroxylases. Together, these evidences support the protective role of the vitamin D endocrine system on cervical cancer cell proliferation. Interestingly, despite having a high HPV16 number of copies, CaSki cells are very sensitive to the effects of antiproliferative factors. Recently, we have demonstrated that the natural compound α-mangostin inhibited the proliferation of CaSki cells, a process that was accompanied by the reduction in the expression of EAG1 and HPV16 E6/E7 oncogenes [70].
It has been reported that calcitriol has regulatory actions on both the expression of some components of the microRNA biogenesis machinery and the microRNA expression in VDR-positive SiHa and HeLa cells but not in C33A VDR-negative cervical cancer cells [54,71]. MicroRNAs are a class of small non-coding molecules of RNAs that globally regulate gene expression patterns. MicroRNAs are involved in a variety of fundamental cellular processes including development, apoptosis, cell differentiation and fate, cell growth, metabolic control and reproductive functions [72]. In addition, microRNA deregulation is associated with several human diseases, including cancer [72]. The canonical microRNA biogenesis pathway starts in the cell nucleus where RNA polymerase II transcribes a primary transcript named pri-microRNA, which is processed to pre-microRNA by the microprocessor complex formed by the ribonuclease Drosha, the double-stranded RNA binding protein DGCR8, and the RNA helicases DDX5, and DDX17. Once exported to the cytoplasm by the action of exportin 5/RAN-GTP, the pre-microRNA is further processed by ribonuclease Dicer to form the mature single-stranded microRNA of 18–25 nucleotides long, which is loaded onto the multiprotein RNA-induced silencing complex, leading to translational repression or mRNA degradation [72]. Among the proteins participating in microRNA biogenesis, the RNA helicase DDX5 and the ribonuclease Dicer have been induced by high concentrations of calcitriol in SiHa cervical cells through a mechanism involving the recruitment of activated VDR to inductive VDREs in their promoter regions [54,71]. These regulatory effects of calcitriol on Dicer and DDX5 were accompanied by an increased expression of several microRNAs with anti-cancer properties including microRNA-22, -29c, -4455, respectively [54]. Interestingly, tumor suppressor microRNA-22 was downregulated by HPV16 E6 in cervical cancer cells [73]. MicroRNA-29c inhibits the epithelial–mesenchymal transition in cervical cancer cells, leading to the inhibition of proliferation, invasion and metastasis [74]. The inhibition of the microRNA-4455 axis expression reduces cervical cancer growth in vitro and in vivo [75]. Thus, it appears that calcitriol-dependent increased bioavailability of DDX5 might cause the RNA substrates to be readily processed by the ribonuclease Dicer, enhancing in this way the maturation rate of microRNAs associated with anti-cancer-related functions. On the other hand, calcitriol downregulated some microRNAs in SiHa cervical cancer cells [54]; however, their role in cervical cancer remains to be investigated.

4. The Vitamin D Endocrine System in Cervical Cancer: Clinical Studies

The data from some clinical trials suggest that vitamin D supplementation reduces the overall cancer mortality [76]; however, other studies do not support this conclusion [77]. Regarding cervical cancer, few studies have linked the vitamin D status with the onset and progression of this pathology. Epidemiological studies showed an inverse correlation between solar irradiance and the cervical cancer incidence [27,28,78,79,80], which probably is mediated by vitamin D3 biosynthesis. In 2010, a Japanese case–control study including 405 patients with incidental cervical neoplasias found that cervical cancer risk was reduced by increasing vitamin D intake [26], suggesting that vitamin D plays a protective role for cervical cancer. To date, no clinical trials have been conducted that have demonstrated the expected beneficial effects of vitamin D3, 25OHD3 or calcitriol per se on women with invasive cervical cancer, but they have been developed in combination with other antineoplastic drugs, including a phase II study (NCT03192059) that enrolled cervical or endometrial cancer patients, who received a cocktail of low-dose of cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy; the antitumor activity was modest but durable, and the toxicity was acceptable but not negligible [81]. A limited number of clinical trials have studied the effect of long-term vitamin D supplementation on precancerous lesions of the cervix. In this regard, an Iranian randomized, double-blind, placebo-controlled clinical trial evaluated the effects of long-term vitamin D3 supplementation on CIN1 regression. The study was carried out during 6 months among 58 Iranian women diagnosed with CIN1, who were randomly assigned to the placebo group (n = 29) or the vitamin D3 supplemented group (50,000 IU twice/month, n = 29). A higher percentage of women in the vitamin D3 supplemented group showed CIN1 regression when compared with the placebo group (84.6 vs. 53.8%, p = 0.01) [31]. Another study reported that vaginal suppositories (containing 12,500 IU of vitamin D), 3 nights per week during 6 weeks had good anti-inflammatory and antidysplastic effects in the CIN1 group, but no beneficial effects were seen in the CIN2 group [82]. The mechanisms explaining the protective effects of vitamin D on CIN1 regression may be related with the clearance of HPV from lesions, as has been previously suggested [29,83]. However, when another related long-term vitamin D3 supplementation trial was conducted in women diagnosed with more advanced cervical precancerous lesions (CIN2/3), the expected beneficial effect on recurrence was not observed [32].
Nonetheless, various studies addressing the effects of intralesional vitamin D3 for the treatment of HPV-induced warts have shown promising results, supporting an antiviral effect of vitamin D3. For example, in a single-blind randomized control trial conducted on 100 patients for one year, the intralesional vitamin D3 administration produced efficacious results in terms of wart clearance as well as the side effects profile [84]. Similarly, in another randomized placebo-controlled study undertaken in patients with recalcitrant extragenital warts, vitamin D3 treatment (600,000 IU) was effective, safe, and tolerable, with extremely low rates of recurrence [85]. The aim of this vitamin D3 treatment is to boost the local immune response, and the suggested mechanism of action is supposed to be related to the regulation of epidermal cells proliferation/differentiation as well as the regulation of cytokine production. In this regard, vitamin D3, through the action of its active metabolite calcitriol, exerts two important biological actions: an anti-inflammatory effect mediated by the inhibition of proinflammatory cytokines such as interleukin 1a, tumor necrosis factor α (TNF-α) and interleukin 6, and the induction of antimicrobial peptides synthesis [44,85,86]. The rationale behind vitamin D3-dependent induction of innate immunity is that, when an infectious agent activates the toll-like receptor, a concatenated sequence of events begins that include the upregulation of the VDR and CYP27B1, resulting in increased production and activity of calcitriol, which in turn transcriptionally induces antimicrobial peptides expression, such as cathelicidin [87]. Accordingly, the expression of cathelicidin after the intralesional injection of vitamin D3 in warts has been demonstrated, with a good clinical response [88], suggesting that the triggered immunological response definitively involves cathelicidin. Of note, not only extragenital warts have been successfully treated with vitamin D3, but also anogenital warts, which are also caused by HPV and commonly sexually transmitted, as observed in an adult male with condyloma acuminata, in whom, after injecting vitamin D3, a complete clearance of the condyloma was achieved [89]. This was also the case in anogenital warts treated topically with a vitamin D3 derivative [90]. Altogether, this evidence suggests a beneficial therapeutic effect of vitamin D3 on HPV defense, requiring further investigation.
Long-term vitamin D3 supplementation also had beneficial effects on glucose and lipid metabolism, and on biomarkers of oxidative stress and inflammation. These findings are of interest because chronic inflammation via several proinflammatory mediators and oxidative stress contributes to cervical carcinogenesis [16].
Therefore, the anti-inflammatory effect of calcitriol may work in a preventive manner for the development of cervical cancer, as has been previously demonstrated using a calcitriol analog in inflammation-dependent tumorigenesis of gastric cancer [91]. This anti-inflammatory effect was mediated in part by the suppression of inflammatory mediators such as cyclooxygenase-2 (COX-2) and the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) [92]. In particular, it is known that the VDR physically interacts with IκB kinase β (IKKβ), blocking TNFα-induced IKK complex formation and NF-κB activity [92].
