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Cancer Chemoresistance: Novel Mechanistic Insights and Emerging Therapeutic Strategies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 38118

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Dr. Mirela Sedic

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Centre for Applied Bioanthropology, Institute for Anthropological Research Ljudevita Gaja 32, 10000 Zagreb, Croatia
Interests: chemotherapy; chemoresistance; cancer biology; colon cancer; cell signaling; proteomics; lipidomics; sphingolipids; biomarkers; personalised medicine
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Dear Colleagues,

Chemoresistance is the major factor that drives metastasis and tumor recurrence, leads to poor clinical outcomes in cancer patients and contributing to high rates of the cancer-related deaths. In order to improve the efficacy of chemotherapy drugs and promote patient survival, it is of the utmost importance to understand how inter-tumor and intra-tumor heterogeneity determine treatment response, to reveal specific genotypes and phenotypes that predispose development of chemoresistance and, finally, to delineate molecular and cellular mechanisms by which cancer cells circumvent chemotherapy-induced cell death. There is an increasing body of evidence demonstrating that treatment exposure can alter the tumor cell secretome, which shapes the behavior of cells in the tumor microenvironment to confer chemoresistance and promote tumor relapse. Thus, tumor-derived circulating material could provide a rich source of clinically relevant early diagnostic and prognostic biomarkers to enable timely management of cancer patients and to predict and monitor treatment response. Furthermore, understanding the underlying cellular and molecular mechanisms governing complex interactions between cancer cells and their microenvironment including both stromal cells and extracellular matrix components could fuel the discovery of novel targets for devising new therapeutic strategies. The objective of this Special Issue of IJMS is to publish original research and review papers in the field of basic and translational cancer research that specifically address these challenges leading to the discovery of new biomarkers and molecular pathways of chemoresistance and identification of novel drug combinations to overcome chemoresistance in cancer.

Dr. Mirela Sedic
Guest Editor

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Keywords

chemoresistance
drug resistance
cancer
targeted therapy
combination therapy
tumor microenvironment
cancer secretome
cell signaling
-omics
biomarker

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Published Papers (12 papers)

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16 pages, 2796 KiB

Open AccessArticle

Insights into Intra-Tumoral Heterogeneity: Transcriptional Profiling of Chemoresistant MPM Cell Subpopulations Reveals Involvement of NFkB and DNA Repair Pathways and Contributes a Prognostic Signature

by Mario Cioce, Andrea Sacconi, Harvey I. Pass, Claudia Canino, Sabrina Strano, Giovanni Blandino and Vito Michele Fazio

Int. J. Mol. Sci. 2021, 22(21), 12071; https://doi.org/10.3390/ijms222112071 - 8 Nov 2021

Cited by 9 | Viewed by 2282

Abstract

Chemoresistance is a hallmark of malignant pleural mesothelioma (MPM) management and the expression of ALDH1A3 is responsible for the survival and activity of MPM chemoresistant cell subpopulations (ALDH^bright cells). We enriched mesothelioma ALDH^bright cells to near homogeneity by FACS sorting and an Aldefluor assay and performed unbiased Affymetrix gene expression profiling. Viability and ELISA assays were used to rule out significant apoptosis in the sorted cell subpopulations and to assess target engagement by butein. Statistical analysis of the results, pathway enrichment and promoter enrichment were employed for the generation of the data. Q-RTPCR was used to validate a subset of the identified, modulated mRNAs In this work, we started from the observation that the mRNA levels of the ALDH1A3 isoform could prognostically stratify MPM patients. Thus, we purified MPM ALDH^bright cells from NCI-H2595 cells and interrogated their gene expression (GES) profile. We analyzed the GES of the purified cells at both a steady state and upon treatment with butein (a multifunctional tetrahydroxy-chalcone), which abates the ALDH^bright cell number, thereby exerting chemo-sensitizing effects in vitro and in vivo. We identified 924 genes modulated in a statistically significant manner as a function of ALDH status and of the response to the inhibitor. Pathway and promoter enrichment identified the molecular determinant of high ALDH status and how butein treatment altered the molecular portrait of those chemoresistant cell subpopulations. Further, we unraveled an eighteen-gene signature with high prognostic significance for MPM patients, and showed that most of the identified prognostic contributors escaped the analysis of unfractionated samples. This work proves that digging into the unexplored field of intra-tumor heterogeneity (ITH) by working at the cell subpopulation level may provide findings of prognostic relevance, in addition to mechanistic insights into tumor resistance to therapy. Full article