Accumulating evidence suggests that the vitamin D endocrine system has a protective role in developing autoimmune diseases. Accordingly, vitamin D deficiency is prevalent in patients with autoimmune diseases such as insulin-dependent diabetes mellitus, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis and systemic lupus erythematosus, where it is not known if vitamin D deficiency itself is a consequence or cause of the diseases [93,94,95]. Interestingly, a 1.5-fold higher risk of high-grade cervical dysplasia and cervical cancer has been reported in women with rheumatoid arthritis and systemic lupus erythematosus compared with women without systemic inflammatory diseases [96]. However, in a cross-sectional study in Mexico in women with systemic lupus erythematosus, the blood 25OHD3 concentration was not associated with cervical HPV infection [97]. Despite these results, it is well established that vitamin D is a protective agent against a broad type of infections, and vitamin D deficiency often worsens infection severity [98]. The calcitriol-dependent protective mechanisms against viral and bacterial infections involve, among others, the modulation of inflammatory immune responses and also the calcitriol-mediated synthesis of antimicrobial peptides such as cathelicidin and defensins [99]. Interestingly, α-defensin HD5 has a protective role in cervical cancer onset by blocking the HPV16 infection through capsid targeting to lysosomal degradation [100]. In this regard, more studies are needed to evaluate the possible antiviral effects of vitamin D metabolites on the HPV life cycle.
Other vitamins such as A, B9, B12, C, E, and K have also received much attention regarding cervical cancer prevention and management. For instance, women who received vitamin A supplementation had better prognoses and improved outcomes, such as clearance of HPV lesions, thereby inhibiting early cervical cancer development [101]. The vitamins B9 and B12 inhibit HPV infection and progression to CIN higher grades [102]. Additionally, it has been reported that vitamin C and E intake is inversely associated with cervical cancer risk [103]. Vitamin K has been involved in preventing the development of certain cancers, including cervical cancer [104].
However, it is noteworthy to mention that, in contrast to vitamins A, B, C, E, and K, vitamin D3 is not truly a vitamin [105]. Rather, it is a pro-hormone synthesized in our body in adequate quantities after sun exposure, as discussed in Section 2. In turn, 25OHD3 is a pre-hormone, a glandular secretory product with minimal or no significant biological activity, that is transformed in peripheral tissues into the active and potent secosteroid hormone calcitriol, whose mechanism of action compares to those of steroid hormones such as estradiol and progesterone, whom also mediate their biological effects in different target-organs via transcription factors.
Table 1 shows a summary of the clinical studies undertaken on cervical cancer, warts, and HPV-positive patients.

5. Conclusions

Few studies reported no beneficial effects of the vitamin D endocrine system in cervical cancer [106]. However, most studies support the concept that calcitriol and its precursors play an important preventive role in cervical cancer, as occurs in other neoplasias [107,108]. In this regard, a high intake of vitamin D is associated with a low risk of cervical cancer [26], while vitamin D deficiency is often seen in patients with CIN and invasive cervical cancer [26,29,31,32]. One of the causes of vitamin D deficiency is obesity, a risk factor for cervical cancer [25]. The low vitamin D status in obese people is related to volumetric dilution, sequestering of vitamin D metabolites in the adipose tissue and low physical activity [25]. Vitamin D deficiency also results from insufficient intake of foods rich in vitamin D and low sun exposure [25]. According to this, cervical cancer has been inversely correlated with solar irradiance, which concours with sun exposure being the most important source of vitamin D [27,28,80,109], and DBP being low in cervical cancer [47], while differential transcriptional activity by VDR polymorphisms in cervical cancer has been reported [56,57]. Moreover, calcitriol has antineoplastic activity in cervical cancer by reducing the proliferation of cell lines and the gene expression of well-known oncogenic proteins such as the potassium channel EAG1, and HCCR1 [52,60], as well as the induction of the critical cell cycle regulator p21 (Figure 2) [60]. Other potential benefits of calcitriol on cervical cancer prevention may be related to the modulation of some components of microRNA machinery biogenesis that increases the maturation of anti-cancer-related microRNAs [54,71]. Interestingly, calcitriol might have direct antiviral activity on the HPV16 life cycle, which is in line with the proposed effects of 25OHD3 on HPV16 replication (Figure 2) [29].
As in other neoplasias, including breast cancer, calcitriol may prevent the onset of cervical cancer; however, once established, calcitriol cannot fight advanced cervical cancer neither alone nor in combination with standard therapy, such as radiation [110].
Despite having health benefits, excess of vitamin D can produce vitamin D intoxication and hypercalcemia, whose symptoms include vomiting, frequent urination and excessive thirst. This rare but possible severe medical condition often results from uncontrolled use of vitamin D supplements [111] and, recently, from self-medication for COVID-19 infection [112].
In summary, preclinical and clinical studies reviewed here supported a protective role of the vitamin D endocrine system in preventing early HPV-dependent cervical lesions, disrupting the continuous process towards invasive cervical cancer, which suggests that an adequate vitamin D status might reduce cervical cancer incidence in women.

Author Contributions

Conceptualization, E.A.; writing—original draft preparation, E.A., B.J.N.-M., J.G.-M., U.C.-H., J.G.-Q., R.G.-B. and L.D.; writing—review and editing, E.A., B.J.N.-M., J.G.-M., U.C.-H., J.G.-Q., R.G.-B. and L.D.; visualization, R.G.-B. made Table 1, E.A.; supervision, E.A.; drawing figures, E.A. All authors have read and agreed to the published version of the manuscript.

Funding

This work received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Siegel, R.L.; Miller, K.D.; Wagle, N.S.; Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin. 2023, 73, 17–48. [Google Scholar] [CrossRef] [PubMed]
  2. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin. 2022, 72, 7–33. [Google Scholar] [CrossRef] [PubMed]
  3. Singh, G.K.; Azuine, R.E.; Siahpush, M. Global Inequalities in Cervical Cancer Incidence and Mortality are Linked to Deprivation, Low Socioeconomic Status, and Human Development. Int. J. MCH AIDS 2012, 1, 17–30. [Google Scholar] [CrossRef] [PubMed]
  4. Arbyn, M.; Xu, L.; Simoens, C.; Martin-Hirsch, P.P. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database Syst. Rev. 2018, 5, CD009069. [Google Scholar] [CrossRef] [PubMed]
  5. Burd, E.M. Human papillomavirus and cervical cancer. Clin. Microbiol. Rev. 2003, 16, 1. [Google Scholar] [CrossRef] [PubMed]
  6. Mishra, G.A.; Pimple, S.A.; Shastri, S.S. An overview of prevention and early detection of cervical cancers. Indian J. Med. Paediatr. Oncol. 2011, 32, 125–132. [Google Scholar] [CrossRef]
  7. Arbyn, M.; Weiderpass, E.; Bruni, L.; de Sanjose, S.; Saraiya, M.; Ferlay, J.; Bray, F. Estimates of incidence and mortality of cervical cancer in 2018: A worldwide analysis. Lancet Glob. Health 2020, 8, e191–e203. [Google Scholar] [CrossRef]
  8. Paulino, E.; de Melo, A.C.; de Andrade, D.A.P.; de Almeida, M.S. Systemic therapy for advanced cervical cancer: Leveraging the historical threshold of overall survival. Crit. Rev. Oncol. Hematol. 2023, 183, 103925. [Google Scholar] [CrossRef]
  9. Alrajjal, A.; Pansare, V.; Choudhury, M.S.R.; Khan, M.Y.A.; Shidham, V.B. Squamous intraepithelial lesions (SIL: LSIL, HSIL, ASCUS, ASC-H, LSIL-H) of Uterine Cervix and Bethesda System. Cytojournal 2021, 18, 16. [Google Scholar] [CrossRef]
  10. Brinton, L.A.; Reeves, W.C.; Brenes, M.M.; Herrero, R.; de Britton, R.C.; Gaitan, E.; Tenorio, F.; Garcia, M.; Rawls, W.E. Parity as a risk factor for cervical cancer. Am. J. Epidemiol. 1989, 130, 486–496. [Google Scholar] [CrossRef]
  11. Vaccarella, S.; Franceschi, S.; Herrero, R.; Munoz, N.; Snijders, P.J.; Clifford, G.M.; Smith, J.S.; Lazcano-Ponce, E.; Sukvirach, S.; Shin, H.R.; et al. Sexual behavior, condom use, and human papillomavirus: Pooled analysis of the IARC human papillomavirus prevalence surveys. Cancer Epidemiol. Biomark. Prev. 2006, 15, 326–333. [Google Scholar] [CrossRef] [PubMed]
  12. Louie, K.S.; de Sanjose, S.; Diaz, M.; Castellsague, X.; Herrero, R.; Meijer, C.J.; Shah, K.; Franceschi, S.; Munoz, N.; Bosch, F.X.; et al. Early age at first sexual intercourse and early pregnancy are risk factors for cervical cancer in developing countries. Br. J. Cancer 2009, 100, 1191–1197. [Google Scholar] [CrossRef] [PubMed]
  13. Huang, Y.; Wu, X.; Lin, Y.; Li, W.; Liu, J.; Song, B. Multiple sexual partners and vaginal microecological disorder are associated with HPV infection and cervical carcinoma development. Oncol. Lett. 2020, 20, 1915–1921. [Google Scholar] [CrossRef]
  14. de Abreu, A.L.; Malaguti, N.; Souza, R.P.; Uchimura, N.S.; Ferreira, E.C.; Pereira, M.W.; Carvalho, M.D.; Pelloso, S.M.; Bonini, M.G.; Gimenes, F.; et al. Association of human papillomavirus, Neisseria gonorrhoeae and Chlamydia trachomatis co-infections on the risk of high-grade squamous intraepithelial cervical lesion. Am. J. Cancer Res. 2016, 6, 1371–1383. [Google Scholar] [PubMed]
  15. Stone, K.M.; Zaidi, A.; Rosero-Bixby, L.; Oberle, M.W.; Reynolds, G.; Larsen, S.; Nahmias, A.J.; Lee, F.K.; Schachter, J.; Guinan, M.E. Sexual behavior, sexually transmitted diseases, and risk of cervical cancer. Epidemiology 1995, 6, 409–414. [Google Scholar] [CrossRef]
  16. Garcia-Quiroz, J.; Vazquez-Almazan, B.; Garcia-Becerra, R.; Diaz, L.; Avila, E. The Interaction of Human Papillomavirus Infection and Prostaglandin E2 Signaling in Carcinogenesis: A Focus on Cervical Cancer Therapeutics. Cells 2022, 11, 2528. [Google Scholar] [CrossRef]
  17. Abraham, A.G.; D’Souza, G.; Jing, Y.; Gange, S.J.; Sterling, T.R.; Silverberg, M.J.; Saag, M.S.; Rourke, S.B.; Rachlis, A.; Napravnik, S.; et al. Invasive cervical cancer risk among HIV-infected women: A North American multicohort collaboration prospective study. J. Acquir. Immune Defic. Syndr. 2013, 62, 405–413. [Google Scholar] [CrossRef]
  18. Moreno, V.; Bosch, F.X.; Munoz, N.; Meijer, C.J.; Shah, K.V.; Walboomers, J.M.; Herrero, R.; Franceschi, S.; International Agency for Research on Cancer (IARC) Multicentric Cervical Cancer Study Group. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: The IARC multicentric case-control study. Lancet 2002, 359, 1085–1092. [Google Scholar] [CrossRef]
  19. Hellberg, D.; Nilsson, S.; Haley, N.J.; Hoffman, D.; Wynder, E. Smoking and cervical intraepithelial neoplasia: Nicotine and cotinine in serum and cervical mucus in smokers and nonsmokers. Am. J. Obs. Gynecol. 1988, 158, 910–913. [Google Scholar] [CrossRef]
  20. Bosch, F.X.; Munoz, N.; de Sanjose, S.; Izarzugaza, I.; Gili, M.; Viladiu, P.; Tormo, M.J.; Moreo, P.; Ascunce, N.; Gonzalez, L.C.; et al. Risk factors for cervical cancer in Colombia and Spain. Int. J. Cancer 1992, 52, 750–758. [Google Scholar] [CrossRef]
  21. Siegel, E.M.; Salemi, J.L.; Villa, L.L.; Ferenczy, A.; Franco, E.L.; Giuliano, A.R. Dietary consumption of antioxidant nutrients and risk of incident cervical intraepithelial neoplasia. Gynecol. Oncol. 2010, 118, 289–294. [Google Scholar] [CrossRef] [PubMed]
  22. Gonzalez, C.A.; Travier, N.; Lujan-Barroso, L.; Castellsague, X.; Bosch, F.X.; Roura, E.; Bueno-de-Mesquita, H.B.; Palli, D.; Boeing, H.; Pala, V.; et al. Dietary factors and in situ and invasive cervical cancer risk in the European prospective investigation into cancer and nutrition study. Int. J. Cancer 2011, 129, 449–459. [Google Scholar] [CrossRef] [PubMed]
  23. Negri, E.; La Vecchia, C.; Bosetti, C.; Franceschi, S.; Parazzini, F. Risk of cervical cancer in women with a family history of breast and female genital tract neoplasms. Int. J. Cancer 2005, 117, 880–881. [Google Scholar] [CrossRef]
  24. Poorolajal, J.; Jenabi, E. The association between BMI and cervical cancer risk: A meta-analysis. Eur. J. Cancer Prev. 2016, 25, 232–238. [Google Scholar] [CrossRef]