(This article belongs to the Special Issue Cancer Chemoresistance: Novel Mechanistic Insights and Emerging Therapeutic Strategies)

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24 pages, 13738 KiB

Open AccessArticle

by Flavia Fondevila, Carolina Méndez-Blanco, Paula Fernández-Palanca, Tania Payo-Serafín, Jos van Pelt, Chris Verslype, Javier González-Gallego and José L. Mauriz

Int. J. Mol. Sci. 2021, 22(21), 11770; https://doi.org/10.3390/ijms222111770 - 29 Oct 2021

Cited by 8 | Viewed by 3412

Abstract

Early acquisition of sorafenib resistance is responsible for the dismal prognosis of advanced hepatocarcinoma (HCC). Autophagy, a catabolic process involved in liver homeostasis, has been associated with chemosensitivity modulation. Forkhead box O3 (FOXO3) is a transcription factor linked to HCC pathogenesis whose role on autophagy-related sorafenib resistance remains controversial. Here, we unraveled the linkage between autophagy and sorafenib resistance in HCC, focusing on the implication of FOXO3 and its potential modulation by regorafenib. We worked with two HepG2-derived sorafenib-resistant HCC in vitro models (HepG2S1 and HepG2S3) and checked HCC patient data from the UALCAN database. Resistant cells displayed an enhanced basal autophagic flux compared to HepG2, showing higher autophagolysosome content and autophagy markers levels. Pharmacological inhibition of autophagy boosted HepG2S1 and HepG2S3 apoptosis and subG1 cells, but reduced viability, indicating the cytoprotective role of autophagy. HCC samples displayed higher FOXO3 levels, being associated with shorter survival and autophagic genes expression. Consistently, chemoresistant in vitro models showed significant FOXO3 upregulation. FOXO3 knockdown suppressed autophagy and caused resistant cell death, demonstrating that overactivation of such pro-survival autophagy during sorafenib resistance is FOXO3-dependent; a cytoprotective mechanism that the second-line drug regorafenib successfully abolished. Therefore, targeting FOXO3-mediated autophagy could significantly improve the clinical efficacy of sorafenib. Full article

(This article belongs to the Special Issue Cancer Chemoresistance: Novel Mechanistic Insights and Emerging Therapeutic Strategies)

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12 pages, 32493 KiB

Open AccessArticle

PR-619, a General Inhibitor of Deubiquitylating Enzymes, Diminishes Cisplatin Resistance in Urothelial Carcinoma Cells through the Suppression of c-Myc: An In Vitro and In Vivo Study

by Fu-Shun Hsu, Wei-Chou Lin, Kuan-Lin Kuo, Yen-Ling Chiu, Chen-Hsun Hsu, Shih-Ming Liao, Jun-Ren Dong, Shing-Hwa Liu, Shih-Chen Chang, Shao-Ping Yang, Yueh-Tang Chen, Ruei-Je Chang and Kuo-How Huang

Int. J. Mol. Sci. 2021, 22(21), 11706; https://doi.org/10.3390/ijms222111706 - 28 Oct 2021

Cited by 11 | Viewed by 2559

Abstract

Cisplatin-based chemotherapy is the standard treatment for bladder urothelial carcinoma (UC). Most patients experience chemoresistance, the primary cause of treatment failure, which leads to disease relapse. The underlying mechanism of chemoresistance involves reduced apoptosis. In this study, we investigated the antitumor effect of the deubiquitylating enzyme inhibitor PR-619 in cisplatin-resistant bladder UC. Deubiquitinase (ubiquitin-specific protease 14 (USP14) and USP21) immunohistochemical staining demonstrated that deubiquitination is related to chemoresistance in patients with metastatic UC and may be a target for overcoming chemoresistance. Cytotoxicity and apoptosis were assessed using fluorescence-activated flow cytometry and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay, and PR-619 was found to enhance the cytotoxic and apoptotic effects of cisplatin in cisplatin-resistant T24/R cells. Mitigated cisplatin chemoresistance was associated with the concurrent suppression of c-Myc expression in T24/R cells. Moreover, the expression of c-Myc was upregulated in human bladder UC specimens from patients with chemoresistance. Experiments in a xenograft nude mouse model confirmed that PR-619 enhanced the antitumor effects of cisplatin. These results are promising for the development of therapeutic strategies to prevent UC chemoresistance through the combined use of chemotherapeutic agents/deubiquitination inhibitors (PR-619) by targeting the c-Myc pathway. Full article