  25. Barrea, L.; Frias-Toral, E.; Pugliese, G.; Garcia-Velasquez, E.; Savastano, S.; Colao, A.; Muscogiuri, G. Vitamin D in obesity and obesity-related diseases: An overview. Minerva Endocrinol. 2021, 46, 177–192. [Google Scholar] [CrossRef] [PubMed]
  26. Hosono, S.; Matsuo, K.; Kajiyama, H.; Hirose, K.; Suzuki, T.; Kawase, T.; Kidokoro, K.; Nakanishi, T.; Hamajima, N.; Kikkawa, F.; et al. Association between dietary calcium and vitamin D intake and cervical carcinogenesis among Japanese women. Eur. J. Clin. Nutr. 2010, 64, 400–409. [Google Scholar] [CrossRef]
  27. Grant, W.B. Does solar ultraviolet irradiation affect cancer mortality rates in China? Asian Pac. J. Cancer Prev. 2007, 8, 236–242. [Google Scholar]
  28. Grant, W.B. An ecological study of cancer incidence and mortality rates in France with respect to latitude, an index for vitamin D production. Dermatoendocrinology 2010, 2, 62–67. [Google Scholar] [CrossRef]
  29. Ozgu, E.; Yilmaz, N.; Baser, E.; Gungor, T.; Erkaya, S.; Yakut, H.I. Could 25-OH vitamin D deficiency be a reason for HPV infection persistence in cervical premalignant lesions? J. Exp. Ther. Oncol. 2016, 11, 177–180. [Google Scholar]
  30. Shim, J.; Perez, A.; Symanski, E.; Nyitray, A.G. Association Between Serum 25-Hydroxyvitamin D Level and Human Papillomavirus Cervicovaginal Infection in Women in the United States. J. Infect. Dis. 2016, 213, 1886–1892. [Google Scholar] [CrossRef]
  31. Vahedpoor, Z.; Jamilian, M.; Bahmani, F.; Aghadavod, E.; Karamali, M.; Kashanian, M.; Asemi, Z. Effects of Long-Term Vitamin D Supplementation on Regression and Metabolic Status of Cervical Intraepithelial Neoplasia: A Randomized, Double-Blind, Placebo-Controlled Trial. Horm. Cancer. 2017, 8, 58–67. [Google Scholar] [CrossRef] [PubMed]
  32. Vahedpoor, Z.; Mahmoodi, S.; Samimi, M.; Gilasi, H.R.; Bahmani, F.; Soltani, A.; Sharifi Esfahani, M.; Asemi, Z. Long-Term Vitamin D Supplementation and the Effects on Recurrence and Metabolic Status of Cervical Intraepithelial Neoplasia Grade 2 or 3: A Randomized, Double-Blind, Placebo-Controlled Trial. Ann. Nutr. Metab. 2018, 72, 151–160. [Google Scholar] [CrossRef] [PubMed]
  33. Holick, M.F. Photosynthesis of vitamin D in the skin: Effect of environmental and life-style variables. Fed. Proc. 1987, 46, 1876–1882. [Google Scholar] [PubMed]
  34. Zhu, J.; DeLuca, H.F. Vitamin D 25-hydroxylase—Four decades of searching, are we there yet? Arch. Biochem. Biophys. 2012, 523, 30–36. [Google Scholar] [CrossRef]
  35. Hewison, M.; Zehnder, D.; Bland, R.; Stewart, P.M. 1alpha-Hydroxylase and the action of vitamin D. J. Mol. Endocrinol. 2000, 25, 141–148. [Google Scholar] [CrossRef]
  36. Olmos-Ortiz, A.; Avila, E.; Durand-Carbajal, M.; Diaz, L. Regulation of calcitriol biosynthesis and activity: Focus on gestational vitamin D deficiency and adverse pregnancy outcomes. Nutrients 2015, 7, 443–480. [Google Scholar] [CrossRef]
  37. Norman, A.W. Minireview: Vitamin D receptor: New assignments for an already busy receptor. Endocrinology 2006, 147, 5542–5548. [Google Scholar] [CrossRef]
  38. Jones, G.; Prosser, D.E.; Kaufmann, M. 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): Its important role in the degradation of vitamin D. Arch. Biochem. Biophys. 2012, 523, 9–18. [Google Scholar] [CrossRef]
  39. Wang, Y.; Zhu, J.; DeLuca, H.F. Where is the vitamin D receptor? Arch. Biochem. Biophys. 2012, 523, 123–133. [Google Scholar] [CrossRef]
  40. Deuster, E.; Jeschke, U.; Ye, Y.; Mahner, S.; Czogalla, B. Vitamin D and VDR in Gynecological Cancers–A Systematic Review. Int. J. Mol. Sci. 2017, 18, 2328. [Google Scholar] [CrossRef]
  41. Yoshizawa, T.; Handa, Y.; Uematsu, Y.; Takeda, S.; Sekine, K.; Yoshihara, Y.; Kawakami, T.; Arioka, K.; Sato, H.; Uchiyama, Y.; et al. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat. Genet. 1997, 16, 391–396. [Google Scholar] [CrossRef] [PubMed]
  42. Heaney, R.P. Vitamin D in health and disease. Clin. J. Am. Soc. Nephrol. 2008, 3, 1535–1541. [Google Scholar] [CrossRef] [PubMed]
  43. Carlberg, C.; Velleuer, E. Vitamin D and the risk for cancer: A molecular analysis. Biochem. Pharm. 2021, 196, 114735. [Google Scholar] [CrossRef] [PubMed]
  44. Diaz, L.; Diaz-Munoz, M.; Garcia-Gaytan, A.C.; Mendez, I. Mechanistic Effects of Calcitriol in Cancer Biology. Nutrients 2015, 7, 5020–5050. [Google Scholar] [CrossRef]
  45. Shao, T.; Klein, P.; Grossbard, M.L. Vitamin D and breast cancer. Oncologist 2012, 17, 36–45. [Google Scholar] [CrossRef] [PubMed]
  46. Salih, M.M.; Almehmadi, M.; Shafie, A.; Alsharif, A.; Alsiwiehri, N.; El-Askary, A.; Alzahrani, K.; Aljuaid, A.; Abdulaziz, O.; Alrehaili, A.A.; et al. Evaluation of CD4+:CD8+ Ratio in Patients With Cervical Cancer and the Levels of Inflammatory Markers. Vivo 2022, 36, 2414–2421. [Google Scholar] [CrossRef]
  47. Keeratichamroen, S.; Subhasitanont, P.; Chokchaichamnankit, D.; Weeraphan, C.; Saharat, K.; Sritana, N.; Kantathavorn, N.; Wiriyaukaradecha, K.; Sricharunrat, T.; Paricharttanakul, N.M.; et al. Identification of potential cervical cancer serum biomarkers in Thai patients. Oncol. Lett. 2020, 19, 3815–3826. [Google Scholar] [CrossRef]
  48. Friedrich, M.; Rafi, L.; Mitschele, T.; Tilgen, W.; Schmidt, W.; Reichrath, J. Analysis of the vitamin D system in cervical carcinomas, breast cancer and ovarian cancer. Recent. Results Cancer Res. 2003, 164, 239–246. [Google Scholar] [CrossRef]
  49. Reichrath, J.; Rafi, L.; Muller, S.M.; Mink, D.; Reitnauer, K.; Tilgen, W.; Schmidt, W.; Friedrich, M. Immunohistochemical analysis of 1,25-dihydroxyvitamin D3 receptor in cervical carcinoma. Histochem. J. 1998, 30, 561–567. [Google Scholar] [CrossRef]
  50. Friedrich, M.; Villena-Heinsen, C.; Axt-Fliedner, R.; Meyberg, R.; Tilgen, W.; Schmidt, W.; Reichrath, J. Analysis of 25-hydroxyvitamin D3-1alpha-hydroxylase in cervical tissue. Anticancer Res. 2002, 22, 183–186. [Google Scholar]
  51. Kloss, M.; Fischer, D.; Thill, M.; Friedrich, M.; Cordes, T.; Salehin, D.; Diedrich, K.; Koster, F. Vitamin D, calcidiol and calcitriol regulate vitamin D metabolizing enzymes in cervical and ovarian cancer cells. Anticancer Res. 2010, 30, 4429–4434. [Google Scholar] [PubMed]
  52. Avila, E.; Garcia-Becerra, R.; Rodriguez-Rasgado, J.A.; Diaz, L.; Ordaz-Rosado, D.; Zugel, U.; Steinmeyer, A.; Barrera, D.; Halhali, A.; Larrea, F.; et al. Calcitriol down-regulates human ether a go-go 1 potassium channel expression in cervical cancer cells. Anticancer Res. 2010, 30, 2667–2672. [Google Scholar] [PubMed]
  53. Cazares-Ordonez, V.; Gonzalez-Duarte, R.J.; Diaz, L.; Ishizawa, M.; Uno, S.; Ortiz, V.; Ordonez-Sanchez, M.L.; Makishima, M.; Larrea, F.; Avila, E. A cis-acting element in the promoter of human ether a go-go 1 potassium channel gene mediates repression by calcitriol in human cervical cancer cells. Biochem. Cell. Biol. 2015, 93, 94–101. [Google Scholar] [CrossRef] [PubMed]
  54. Gonzalez-Duarte, R.J.; Cazares-Ordonez, V.; Romero-Cordoba, S.; Diaz, L.; Ortiz, V.; Freyre-Gonzalez, J.A.; Hidalgo-Miranda, A.; Larrea, F.; Avila, E. Calcitriol increases Dicer expression and modifies the microRNAs signature in SiHa cervical cancer cells. Biochem. Cell. Biol. 2015, 93, 376–384. [Google Scholar] [CrossRef] [PubMed]
  55. Friedrich, M.; Meyberg, R.; Axt-Fliedner, R.; Villena-Heinsen, C.; Tilgen, W.; Schmidt, W.; Reichrath, J. Vitamin D receptor (VDR) expression is not a prognostic factor in cervical cancer. Anticancer Res. 2002, 22, 299–304. [Google Scholar]
  56. Li, D.; Liu, Y.; Kong, D.; Papukashvili, D.; Rcheulishvili, N.; Zhao, H.; Li, Y.; Hou, C.; Ma, J.; Lu, X.; et al. Vitamin D Receptor Gene Polymorphisms and the Risk of CIN2+ in Shanxi Population. Biomed. Res. Int. 2022, 2022, 6875996. [Google Scholar] [CrossRef]
  57. Phuthong, S.; Settheetham-Ishida, W.; Natphopsuk, S.; Ishida, T. Genetic Polymorphisms of Vitamin D Receptor Gene are Associated with Cervical Cancer Risk in Northeastern Thailand. Asian Pac. J. Cancer. Prev. 2020, 21, 2935–2939. [Google Scholar] [CrossRef]
  58. Gnagnarella, P.; Pasquali, E.; Serrano, D.; Raimondi, S.; Disalvatore, D.; Gandini, S. Vitamin D receptor polymorphism FokI and cancer risk: A comprehensive meta-analysis. Carcinogenesis 2014, 35, 1913–1919. [Google Scholar] [CrossRef]
  59. Feldman, D.; Krishnan, A.V.; Swami, S.; Giovannucci, E.; Feldman, B.J. The role of vitamin D in reducing cancer risk and progression. Nat. Rev. Cancer 2014, 14, 342–357. [Google Scholar] [CrossRef]
  60. Wang, G.; Lei, L.; Zhao, X.; Zhang, J.; Zhou, M.; Nan, K. Calcitriol Inhibits Cervical Cancer Cell Proliferation Through Downregulation of HCCR1 Expression. Oncol. Res. 2014, 22, 301–309. [Google Scholar] [CrossRef]
  61. Bhoora, S.; Pillay, T.S.; Punchoo, R. Cholecalciferol induces apoptosis via autocrine metabolism in epidermoid cervical cancer cells. Biochem. Cell Biol. 2022, 100, 387–402. [Google Scholar] [CrossRef] [PubMed]
  62. Pardo, L.A.; del Camino, D.; Sanchez, A.; Alves, F.; Bruggemann, A.; Beckh, S.; Stuhmer, W. Oncogenic potential of EAG K(+) channels. EMBO J. 1999, 18, 5540–5547. [Google Scholar] [CrossRef] [PubMed]
  63. Farias, L.M.; Ocana, D.B.; Diaz, L.; Larrea, F.; Avila-Chavez, E.; Cadena, A.; Hinojosa, L.M.; Lara, G.; Villanueva, L.A.; Vargas, C.; et al. Ether a go-go potassium channels as human cervical cancer markers. Cancer Res. 2004, 64, 6996–7001. [Google Scholar] [CrossRef] [PubMed]
  64. Ortiz, C.S.; Montante-Montes, D.; Saqui-Salces, M.; Hinojosa, L.M.; Gamboa-Dominguez, A.; Hernandez-Gallegos, E.; Martinez-Benitez, B.; Del Rosario Solis-Pancoatl, M.; Garcia-Villa, E.; Ramirez, A.; et al. Eag1 potassium channels as markers of cervical dysplasia. Oncol. Rep. 2011, 26, 1377–1383. [Google Scholar] [CrossRef] [PubMed]
  65. Diaz, L.; Ceja-Ochoa, I.; Restrepo-Angulo, I.; Larrea, F.; Avila-Chavez, E.; Garcia-Becerra, R.; Borja-Cacho, E.; Barrera, D.; Ahumada, E.; Gariglio, P.; et al. Estrogens and human papilloma virus oncogenes regulate human ether-a-go-go-1 potassium channel expression. Cancer Res. 2009, 69, 3300–3307. [Google Scholar] [CrossRef] [PubMed]
  66. Cho, G.W.; Shin, S.M.; Kim, H.K.; Ha, S.A.; Kim, S.; Yoon, J.H.; Hur, S.Y.; Kim, T.E.; Kim, J.W. HCCR-1, a novel oncogene, encodes a mitochondrial outer membrane protein and suppresses the UVC-induced apoptosis. BMC Cell Biol. 2007, 8, 50. [Google Scholar] [CrossRef]
  67. Setiawan, I.; Lesmana, R.; Goenawan, H.; Suardi, D.; Gatera, V.A.; Abdulah, R.; Judistiani, R.T.D.; Supratman, U.; Setiabudiawan, B. Calcitriol potentially alters HeLa cell viability via inhibition of autophagy. J. Cancer Res. 2022, 18, 1144–1151. [Google Scholar] [CrossRef]
  68. Bhoora, S.; Pather, Y.; Marais, S.; Punchoo, R. Cholecalciferol Inhibits Cell Growth and Induces Apoptosis in the CaSki Cell Line. Med. Sci. 2020, 8, 12. [Google Scholar] [CrossRef]
  69. Punchoo, R.; Dreyer, G.; Pillay, T.S. 25-Hydroxycholecalciferol inhibits cell growth and induces apoptosis in SiHa cervical cells via autocrine vitamin D metabolism. Biomedicines 2023, 11, 871. [Google Scholar] [CrossRef]
  70. Diaz, L.; Bernadez-Vallejo, S.V.; Vargas-Castro, R.; Avila, E.; Gomez-Ceja, K.A.; Garcia-Becerra, R.; Segovia-Mendoza, M.; Prado-Garcia, H.; Lara-Sotelo, G.; Camacho, J.; et al. The Phytochemical alpha-Mangostin Inhibits Cervical Cancer Cell Proliferation and Tumor Growth by Downregulating E6/E7-HPV Oncogenes and KCNH1 Gene Expression. Int. J. Mol. Sci. 2023, 24, 3055. [Google Scholar] [CrossRef]
  71. Gonzalez-Duarte, R.J.; Cazares-Ordonez, V.; Diaz, L.; Ortiz, V.; Larrea, F.; Avila, E. The expression of RNA helicase DDX5 is transcriptionally upregulated by calcitriol through a vitamin D response element in the proximal promoter in SiHa cervical cells. Mol. Cell Biochem. 2015, 410, 65–73. [Google Scholar] [CrossRef] [PubMed]
  72. O’Brien, J.; Hayder, H.; Zayed, Y.; Peng, C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front. Endocrinol. 2018, 9, 402. [Google Scholar] [CrossRef] [PubMed]
  73. Wongjampa, W.; Ekalaksananan, T.; Chopjitt, P.; Chuerduangphui, J.; Kleebkaow, P.; Patarapadungkit, N.; Pientong, C. Suppression of miR-22, a tumor suppressor in cervical cancer, by human papillomavirus 16 E6 via a p53/miR-22/HDAC6 pathway. PLoS ONE 2018, 13, e0206644. [Google Scholar] [CrossRef] [PubMed]
  74. Zou, T.; Gao, Y.; Qie, M. MiR-29c-3p inhibits epithelial-mesenchymal transition to inhibit the proliferation, invasion and metastasis of cervical cancer cells by targeting SPARC. Ann. Transl. Med. 2021, 9, 125. [Google Scholar] [CrossRef]