(This article belongs to the Special Issue Cancer Chemoresistance: Novel Mechanistic Insights and Emerging Therapeutic Strategies)

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24 pages, 5675 KiB

Open AccessArticle

The Sphingosine Kinase 2 Inhibitor ABC294640 Restores the Sensitivity of BRAFV600E Mutant Colon Cancer Cells to Vemurafenib by Reducing AKT-Mediated Expression of Nucleophosmin and Translationally-Controlled Tumour Protein

by Petra Grbčić, Thomas O. Eichmann, Sandra Kraljević Pavelić and Mirela Sedić

Int. J. Mol. Sci. 2021, 22(19), 10767; https://doi.org/10.3390/ijms221910767 - 5 Oct 2021

Cited by 9 | Viewed by 3011

Abstract

Vemurafenib (PLX4032), small-molecule inhibitor of mutated BRAFV600E protein, has emerged as a potent anti-cancer agent against metastatic melanoma harboring BRAFV600E mutation. Unfortunately, the effect of PLX4032 in the treatment of metastatic BRAF mutated colorectal cancer (CRC) is less potent due to high incidence of fast-developing chemoresistance. It has been demonstrated that sphingolipids are important mediators of chemoresistance to various therapies in colon cancer. In this study, we will explore the role of major regulators of sphingolipid metabolism and signaling in the development of resistance to vemurafenib in BRAF mutant colon cancer cells. The obtained data revealed significantly increased expression levels of activated sphingosine kinases (SphK1 and SphK2) in resistant cells concomitant with increased abundance of sphingosine-1-phosphate (S1P) and its precursor sphingosine, which was accompanied by increased expression levels of the enzymes regulating the ceramide salvage pathway, namely ceramide synthases 2 and 6 and acid ceramidase, especially after the exposure to vemurafenib. Pharmacological inhibition of SphK1/SphK2 activities or modulation of ceramide metabolism by exogenous C6-ceramide enhanced the anti-proliferative effect of PLX4032 in resistant RKO cells in a synergistic manner. It is important to note that the inhibition of SphK2 by ABC294640 proved effective at restoring the sensitivity of resistant cells to vemurafenib at the largest number of combinations of sub-toxic drug concentrations with minimal cytotoxicity. Furthermore, the obtained findings revealed that enhanced anti-proliferative, anti-migratory, anti-clonogenic and pro-apoptotic effects of a combination treatment with ABC294640 and PLX4032 relative to either drug alone were accompanied by the inhibition of S1P-regulated AKT activity and concomitant abrogation of AKT-mediated cellular levels of nucleophosmin and translationally-controlled tumour protein. Collectively, our study suggests the possibility of using the combination of ABC294640 and PLX4032 as a novel therapeutic approach to combat vemurafenib resistance in BRAF mutant colon cancer, which warrants additional preclinical validation studies. Full article

(This article belongs to the Special Issue Cancer Chemoresistance: Novel Mechanistic Insights and Emerging Therapeutic Strategies)

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17 pages, 3141 KiB

Open AccessArticle

Effects of Dihydrotanshinone I on Proliferation and Invasiveness of Paclitaxel-Resistant Anaplastic Thyroid Cancer Cells

by Lorenzo Allegri, Francesca Capriglione, Valentina Maggisano, Giuseppe Damante and Federica Baldan

Int. J. Mol. Sci. 2021, 22(15), 8083; https://doi.org/10.3390/ijms22158083 - 28 Jul 2021

Cited by 8 | Viewed by 1898

Abstract

ATC is a very rare, but extremely aggressive form of thyroid malignancy, responsible for the highest mortality rate registered for thyroid cancer. In patients without known genetic aberrations, the current treatment is still represented by palliative surgery and systemic mono- or combined chemotherapy, which is often not fully effective for the appearance of drug resistance. Comprehension of the mechanisms involved in the development of the resistance is therefore an urgent issue to suggest novel therapeutic approaches for this very aggressive malignancy. In this study, we created a model of anaplastic thyroid cancer (ATC) cells resistant to paclitaxel and investigated the characteristics of these cells by analyzing the profile of gene expression and comparing it with that of paclitaxel-sensitive original ATC cell lines. In addition, we evaluated the effects of Dihydrotanshinone I (DHT) on the viability and invasiveness of paclitaxel-resistant cells. ATC paclitaxel-resistant cells highlighted an overexpression of ABCB1 and a hyper-activation of the NF-κB compared to sensitive cells. DHT treatment resulted in a reduction of viability and clonogenic ability of resistant cells. Moreover, DHT induces a decrement of NF-κB activity in SW1736-PTX and 8505C-PTX cells. In conclusion, to the best of our knowledge, the results of the present study are the first to demonstrate the antitumor effects of DHT on ATC cells resistant to Paclitaxel in vitro. Full article