  75. Fu, J.; Zhang, Y.; Wang, M.; Hu, J.; Fang, Y. Inhibition of the long non-coding RNA UNC5B-AS1/miR-4455/RSPO4 axis reduces cervical cancer growth in vitro and in vivo. J. Gene Med. 2021, 23, e3382. [Google Scholar] [CrossRef]
  76. Lappe, J.M.; Travers-Gustafson, D.; Davies, K.M.; Recker, R.R.; Heaney, R.P. Vitamin D and calcium supplementation reduces cancer risk: Results of a randomized trial. Am. J. Clin. Nutr. 2007, 85, 1586–1591. [Google Scholar] [CrossRef]
  77. Zhang, R.; Zhang, Y.; Liu, Z.; Pei, Y.; Xu, P.; Chong, W.; Hai, Y.; He, L.; He, Y.; Yu, J.; et al. Association between Vitamin D Supplementation and Cancer Mortality: A Systematic Review and Meta-Analysis. Cancers 2022, 14, 3717. [Google Scholar] [CrossRef]
  78. Adams, S.; Lin, J.; Brown, D.; Shriver, C.D.; Zhu, K. Ultraviolet Radiation Exposure and the Incidence of Oral, Pharyngeal and Cervical Cancer and Melanoma: An Analysis of the SEER Data. Anticancer Res. 2016, 36, 233–237. [Google Scholar]
  79. Fleischer, A.B., Jr.; Fleischer, S.E. Solar radiation and the incidence and mortality of leading invasive cancers in the United States. Dermatoendocrinology 2016, 8, e1162366. [Google Scholar] [CrossRef]
  80. Grant, W.B. A meta-analysis of second cancers after a diagnosis of nonmelanoma skin cancer: Additional evidence that solar ultraviolet-B irradiance reduces the risk of internal cancers. J. Steroid. Biochem. Mol. Biol. 2007, 103, 668–674. [Google Scholar] [CrossRef]
  81. De Jaeghere, E.A.; Tuyaerts, S.; Van Nuffel, A.M.T.; Belmans, A.; Bogaerts, K.; Baiden-Amissah, R.; Lippens, L.; Vuylsteke, P.; Henry, S.; Trinh, X.B.; et al. Pembrolizumab, radiotherapy, and an immunomodulatory five-drug cocktail in pretreated patients with persistent, recurrent, or metastatic cervical or endometrial carcinoma: Results of the phase II PRIMMO study. Cancer Immunol. Immunother. 2023, 72, 475–491. [Google Scholar] [CrossRef] [PubMed]
  82. Schulte-Uebbing, C.; Schlett, S.; Craiut, I.; Antal, L.; Olah, H. Chronical cervical infections and dysplasia (CIN I, CIN II): Vaginal vitamin D (high dose) treatment: A new effective method? Dermatoendocrinology 2014, 6, e27791. [Google Scholar] [CrossRef] [PubMed]
  83. Troja, C.; Hoofnagle, A.N.; Szpiro, A.; Stern, J.E.; Lin, J.; Winer, R.L. Understanding the Role of Emerging Vitamin D Biomarkers on Short-term Persistence of High-Risk Human Papillomavirus Infection Among Mid-Adult Women. J. Infect. Dis. 2021, 224, 123–132. [Google Scholar] [CrossRef]
  84. Singh, A.K.; Devi, K.N.; Bist, J.S. A comparative evaluation of therapeutic response in warts to intralesional vitamin D3 versus intralesional measles, mumps, and rubella vaccine. Dermatol. Ther. 2022, 35, e15813. [Google Scholar] [CrossRef] [PubMed]
  85. Mohta, A.; Kushwaha, R.K.; Agrawal, A.; Sharma, M.K.; Gautam, U.; Jain, S.K. Evaluation of the Efficacy of Intralesional Measles, Mumps, and Rubella Vaccine with Intralesional Vitamin D3 as Immunotherapies in the Treatment of Recalcitrant Cutaneous Warts in Adult- A Randomized Placebo-Controlled Study. Indian Derm. Online J. 2021, 12, 879–887. [Google Scholar] [CrossRef]
  86. Kavya, M.; Shashikumar, B.M.; Harish, M.R.; Shweta, B.P. Safety and Efficacy of Intralesional Vitamin D3 in Cutaneous Warts: An Open Uncontrolled Trial. J. Cutan. Aesthet. Surg. 2017, 10, 90–94. [Google Scholar] [CrossRef]
  87. Liu, P.T.; Stenger, S.; Li, H.; Wenzel, L.; Tan, B.H.; Krutzik, S.R.; Ochoa, M.T.; Schauber, J.; Wu, K.; Meinken, C.; et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006, 311, 1770–1773. [Google Scholar] [CrossRef]
  88. El-Esawy, F.M.; Sorour, N.E.; Akl, E.M.; Abdou, A.G.; El-Sayed, S.E. Immunohistochemical Expression of Cathelicidin in Verruca Vulgaris before and after intralesional injection of Vitamin D3. Benha. J. Appl. Sci. 2018, 3, 89–92. [Google Scholar] [CrossRef]
  89. Jha, N. Complete clearance of condyloma acuminata using injection Vitamin D3. Australas J. Derm. 2021, 62, e417–e418. [Google Scholar] [CrossRef]
  90. Rind, T.; Oiso, N.; Kawada, A. Successful Treatment of Anogenital Wart with a Topical Vitamin D(3) Derivative in an Infant. Case Rep. Derm. 2010, 2, 46–49. [Google Scholar] [CrossRef]
  91. Park, M.R.; Lee, J.H.; Park, M.S.; Hwang, J.E.; Shim, H.J.; Cho, S.H.; Chung, I.J.; Bae, W.K. Suppressive effect of 19-nor-1alpha-25-dihydroxyvitamin D2 on gastric cancer cells and peritoneal metastasis model. J. Korean Med. Sci. 2012, 27, 1037–1043. [Google Scholar] [CrossRef] [PubMed]
  92. Chen, Y.; Zhang, J.; Ge, X.; Du, J.; Deb, D.K.; Li, Y.C. Vitamin D receptor inhibits nuclear factor kappaB activation by interacting with IkappaB kinase beta protein. J. Biol. Chem. 2013, 288, 19450–19458. [Google Scholar] [CrossRef] [PubMed]
  93. Kostoglou-Athanassiou, I.; Athanassiou, P.; Lyraki, A.; Raftakis, I.; Antoniadis, C. Vitamin D and rheumatoid arthritis. Adv. Endocrinol. Metab. 2012, 3, 181–187. [Google Scholar] [CrossRef] [PubMed]
  94. Becker, A.; Fischer, R.; Schneider, M. Bone density and 25-OH vitamin D serum level in patients with systemic lupus erythematosus. Z. Rheumatol. 2001, 60, 352–358. [Google Scholar] [CrossRef] [PubMed]
  95. Fletcher, J.; Cooper, S.C.; Ghosh, S.; Hewison, M. The Role of Vitamin D in Inflammatory Bowel Disease: Mechanism to Management. Nutrients 2019, 11, 1019. [Google Scholar] [CrossRef]
  96. Kim, S.C.; Glynn, R.J.; Giovannucci, E.; Hernandez-Diaz, S.; Liu, J.; Feldman, S.; Karlson, E.W.; Schneeweiss, S.; Solomon, D.H. Risk of high-grade cervical dysplasia and cervical cancer in women with systemic inflammatory diseases: A population-based cohort study. Ann. Rheum. Dis. 2015, 74, 1360–1367. [Google Scholar] [CrossRef]
  97. Garcia-Carrasco, M.; Mendoza-Pinto, C.; Munguia-Realpozo, P.; Rodriguez-Gallegos, A.; Vallejo-Ruiz, V.; Munoz-Guarneros, M.; Mendez-Martinez, S.; Soto-Santillan, P.; Pezzat-Said, E.; Reyes-Leyva, J.; et al. Lack of association between serum 25-hydroxyvitamin D levels and cervical human papillomavirus infection in systemic lupus erythematosus. Lupus 2015, 24, 606–612. [Google Scholar] [CrossRef]
  98. Gunville, C.F.; Mourani, P.M.; Ginde, A.A. The role of vitamin D in prevention and treatment of infection. Inflamm. Allergy Drug. Targets 2013, 12, 239–245. [Google Scholar] [CrossRef]
  99. Gombart, A.F. The vitamin D-antimicrobial peptide pathway and its role in protection against infection. Future Microbiol. 2009, 4, 1151–1165. [Google Scholar] [CrossRef]
  100. Wiens, M.E.; Smith, J.G. Alpha-Defensin HD5 Inhibits Human Papillomavirus 16 Infection via Capsid Stabilization and Redirection to the Lysosome. mBio 2017, 8, 1. [Google Scholar] [CrossRef]
  101. Sinopoli, A.; Caminada, S.; Isonne, C.; Santoro, M.M.; Baccolini, V. What Are the Effects of Vitamin A Oral Supplementation in the Prevention and Management of Viral Infections? A Systematic Review of Randomized Clinical Trials. Nutrients 2022, 14, 4081. [Google Scholar] [CrossRef] [PubMed]
  102. Piyathilake, C.J.; Macaluso, M.; Chambers, M.M.; Badiga, S.; Siddiqui, N.R.; Bell, W.C.; Edberg, J.C.; Partridge, E.E.; Alvarez, R.D.; Johanning, G.L. Folate and vitamin B12 may play a critical role in lowering the HPV 16 methylation-associated risk of developing higher grades of CIN. Cancer Prev. Res. 2014, 7, 1128–1137. [Google Scholar] [CrossRef]
  103. Kim, J.; Kim, M.K.; Lee, J.K.; Kim, J.H.; Son, S.K.; Song, E.S.; Lee, K.B.; Lee, J.P.; Lee, J.M.; Yun, Y.M. Intakes of vitamin A, C, and E, and beta-carotene are associated with risk of cervical cancer: A case-control study in Korea. Nutr. Cancer 2010, 62, 181–189. [Google Scholar] [CrossRef] [PubMed]
  104. Markowska, A.; Antoszczak, M.; Markowska, J.; Huczynski, A. Role of Vitamin K in Selected Malignant Neoplasms in Women. Nutrients 2022, 14, 3401. [Google Scholar] [CrossRef]
  105. Courbebaisse, M.; Cavalier, E. Vitamin D in 2020: An Old Pro-Hormone with Potential Effects beyond Mineral Metabolism. Nutrients 2020, 12, 3378. [Google Scholar] [CrossRef] [PubMed]
  106. Zhu, G.; Li, Z.; Tang, L.; Shen, M.; Zhou, Z.; Wei, Y.; Zhao, Y.; Bai, S.; Song, L. Associations of Dietary Intakes with Gynecological Cancers: Findings from a Cross-Sectional Study. Nutrients 2022, 14, 5026. [Google Scholar] [CrossRef]
  107. Ono, A.; Koshiyama, M.; Nakagawa, M.; Watanabe, Y.; Ikuta, E.; Seki, K.; Oowaki, M. The Preventive Effect of Dietary Antioxidants on Cervical Cancer Development. Medicina 2020, 56, 604. [Google Scholar] [CrossRef]
  108. Vuolo, L.; Di Somma, C.; Faggiano, A.; Colao, A. Vitamin D and cancer. Front. Endocrinol. 2012, 3, 58. [Google Scholar] [CrossRef]
  109. Grant, W.B. Review of Recent Advances in Understanding the Role of Vitamin D in Reducing Cancer Risk: Breast, Colorectal, Prostate, and Overall Cancer. Anticancer Res. 2020, 40, 491–499. [Google Scholar] [CrossRef]
  110. Zhang, F.; Yu, Y.; Song, S.; Wang, M.; Ma, Y.; Xing, L. Calcitriol does not significantly enhance the efficacy of radiation of human cervical tumors in mice. Eur. J. Gynaecol. Oncol. 2015, 36, 452–456. [Google Scholar]
  111. Batman, A.; Ciftciler, R. The effect of hypervitaminosis D and intoxication on hematological parameters. Minerva Endocrinol. 2022, 47, 279–285. [Google Scholar] [CrossRef] [PubMed]
  112. Pini, S.; Scaparrotta, G.; Fragasso, A.; Stefanelli, L.F.; Nalesso, F.; Calo, L.A. Vitamin D intoxication induced severe hypercalcemia from self-medication for COVID-19 infection: A public health problem? Minerva Endocrinol. 2022, 47, 371–374. [Google Scholar] [CrossRef] [PubMed]
Ijms 24 08665 g001 550
Figure 1. The vitamin D endocrine system. The cutaneous vitamin D3 formed via a sunlight-dependent process from 7-dehydrocholesterol is transported to the liver by the vitamin D-binding protein (DBP), which is 25-hydroxylated by several vitamin D3 25-hydroxylases (CYP27A1, CYP3A4, and CYP2R1) to form 25-hydroxyvitamin D3 (25OHD3), which is considered the stable biomarker of vitamin D status. This metabolite is transported to the kidneys by DBP where it is hydroxylated by 25OHD3 1α-hydroxylase (CYP27B1) to form 1,25-dihydroxyvitamin D3 or calcitriol, the hormonal form of vitamin D3. In vitamin D3 target cells containing the vitamin D receptor (VDR) and other transcriptional modulators, calcitriol regulates the transcription of mRNAs and microRNAs mediated by RNA polymerase II; otherwise, in cells expressing calcitriol-inducible 25OHD3 24-hydroxylase (CYP24A1), calcitroic acid is formed, which is inactive and is excreted in bile.
Figure 1. The vitamin D endocrine system. The cutaneous vitamin D3 formed via a sunlight-dependent process from 7-dehydrocholesterol is transported to the liver by the vitamin D-binding protein (DBP), which is 25-hydroxylated by several vitamin D3 25-hydroxylases (CYP27A1, CYP3A4, and CYP2R1) to form 25-hydroxyvitamin D3 (25OHD3), which is considered the stable biomarker of vitamin D status. This metabolite is transported to the kidneys by DBP where it is hydroxylated by 25OHD3 1α-hydroxylase (CYP27B1) to form 1,25-dihydroxyvitamin D3 or calcitriol, the hormonal form of vitamin D3. In vitamin D3 target cells containing the vitamin D receptor (VDR) and other transcriptional modulators, calcitriol regulates the transcription of mRNAs and microRNAs mediated by RNA polymerase II; otherwise, in cells expressing calcitriol-inducible 25OHD3 24-hydroxylase (CYP24A1), calcitroic acid is formed, which is inactive and is excreted in bile.
Ijms 24 08665 g001
Ijms 24 08665 g002 550
Figure 2. Antitumoral actions of calcitriol in cervical cancer cells. In cervical cells, calcitriol activates the vitamin D receptor (VDR), which binds with retinoid receptor X (RXR) and the heterodimer VDR-RXR is recruited to vitamin D-responsive elements in promoter regions of vitamin D-target genes, modulating the transcription mediated by RNA polymerase II. By this mechanism, calcitriol blocks the expression of some oncogenes such as the oncogenic potassium channel EAG1 or human cervical cancer oncogene HCCR-1; furthermore, calcitriol reduces proliferation and inflammation. On the other hand, calcitriol increases the expression of some critical cell cycle regulators such as p21, increases the maturation of some microRNAs with anti-cancer-related functions and promotes the expression of peptides with antiviral activity such as cathelicidin and defensins that could limit HPV infection. Together, these mechanisms support the protective role of calcitriol on cervical cancer.