(This article belongs to the Special Issue Cancer Chemoresistance: Novel Mechanistic Insights and Emerging Therapeutic Strategies)

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19 pages, 2520 KiB

Open AccessArticle

Elevation of Chemosensitivity of Lung Adenocarcinoma A549 Spheroid Cells by Claudin-2 Knockdown through Activation of Glucose Transport and Inhibition of Nrf2 Signal

by Ayaka Ito, Haruka Nasako, Risa Akizuki, Yui Takashina, Hiroaki Eguchi, Toshiyuki Matsunaga, Yuta Yoshino, Satoshi Endo and Akira Ikari

Int. J. Mol. Sci. 2021, 22(12), 6582; https://doi.org/10.3390/ijms22126582 - 19 Jun 2021

Cited by 8 | Viewed by 2351

Abstract

Claudin-2 (CLDN2), a tight junctional protein, is involved in the chemoresistance in a three-dimensional spheroid culture model of human lung adenocarcinoma A549 cells. However, the mechanism has not been fully clarified. We found that the knockdown of CLDN2 expression by siRNA in the spheroid reduces the expression of glucose transporters and metabolic enzymes. In a two-dimensional culture model, the expression of these proteins was increased by glucose deprivation or fasentin, an inhibitor of glucose transporter. In addition, the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant enzymes including heme oxygenase-1, NAD(P)H:quinone oxidoreductase-1, and a glutamate–cysteine ligase modifier subunit were increased by fasentin. The fluorescence intensities of JC-1, a probe of mitochondrial membrane potential, and MitoROS 580, a probe of mitochondrial superoxide production, were increased by fasentin. These results suggest that mitochondrial production of reactive oxygen species is increased by glucose deficiency. The knockdown of CLDN2 enhanced the flux of 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose (2-NBDG), a fluorescent deoxyglucose derivative, in a transwell assay, and the accumulation of glucose and 2-NBDG in spheroid cells. The expression of Nrf2 was decreased by CLDN2 knockdown, which was inhibited by fasentin and sulforaphane, a typical Nrf2 activator, in spheroid cells. The sensitivity of spheroid cells to doxorubicin, an anthracycline antitumor antibiotic, was enhanced by CLDN2 knockdown, which was inhibited by fasentin and sulforaphane. We suggest that CLDN2 induces chemoresistance in spheroid cells mediated through the inhibition of glucose transport and activation of the Nrf2 signal. Full article

(This article belongs to the Special Issue Cancer Chemoresistance: Novel Mechanistic Insights and Emerging Therapeutic Strategies)

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24 pages, 4909 KiB

Open AccessArticle

Proteomic Profiling of BRAFV600E Mutant Colon Cancer Cells Reveals the Involvement of Nucleophosmin/c-Myc Axis in Modulating the Response and Resistance to BRAF Inhibition by Vemurafenib

by Petra Grbčić, Dora Fučkar Čupić, Tania Gamberi, Sandra Kraljević Pavelić and Mirela Sedić

Int. J. Mol. Sci. 2021, 22(12), 6174; https://doi.org/10.3390/ijms22126174 - 8 Jun 2021

Cited by 9 | Viewed by 3443

Abstract

BRAFV600E mutations are found in approximately 10% of colorectal cancer patients and are associated with worse prognosis and poor outcomes with systemic therapies. The aim of this study was to identify novel druggable features of BRAFV600E-mutated colon cancer (CC) cells associated with the response and resistance to BRAFV600E inhibitor vemurafenib. Towards this aim, we carried out global proteomic profiling of BRAFV600E mutant vs. KRAS mutant/BRAF wild-type and double wild-type KRAS/BRAF CC cells followed by bioinformatics analyses. Validation of selected proteomic features was performed by immunohistochemistry and in silico using the TCGA database. We reveal an increased abundance and activity of nucleophosmin (NPM1) in BRAFV600E-mutated CC in vitro, in silico and in tumor tissues from colon adenocarcinoma patients and demonstrate the roles of NPM1 and its interaction partner c-Myc in conveying the resistance to vemurafenib. Pharmacological inhibition of NPM1 effectively restored the sensitivity of vemurafenib-resistant BRAF-mutated CC cells by down-regulating c-Myc expression and activity and consequently suppressing its transcriptional targets RanBP1 and phosphoserine phosphatase that regulate centrosome duplication and serine biosynthesis, respectively. Altogether, findings from this study suggest that the NPM1/c-Myc axis could represent a promising therapeutic target to thwart resistance to vemurafenib in BRAF-mutated CC. Full article

(This article belongs to the Special Issue Cancer Chemoresistance: Novel Mechanistic Insights and Emerging Therapeutic Strategies)

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12 pages, 2092 KiB

Open AccessArticle

Caffeic Acid Enhances the Anti-Leukemic Effect of Imatinib on Chronic Myeloid Leukemia Cells and Triggers Apoptosis in Cells Sensitive and Resistant to Imatinib

by Giordana Feriotto, Federico Tagliati, Riccardo Giriolo, Fabio Casciano, Claudio Tabolacci, Simone Beninati, Mahmud Tareq Hassan Khan and Carlo Mischiati

Int. J. Mol. Sci. 2021, 22(4), 1644; https://doi.org/10.3390/ijms22041644 - 6 Feb 2021

Cited by 20 | Viewed by 2608

Abstract

Among the phenolic acids tested on the K562 cell line, a model of chronic myeloid leukemia (CML), caffeic acid (CA) was biologically active on sensitive and imatinib (IM)-resistant cells at micro-molar concentration, either in terms of reduction of cell proliferation or triggering of apoptosis. The CA treatment provoked mitochondrial membrane depolarization, genomic DNA fragmentation and phosphatidylserine exposure, hallmarks of apoptosis. Cell cycle analysis following the treatment with comparable cytotoxic concentrations of IM or CA showed marked differences in the distribution profiles. The reduction of cell proliferation by CA administration was associated with increased expression of two cell cycle repressor genes, CDKN1A and CHES1, while IM at a cytotoxic concentration increased the CHES1 but not the CDKN1A expression. In addition, CA treatment affected the proliferation and triggered the apoptosis in IM-resistant cells. Taken together, these data suggested that CA induced the anti-proliferative effect and triggered apoptosis of CML cells by a different mechanism than IM. Finally, the combined administration of IM and CA at suboptimal concentrations evidenced a synergy of action in determining the anti-proliferative effect and triggering apoptosis. The ability of CA to potentiate the anti-leukemic effect of IM highlighted the nutraceutical potential of CA in CML. Full article

(This article belongs to the Special Issue Cancer Chemoresistance: Novel Mechanistic Insights and Emerging Therapeutic Strategies)

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15 pages, 4836 KiB

Open AccessArticle

Gene Expression Signature of Acquired Chemoresistance in Neuroblastoma Cells

by Mohamed Jemaà, Wondossen Sime, Yasmin Abassi, Vito Alessandro Lasorsa, Julie Bonne Køhler, Martin Michaelis, Jindrich Cinatl, Mario Capasso and Ramin Massoumi

Int. J. Mol. Sci. 2020, 21(18), 6811; https://doi.org/10.3390/ijms21186811 - 16 Sep 2020

Cited by 5 | Viewed by 2557

Abstract

Drug resistance of childhood cancer neuroblastoma is a serious clinical problem. Patients with relapsed disease have a poor prognosis despite intense treatment. In the present study, we aimed to identify chemoresistance gene expression signatures in vincristine resistant neuroblastoma cells. We found that vincristine-resistant neuroblastoma cells formed larger clones and survived under reduced serum conditions as compared with non-resistant parental cells. To identify the possible mechanisms underlying vincristine resistance in neuroblastoma cells, we investigated the expression profiles of genes known to be involved in cancer drug resistance. This specific gene expression patterns could predict the behavior of a tumor in response to chemotherapy and for predicting the prognosis of high-risk neuroblastoma patients. Our signature could help chemoresistant neuroblastoma patients in avoiding useless and harmful chemotherapy cycles. Full article

(This article belongs to the Special Issue Cancer Chemoresistance: Novel Mechanistic Insights and Emerging Therapeutic Strategies)

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15 pages, 4132 KiB

Open AccessArticle

Discovery of epi-Enprioline as a Novel Drug for the Treatment of Vincristine Resistant Neuroblastoma

by Wondossen Sime, Mohamed Jemaà, Yasmin Abassi, Vito Alessandro Lasorsa, Julie Bonne Køhler, Karin Hansson, Daniel Bexell, Martin Michaelis, Jindrich Cinatl, Daniel Strand, Mario Capasso and Ramin Massoumi

Int. J. Mol. Sci. 2020, 21(18), 6577; https://doi.org/10.3390/ijms21186577 - 8 Sep 2020

Cited by 2 | Viewed by 2239

Abstract

Neuroblastoma is a childhood solid tumour originating from undifferentiated neural progenitor cells of the sympathetic nervous system. Drug resistance of childhood cancer neuroblastoma is a serious clinical problem. In the present study, we aimed to identify novel drugs that can inhibit the growth and survival of chemoresistant neuroblastoma. High-throughput screening identified a small molecule, epi-enprioline that was able to induce apoptosis of vincristine-resistant neuroblastoma cells via the mitochondrial apoptotic pathway. Epi-enprioline reduced tumour growth in multiple preclinical models, including an orthotopic neuroblastoma patient-derived xenograft model in vivo. In summary, our data suggest that epi-enprioline can be considered as a lead compound for the treatment of vincristine-resistant neuroblastoma uncovering a novel strategy, which can be further explored as a treatment for drug-resistant neuroblastoma. Full article

(This article belongs to the Special Issue Cancer Chemoresistance: Novel Mechanistic Insights and Emerging Therapeutic Strategies)

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Review

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22 pages, 37545 KiB

Open AccessReview

Battling Chemoresistance in Cancer: Root Causes and Strategies to Uproot Them

by Alisha Ramos, Samira Sadeghi and Hossein Tabatabaeian

Int. J. Mol. Sci. 2021, 22(17), 9451; https://doi.org/10.3390/ijms22179451 - 31 Aug 2021

Cited by 75 | Viewed by 7180

Abstract

With nearly 10 million deaths, cancer is the leading cause of mortality worldwide. Along with major key parameters that control cancer treatment management, such as diagnosis, resistance to the classical and new chemotherapeutic reagents continues to be a significant problem. Intrinsic or acquired chemoresistance leads to cancer recurrence in many cases that eventually causes failure in the successful treatment and death of cancer patients. Various determinants, including tumor heterogeneity and tumor microenvironment, could cause chemoresistance through a diverse range of mechanisms. In this review, we summarize the key determinants and the underlying mechanisms by which chemoresistance appears. We then describe which strategies have been implemented and studied to combat such a lethal phenomenon in the management of cancer treatment, with emphasis on the need to improve the early diagnosis of cancer complemented by combination therapy. Full article

(This article belongs to the Special Issue Cancer Chemoresistance: Novel Mechanistic Insights and Emerging Therapeutic Strategies)

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19 pages, 2579 KiB

Open AccessReview

Hypoxia-Induced Non-Coding RNAs Controlling Cell Viability in Cancer

by Maria Magdalena Barreca, Chiara Zichittella, Riccardo Alessandro and Alice Conigliaro

Int. J. Mol. Sci. 2021, 22(4), 1857; https://doi.org/10.3390/ijms22041857 - 12 Feb 2021

Cited by 19 | Viewed by 2931

Abstract

Hypoxia, a characteristic of the tumour microenvironment, plays a crucial role in cancer progression and therapeutic response. The hypoxia-inducible factors (HIF-1α, HIF-2α, and HIF-3α), are the master regulators in response to low oxygen partial pressure, modulating hypoxic gene expression and signalling transduction pathways. HIFs’ activation is sufficient to change the cell phenotype at multiple levels, by modulating several biological activities from metabolism to the cell cycle and providing the cell with new characteristics that make it more aggressive. In the past few decades, growing numbers of studies have revealed the importance of non-coding RNAs (ncRNAs) as molecular mediators in the establishment of hypoxic response, playing important roles in regulating hypoxic gene expression at the transcriptional, post-transcriptional, translational, and posttranslational levels. Here, we review recent findings on the different roles of hypoxia-induced ncRNAs in cancer focusing on the data that revealed their involvement in tumour growth. Full article

(This article belongs to the Special Issue Cancer Chemoresistance: Novel Mechanistic Insights and Emerging Therapeutic Strategies)

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