Figure 2. Antitumoral actions of calcitriol in cervical cancer cells. In cervical cells, calcitriol activates the vitamin D receptor (VDR), which binds with retinoid receptor X (RXR) and the heterodimer VDR-RXR is recruited to vitamin D-responsive elements in promoter regions of vitamin D-target genes, modulating the transcription mediated by RNA polymerase II. By this mechanism, calcitriol blocks the expression of some oncogenes such as the oncogenic potassium channel EAG1 or human cervical cancer oncogene HCCR-1; furthermore, calcitriol reduces proliferation and inflammation. On the other hand, calcitriol increases the expression of some critical cell cycle regulators such as p21, increases the maturation of some microRNAs with anti-cancer-related functions and promotes the expression of peptides with antiviral activity such as cathelicidin and defensins that could limit HPV infection. Together, these mechanisms support the protective role of calcitriol on cervical cancer.
Ijms 24 08665 g002
Table
Table 1. Clinical studies of vitamin D in cervical cancer, warts, and HPV-positive patients.
Table 1. Clinical studies of vitamin D in cervical cancer, warts, and HPV-positive patients.
Patient Population (n)DiagnosticPrincipal FindingsRef.
Japanese women
Cases: 405
Controls: 11,814		Invasive cervical cancer (333 cases) or CIN3 (72 cases)Inverse association between dietary calcium and vitamin D intake and cervical neoplasia risk.[26]
Chinese womenThe annual cancer mortality rate data were obtained from 65 rural counties included in the nationwide survey of all deaths over three yearsThe indices of solar UV radiation, latitude, and heat index were correlated with reduced mortality rates for cervical cancer. It suggests that vitamin D production via solar UVB reduces the risk of cervical cancer.[27]
French women
Incidence data were presented as estimates for 2000 patients		Uterine cancerSignificant positive correlations with the latitude for uterine cervix cancer, indicating that solar UVB reduces the risk of cancer through the production of vitamin D.[28]
Turkish women
Cases: 23
Controls: 62		HPV DNA-positive patientsSerum vitamin D levels were significantly lower in the study group (8085 IU/mL) than in the control group (11,472 IU/mL).[29]
American woman
Cases: 2353		Cervicovaginal HPV infectionThe vitamin D level is inversely associated with the prevalence of cervicovaginal HPV infection in sexually active women.[30]
Iranian women
Cases: 29
Controls: 29		Patients with CIN1Vitamin D3 administration (50,000 IU vitamin D3 every two weeks for six months) resulted in CIN1 regression and had beneficial effects on glucose homeostasis parameters, plasma levels of NO and MDA.[31]
Iranian women
Cases: 29
Controls: 29		Patients with CIN2/3Vitamin D3 administration (50,000 IU vitamin D3 every two weeks for six months) had beneficial effects on the metabolic status; however, it did not affect CIN2/3 recurrence.[32]
Chinese women
Cases: 188
Controls: 188		Patients with CIN2 with HPV16-positiveAssociation between VDR polymorphisms (FokI and TaqI) in HPV16-positive cervical lesions and the risk of CIN2.[56]
Thai women
Cases: 204
Controls: 204		Patients with squamous cell carcinoma of the cervixAssociation between VDR polymorphisms (TaqI) and cervical cancer risk.[57]
American woman
Cases: 71,209		Cervical cancerInverse association between UVR exposure and the incidence of cervical cancer.[78]
American woman
The cancer statistics incidence and mortality were obtained from the CDCP		Cervix uteri cancerAssociation between increasing solar energy and increasing cervix uteri cancer incidence.
No association between solar energy and cervix uteri cancer mortality.		[79]
Different nationalities
Data from the literature		Cervical cancerUVB irradiance significantly reduces the risk of cervical cancer.[80]
Belgian women
Cases: cervical (18) and endometrial (25) cancer		Patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancerPatients who received a drug cocktail that included vitamin D had a modest but durable antitumor activity with acceptable but not negligible toxicity.[81]
German women
Cases: 200		Women with chronic recurrent cervical infections and with cervix dysplasia (CIN 1, CIN 2)Patients who received treatment with vaginal suppositories with 12,500 IU of vitamin D three nights per week for six weeks had good anti-inflammatory and antidysplastic effects in the CIN1 group. No beneficial effects were seen in the CIN2 group.[82]
American women
Cases: 72		Patients with prevalent high-risk HPVA positive association between vitamin D levels and 14 high-risk HPV types persistence per 10 ng/mL increase.[83]
Indian women and men
Group A: 50, MMR vaccine
Group B: 50, vitamin D3 treatment		Patients with single or multiple wartsThe intralesional vitamin D3 administration produced efficacious results in terms of warts clearance as well as side effects profile.[84]
Indian women and men
Group A: 33, MMR vaccine
Group B: 31, vitamin D3 treatment
Group C: 24, saline solution		Patients with two or more recalcitrant extragenital warts of any duration at various sites of the bodyThe intralesional vitamin D3 administration (600,000 IU every two weeks, four injections, or till the complete clearance of warts) was effective, safe, and tolerable, with low recurrence rates.[85]
Indian women and men
Cases: 42		Patients with cutaneous wartsIntralesional vitamin D3 (600,000 IU every two weeks, four injections, or till the complete clearance of warts) was safe and effective for treating multiple cutaneous warts.[86]
Egyptian women and men
Cases: 20		Patients with verruca vulgarisGood clinical response and expression of cathelicidin in warts after an intralesional injection of vitamin D3.[88]
Indian manPatient with condyloma acuminataThree intralesional injections of vitamin D3 (600,000 IU every two weeks) resulted in complete clearance of condyloma acuminata. No recurrence was seen in a period of 6 months of follow-up.[89]
Japanese infantPatient with anogenital wartApplying topical calcipotriene (vitamin D3 derivative) in the affected lesion twice daily for four months showed complete regression. No recurrence was seen in 6 months of follow-up.[90]
Mexican women
Cases: 67		HPV-infected women with systemic lupus erythematosusNo association between vitamin D deficiency and cervical HPV.[97]
American women
Cases: 162
Control: 12,275		Cervical cancerIntakes of vitamin D showed no relationship with gynecological cancers.[106]
Cervical intraepithelial neoplasia grade (CIN), malondialdehyde (MDA), nitric oxide (NO), measles, mumps, and rubella (MMR), Centers for Disease Control and Prevention (CDCP).
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Avila, E.; Noriega-Mejía, B.J.; González-Macías, J.; Cortes-Hernández, U.; García-Quiroz, J.; García-Becerra, R.; Díaz, L. The Preventive Role of the Vitamin D Endocrine System in Cervical Cancer. Int. J. Mol. Sci. 2023, 24, 8665. https://doi.org/10.3390/ijms24108665

AMA Style

Avila E, Noriega-Mejía BJ, González-Macías J, Cortes-Hernández U, García-Quiroz J, García-Becerra R, Díaz L. The Preventive Role of the Vitamin D Endocrine System in Cervical Cancer. International Journal of Molecular Sciences. 2023; 24(10):8665. https://doi.org/10.3390/ijms24108665

Chicago/Turabian Style

Avila, Euclides, Bryan Javier Noriega-Mejía, Jocelyn González-Macías, Ulises Cortes-Hernández, Janice García-Quiroz, Rocío García-Becerra, and Lorenza Díaz. 2023. "The Preventive Role of the Vitamin D Endocrine System in Cervical Cancer" International Journal of Molecular Sciences 24, no. 10: 8665. https://doi.org/10.3390/ijms24108665

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop