International Journal of Molecular Sciences

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16 pages, 3183 KiB

Open AccessArticle

Long-Term Hypoxia Upregulates Wnt and TGFβ1 Signaling in Eccrine Sweat Gland Cells In Vitro

by Yanlin Lyu, Hiroko Kato, Qianwen Luo, Naoya Otani, Tateki Kubo, Kiyotoshi Sekiguchi and Fumitaka Fujita

Int. J. Mol. Sci. 2025, 26(14), 6664; https://doi.org/10.3390/ijms26146664 - 11 Jul 2025

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Abstract

Eccrine sweat glands play a vital role in human thermoregulation; however, their self-repair function is minimal. Therefore, developing methods to regenerate and improve sweat gland function that use cultured sweat gland cells presents an urgent issue. The tissue microenvironment, especially hypoxic niches, essentially [...] Read more.

Eccrine sweat glands play a vital role in human thermoregulation; however, their self-repair function is minimal. Therefore, developing methods to regenerate and improve sweat gland function that use cultured sweat gland cells presents an urgent issue. The tissue microenvironment, especially hypoxic niches, essentially maintain cell stemness, highlighting the importance of oxygen concentration in the culture environment. Therefore, we evaluated the effects of different oxygen environments on human sweat glands and their regulatory mechanisms. Human eccrine sweat glands express HIF-1α and HIF-2α, suggesting that they respond to hypoxia in vivo. Primary human-derived eccrine sweat gland cells were cultured for two weeks using the spheroid culture method at 0.5%, 2%, 10%, and 21% O₂ concentration. HIF-1, Wnt/β-Catenin, and TGFβ1 signaling increased in sweat gland cells cultured in 0.5% O₂ conditions, along with increased undifferentiated cell marker expression. The results of this study will contribute to in vitro research models of sweat glands and treatment development for damage to sweat glands, including burns. Full article

(This article belongs to the Special Issue Molecular Biology of Hypoxia)

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12 pages, 5543 KiB

Open AccessArticle

Hypoxic Conditions Promote Cartilage Repair in a Rat Knee Osteochondral Defect Model via Hypoxia-Inducible Factor-1α

by Kei Nakamura, Atsuo Inoue, Yuji Arai, Shuji Nakagawa, Yuta Fujii, Ryota Cha, Keisuke Sugie, Kentaro Hayashi, Tsunao Kishida, Osam Mazda and Kenji Takahashi

Int. J. Mol. Sci. 2025, 26(13), 6370; https://doi.org/10.3390/ijms26136370 - 2 Jul 2025

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Abstract

Bone marrow stimulation is a treatment for articular cartilage injuries that promotes cartilage repair by inducing the migration and accumulation of mesenchymal stem cells (MSCs), but often results in fibrocartilage with limited durability. This study aimed to investigate the effect of hypoxic conditions [...] Read more.

Bone marrow stimulation is a treatment for articular cartilage injuries that promotes cartilage repair by inducing the migration and accumulation of mesenchymal stem cells (MSCs), but often results in fibrocartilage with limited durability. This study aimed to investigate the effect of hypoxic conditions on cartilage repair using a rat osteochondral defect model. Osteochondral defects (1.0 mm in diameter) were created in the femoral trochlear groove, and rats were exposed to hypoxic conditions (12% O₂) for 4 weeks postoperatively. Histological analysis was performed, and protein expression of hypoxia-inducible factor-1α (HIF-1α) and SRY-box transcription factor 9 (SOX9) in the repair tissue was evaluated after 1 week. As a result, after 1 week, protein expression of HIF-1α and SOX9 in the Hypoxia group was significantly increased compared to the Normoxia group. After 4 weeks, the Hypoxia group exhibited a hyaline cartilage-like tissue structure with a significantly lower Modified Wakitani score compared to the Normoxia group. Furthermore, after 4 weeks, the inhibition of HIF-1α suppressed cartilage repair. These findings suggest that hypoxic conditions promote SOX9 expression via HIF-1α during the early phase of MSC chondrogenic differentiation and promote the formation of hyaline cartilage-like repair tissue. In conclusion, bone marrow stimulation under hypoxic conditions may enhance the repair effect on articular cartilage injuries. Full article

(This article belongs to the Special Issue Molecular Biology of Hypoxia)

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15 pages, 9305 KiB

Open AccessArticle

Attenuation of Ventilation-Induced Endoplasmic Reticulum Stress Associated with Lung Injury Through Phosphoinositide 3-Kinase-Gamma in a Murine Endotoxemia Model

by Li-Fu Li, Chung-Chieh Yu, Chih-Yu Huang, Huang-Pin Wu, Chien-Ming Chu, Ping-Chi Liu and Yung-Yang Liu

Int. J. Mol. Sci. 2025, 26(12), 5761; https://doi.org/10.3390/ijms26125761 - 16 Jun 2025

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Abstract

Patients with sepsis often receive mechanical ventilation (MV). Continued use of MV may increase overdistention in the lungs, inflammatory mediator production, and inflammatory cell recruitment, eventually causing ventilator-induced lung injury (VILI). Endoplasmic reticulum (ER) stress caused by MV, oxidative stress, and sepsis results [...] Read more.

Patients with sepsis often receive mechanical ventilation (MV). Continued use of MV may increase overdistention in the lungs, inflammatory mediator production, and inflammatory cell recruitment, eventually causing ventilator-induced lung injury (VILI). Endoplasmic reticulum (ER) stress caused by MV, oxidative stress, and sepsis results in dissociation of GRP78 from transmembrane proteins (PERK, IRE1α, and ATF6) and generates abundant incorrect protein structures. Phosphoinositide 3-kinase-γ (PI3K-γ) has been demonstrated to modulate ER stress associated with sepsis and acute lung injury (ALI). However, the regulatory mechanisms by which ER stress is involved in VILI remain unclear. In this study, MV was hypothesized to augment lung injury and induce ER stress through the PI3K-γ pathway, regardless of endotoxemia. Wild-type or PI3K-γ-deficient C57BL/6 mice were exposed to 30 mL/kg tidal volume of MV with or without endotoxemia for 5 h. The control group comprised nonventilated mice. MV with endotoxemia increased microvascular permeability, lung edema, interleukin-6 and metalloproteinase-9 production, oxidative loads, ER stress biomarkers (GRP78, IRE-1α, PERK), morphological rearrangement, PI3K-γ expression, and bronchial epithelial apoptosis in rodent lungs. The increase in lung injury was substantially reduced in PI3K-γ-deficient mice and in mice administered 4-phenylbutyric acid. In conclusion, MV-augmented ALI after endotoxemia partially depends on the PI3K-γ pathway. Full article

(This article belongs to the Special Issue Molecular Biology of Hypoxia)

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16 pages, 3053 KiB

Open AccessArticle

PLAC8 Expression Regulates Trophoblast Invasion and Conversion into an Endothelial Phenotype (eEVT)

by Laura J. Barragán-Zúñiga, Rodrigo Escalona-Rivano, Catalina Cordero-Tirado, Martha Sosa-Macías, Ivo Carrasco-Wong, Jaime Gutiérrez and Carlos Galaviz-Hernandez

Int. J. Mol. Sci. 2025, 26(11), 5371; https://doi.org/10.3390/ijms26115371 - 4 Jun 2025

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Abstract

PLAC8, expressed by interstitial extravillous trophoblasts (iEVTs), plays a crucial role in trophoblast invasion, differentiation, and immunotolerance. Its dysregulation may contribute to pregnancy complications, such as preeclampsia. This study investigates the role of PLAC8 in trophoblast invasiveness and endothelial-like differentiation under different oxygen [...] Read more.

PLAC8, expressed by interstitial extravillous trophoblasts (iEVTs), plays a crucial role in trophoblast invasion, differentiation, and immunotolerance. Its dysregulation may contribute to pregnancy complications, such as preeclampsia. This study investigates the role of PLAC8 in trophoblast invasiveness and endothelial-like differentiation under different oxygen tensions. Swan-71 cells were transiently transfected with PLAC8 overexpression or knockdown plasmids. Invasion was assessed using Matrigel-coated transwells, endothelial-like differentiation through tube formation assays, and vasculogenic marker expression (VEGF, PGF, ANGPT2) by RT-PCR. Hypoxia experiments were performed at different oxygen conditions. PLAC8 overexpression enhanced trophoblast invasion but reduced endothelial-like differentiation, downregulating VEGF and PGF while upregulating ANGPT2. Hypoxia increased PLAC8 expression, indicating oxygen tension as a regulatory factor. PLAC8 manipulation did not affect cell viability. PLAC8 modulates trophoblast behavior by promoting invasion while inhibiting endothelial-like differentiation. Its regulation of vasculogenic and angiogenic factors suggests a critical role in placental homeostasis and potential relevance to pregnancy disorders, such as preeclampsia. Full article

(This article belongs to the Special Issue Molecular Biology of Hypoxia)

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16 pages, 1357 KiB

Open AccessArticle

Modulation of the Antitumor Response to Metformin, Caffeine, and Sodium Dichloroacetate by the Hypoxic Microenvironment in Lung Cancer Cells

by Misael Osmar Garcia-Martin, Manuel Castillejos-Lopez, Heriberto Prado-Garcia, Susana Romero-Garcia, Juan Carlos Huerta-Cruz, José Alberto Choreño-Parra, Georgina Gonzalez-Avila, Luz A. Colín-Godínez, Daniel Paz-Gomez, Ángeles Carlos-Reyes, Victor Ruiz, Yair Romero, Edgar Flores-Soto, Juan Rodríguez-Silverio, Roberto Lara-Lemus, Rafael Velázquez-Cruz, Citlaltepetl Salinas-Lara, Luz María Torres-Espíndola and Arnoldo Aquino-Gálvez

Int. J. Mol. Sci. 2025, 26(11), 5014; https://doi.org/10.3390/ijms26115014 - 23 May 2025

Viewed by 923

Abstract

Metformin, caffeine, and dichloroacetate (DCA) have shown antitumor effects. The hypoxic tumor microenvironment can modulate drug response. We aimed to analyze the interaction of metformin with caffeine or DCA in lung cancer cells (HCC827) under normoxia and hypoxia conditions. Cell viability was evaluated [...] Read more.

Metformin, caffeine, and dichloroacetate (DCA) have shown antitumor effects. The hypoxic tumor microenvironment can modulate drug response. We aimed to analyze the interaction of metformin with caffeine or DCA in lung cancer cells (HCC827) under normoxia and hypoxia conditions. Cell viability was evaluated using the crystal violet assay after individual and combined drug treatment under normoxia (21% O₂) and hypoxia (1% O₂) conditions. Combination effects were analyzed using isobolographic analysis. The results show that under normoxia conditions, the combination of metformin with DCA (γ = 0.98 ± 0.35, p > 0.05) or caffeine (γ = 0.90 ± 0.34, p > 0.05) revealed additivity. However, in hypoxia, both combinations exhibited significant antagonism, with γ values appearing greater than one for metformin + DCA (γ = 4.20 ± 1.44, p < 0.05) and metformin + caffeine (γ = 2.88 ± 0.90, p < 0.05). Hypoxia significantly alters the pharmacological interaction of metformin with caffeine or DCA, which could limit their combined therapeutic potential in hypoxic tumors despite metformin’s activity in this environment. The importance of considering tumor oxygenation status in the design of combined therapies for lung cancer is emphasized. Full article

(This article belongs to the Special Issue Molecular Biology of Hypoxia)

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16 pages, 4733 KiB

Open AccessArticle

Inhibition of MCP1 (CCL2) Enhances Antitumor Activity of NK Cells Against HCC Cells Under Hypoxia

by Hwan Hee Lee, Juhui Kim, Eunbi Park, Hyojeung Kang and Hyosun Cho

Int. J. Mol. Sci. 2025, 26(10), 4900; https://doi.org/10.3390/ijms26104900 - 20 May 2025

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Abstract

Hypoxia, a low-oxygen state, is a common feature of solid tumors. MCP1 (CCL2) is a small cytokine that is closely related to hypoxia and has a positive effect on tumor development. Hypoxia causes resistance to various treatments for solid tumors and the evasion [...] Read more.

Hypoxia, a low-oxygen state, is a common feature of solid tumors. MCP1 (CCL2) is a small cytokine that is closely related to hypoxia and has a positive effect on tumor development. Hypoxia causes resistance to various treatments for solid tumors and the evasion of cancer immune surveillance by lymphocytes. Natural killer (NK) cells are innate lymphocytes that play an important role in cancer development, particularly in the liver. First, it was found that the incubation of HCC in hypoxia (2–5% O₂) significantly increased the production of several inflammatory cytokines, including MCP1, compared to that of normal oxygen (20% O₂). Subsequently, blocking MCP1 with an anti-MCP1 antibody in HCC cultures inhibited the growth and migration of HCC cells in vitro and in vivo. This was associated with a decrease in the expression of HIF-1α/STAT3 in HCC under hypoxia. Furthermore, blocking MCP1 in HCC cell cultures under hypoxia significantly increased the chemotaxis and activation of NK-92 cells against HCC cells. MCP1 blockade in HCC cell cultures under hypoxia induced a shift in NK cells to the CD56^+dim population and an increase in the expression of the activation receptors NKG2D and NKp44. In conclusion, modulation of MCP1 could enhance NK activity against hypoxic HCC cells. Full article

(This article belongs to the Special Issue Molecular Biology of Hypoxia)

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12 pages, 2478 KiB

Open AccessArticle

FDX1 Regulates the Phosphorylation of ATM, DNA-PKcs Akt, and EGFR and Affects Radioresistance Under Severe Hypoxia in the Glioblastoma Cell Line T98G

by Takuma Hashimoto, Kazuki Tsubota, Khaled Hatabi and Yoshio Hosoi

Int. J. Mol. Sci. 2025, 26(7), 3378; https://doi.org/10.3390/ijms26073378 - 4 Apr 2025

Cited by 1 | Viewed by 697

Abstract

Hypoxic cells exhibit radioresistance, which is associated with poor prognosis in cancer patients. Understanding the molecular mechanisms underlying radioresistance in hypoxic tumor cells is crucial for improving radiotherapy efficacy. In this study, we examined the role of FDX1 in regulating cellular responses to [...] Read more.

Hypoxic cells exhibit radioresistance, which is associated with poor prognosis in cancer patients. Understanding the molecular mechanisms underlying radioresistance in hypoxic tumor cells is crucial for improving radiotherapy efficacy. In this study, we examined the role of FDX1 in regulating cellular responses to severe hypoxia in glioblastoma cell lines T98G and A172. We found that FDX1 expression was upregulated under severe hypoxia, and its knockdown reduced the hypoxia-induced activation of key radioresistance factors and cellular survival mechanisms, including ATM, DNA-PKcs, Akt, and EGFR. FDX1 knockdown also sensitized T98G cells to radiation under severe hypoxia. Furthermore, FDX1 was found to regulate HIF-1α protein level, while HIF-1α did not regulate FDX1 expression. These results suggest that FDX1 may be a novel therapeutic target to overcome radioresistance in glioblastoma under severe hypoxia. Full article

(This article belongs to the Special Issue Molecular Biology of Hypoxia)

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12 pages, 1859 KiB

Open AccessArticle

Differential Effects of the Prolyl-Hydroxylase Inhibitor on the Cellular Response to Radiation

by Masaki Murao, Takahiro Fukazawa, Ujjal K. Bhawal, Nitesh Tewari, Nobuaki Shime, Nobuyuki Hirohashi and Keiji Tanimoto

Int. J. Mol. Sci. 2025, 26(6), 2742; https://doi.org/10.3390/ijms26062742 - 18 Mar 2025

Viewed by 625

Abstract

The prolyl-hydroxylase inhibitor (PHI), used effectively in several countries for the treatment of renal anemia, activates the multifunctional hypoxia-inducible factors (HIFs). While hypoxic conditions in tumors are known to affect the response to radiation therapy, the effect of PHI on the radiation response [...] Read more.

The prolyl-hydroxylase inhibitor (PHI), used effectively in several countries for the treatment of renal anemia, activates the multifunctional hypoxia-inducible factors (HIFs). While hypoxic conditions in tumors are known to affect the response to radiation therapy, the effect of PHI on the radiation response of cancer cells has not been determined. Hypoxic pretreatment increased the radiation sensitivity of A549 lung adenocarcinoma cells, whereas hypoxic culture after irradiation decreased the radiation sensitivity of HSC2 oral squamous cell carcinoma cells. Treatment of PC9 lung adenocarcinoma and HSC2 cells with the PHI FG-4592 significantly increased radiation resistance, whereas A549 and TIG3 lung fibroblast cells tended to be sensitized, suggesting cell type-specific differential effects of PHI. Quantitative RT-PCR analyses revealed that the basal and radiation-inducible expressions of DEC2, BAX, and BCL2 may be related to PHI-mediated radiation responses. Knock-down experiments showed that silencing of DEC2 sensitized both A549 and PC9 cells under PHI-treated conditions. On the other hand, silencing of p53, which regulates BAX/BCL2, desensitized A549 cells expressing wild-type p53, but not PC9 cells, with mutant-type p53, to irradiation, regardless of whether PHI was treated or not. Taken together, PHI modifies radiation responses in a cell type-specific manner, possibly through DEC2 signaling. Full article

(This article belongs to the Special Issue Molecular Biology of Hypoxia)

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18 pages, 8094 KiB

Open AccessArticle

Molecular Modulation of Threadfin Fish Brain to Hypoxia Challenge and Recovery Revealed by Multi-Omics Profiling

by Xiaoli Ma and Wen-Xiong Wang

Int. J. Mol. Sci. 2025, 26(4), 1703; https://doi.org/10.3390/ijms26041703 - 17 Feb 2025

Cited by 1 | Viewed by 796

Abstract

Migratory fish often encounter hypoxic zones during migration, which can lead to varying degrees of hypoxic stress. This issue has become increasingly severe due to human activities and climate change, which have resulted in the expansion of hypoxic zones in aquatic environments. However, [...] Read more.

Migratory fish often encounter hypoxic zones during migration, which can lead to varying degrees of hypoxic stress. This issue has become increasingly severe due to human activities and climate change, which have resulted in the expansion of hypoxic zones in aquatic environments. However, there is limited research on how these species respond to hypoxic stress and subsequent recovery. In this study, we used Eleutheronema tetradactylum, a well-recognized migratory and economically valuable fish species, as a model organism. Histological analysis revealed extensive neuronal damage during hypoxia exposure, with limited recovery observed even after 12 h of reoxygenation. Differential gene expression analysis highlighted progressive alterations in genes associated with stress response, neuroactive ligand interactions, and cellular repair mechanisms. Time-series analysis of differentially expressed genes (DEGs) identified critical expression profiles throughout the hypoxia-recovery process and revealed hub genes for each stage. Furthermore, dynamic changes in miRNA expression and proteomic profiles indicated active regulation of several key biological pathways, including MAPK, HIF-1, and ECM-receptor interactions. Through miRNA-mRNA-protein correlation analysis, we propose a model that predicts key regulatory pathways and critical miRNA-mRNA-protein interactions across the various stages of hypoxia-recovery in the brain of E. tetradactylum. This study presents the first integrated analysis of miRNA, mRNA, and protein throughout the entire hypoxia-recovery process in fish brains. The molecular interactions and regulatory pathways identified in this model could serve as valuable biomarkers for future research on hypoxia-recovery mechanisms in fish. Full article

(This article belongs to the Special Issue Molecular Biology of Hypoxia)

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29 pages, 5048 KiB

Open AccessArticle

DNA Damage and Inflammatory Response of p53 Null H358 Non-Small Cell Lung Cancer Cells to X-Ray Exposure Under Chronic Hypoxia

by Hasan Nisar, Melanie Brauny, Frederik M. Labonté, Claudia Schmitz, Bikash Konda and Christine E. Hellweg

Int. J. Mol. Sci. 2024, 25(23), 12590; https://doi.org/10.3390/ijms252312590 - 23 Nov 2024

Cited by 1 | Viewed by 1633

Abstract

Hypoxia-induced radioresistance limits therapeutic success in cancer. In addition, p53 mutations are widespread in tumors including non-small cell lung carcinomas (NSCLCs), and they might modify the radiation response of hypoxic tumor cells. We therefore analyzed the DNA damage and inflammatory response in chronically [...] Read more.

Hypoxia-induced radioresistance limits therapeutic success in cancer. In addition, p53 mutations are widespread in tumors including non-small cell lung carcinomas (NSCLCs), and they might modify the radiation response of hypoxic tumor cells. We therefore analyzed the DNA damage and inflammatory response in chronically hypoxic (1% O₂, 48 h) p53 null H358 NSCLC cells after X-ray exposure. We used the colony-forming ability assay to determine cell survival, γH2AX immunofluorescence microscopy to quantify DNA double-strand breaks (DSBs), flow cytometry of DAPI-stained cells to measure cell cycle distribution, ELISAs to quantify IL-6 and IL-8 secretion in cell culture supernatants, and RNA sequencing to determine gene expression. Chronic hypoxia increased the colony-forming ability and radioresistance of H358 cells. It did not affect the formation or resolution of X-ray-induced DSBs. It reduced the fraction of cells undergoing G2 arrest after X-ray exposure and delayed the onset of G2 arrest. Hypoxia led to an earlier enhancement in cytokines secretion rate after X-irradiation compared to normoxic controls. Gene expression changes were most pronounced after the combined exposure to hypoxia and X-rays and pertained to senescence and different cell death pathways. In conclusion, hypoxia-induced radioresistance is present despite the absence of functional p53. This resistance is related to differences in clonogenicity, cell cycle regulation, cytokine secretion, and gene expression under chronic hypoxia, but not to differences in DNA DSB repair kinetics. Full article

(This article belongs to the Special Issue Molecular Biology of Hypoxia)

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Review

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22 pages, 2088 KiB

Open AccessReview

The Hypoxia–Retinoid Axis in Idiopathic Pulmonary Fibrosis: Multifaceted Etiology and Therapeutic Potential

by Daniel Paz-Gomez, Manuel Castillejos-López, Yair Romero, Edgar Flores-Soto, Bianca S. Romero-Martinez, Joel Armando Vázquez-Pérez, Georgina Gonzalez-Avila, Victor Ruiz, Ángeles Carlos-Reyes, Rafael Velázquez-Cruz, José Alberto Choreño-Parra, Roberto Lara-Lemus, Fausto Rojas-Duran, David Martínez Briseño, Joaquín Zuñiga, Luz María Torres-Espíndola and Arnoldo Aquino-Gálvez

Int. J. Mol. Sci. 2025, 26(11), 5302; https://doi.org/10.3390/ijms26115302 - 31 May 2025

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease with limited therapeutic options. This review focuses on the role of retinoids, particularly all-trans retinoic acid (atRA), and hypoxia in the pathogenesis of IPF. Despite an established understanding of genetic and environmental [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease with limited therapeutic options. This review focuses on the role of retinoids, particularly all-trans retinoic acid (atRA), and hypoxia in the pathogenesis of IPF. Despite an established understanding of genetic and environmental factors in IPF, the interplay between retinoid signaling and the response to hypoxia remains poorly explored due to its complexity. Preclinical evidence suggests that atRA could help reduce pulmonary fibrosis by modulating TGF-β signaling pathways and epithelial-to-mesenchymal transition (EMT). Additionally, we mention other diseases where a relationship between hypoxia and retinoids has been observed. We review how hypoxia, a key factor in the progression of IPF, may influence the efficacy of retinoid therapy. Combination strategies are explored to overcome hypoxia-induced treatment resistance. Finally, we address the complex role of retinoids in lung regeneration, balancing their potential benefits against the risk of exacerbating fibrotic processes. This review suggests that retinoids have potential as a treatment or adjuvant for IPF and highlights the need for further research to elucidate the precise mechanisms of retinoid action in IPF, particularly in hypoxia. Full article

(This article belongs to the Special Issue Molecular Biology of Hypoxia)

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24 pages, 2607 KiB

Open AccessReview

HIF-1α-Mediated Disruption of Cellular Junctions: The Impact of Hypoxia on the Tumor Microenvironment and Invasion

by Michael Springer, Zeynep Aydin Burakgazi, Anastasiia Domukhovska, Ben Nafchi, Michael C. Beary, Arielle Acquisto, Juliette Acquisto, Vladyslav Komarov, Madison Jensen, Brandon Gulledge, Maksym Poplavskyi, Md Gias Uddin, Gamal Rayan and Shoshanna N. Zucker

Int. J. Mol. Sci. 2025, 26(11), 5101; https://doi.org/10.3390/ijms26115101 - 26 May 2025

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Abstract

Hypoxia is a critical factor affecting tissue homeostasis that dramatically alters the tumor microenvironment (TME) through genetic, metabolic, and structural changes, promoting tumor survival and proliferation. Hypoxia-inducible factor-1α (HIF-1α) plays a central role in this process by regulating hundreds of genes involved in [...] Read more.

Hypoxia is a critical factor affecting tissue homeostasis that dramatically alters the tumor microenvironment (TME) through genetic, metabolic, and structural changes, promoting tumor survival and proliferation. Hypoxia-inducible factor-1α (HIF-1α) plays a central role in this process by regulating hundreds of genes involved in the processes of tumorigenesis, angiogenesis, metabolic reprogramming, and immune evasion. This review provides a comprehensive examination of the role of HIF-1α in hypoxia and how hypoxia weakens intercellular junctions—including gap junctions, adherens junctions, tight junctions, and desmosomes. The disruption of gap junctions decreases intercellular communication, which alters signal transduction cascades and tumor suppressive properties. Adherens junctions are comprised of proteins that characterize the tissues and link cells to the actin cytoskeleton, whereby their disruption promotes the epithelial-to-mesenchymal transition (EMT). Under hypoxic conditions, the tight junction proteins are dysregulated, altering paracellular transport and cell polarity. In addition, desmosomes provide linkage to intermediate filaments, and hypoxia compromises tissue integrity. Collectively, the influence of hypoxia on cellular junctions promotes tumorigenesis through reducing cell communication, cytoskeletal interactions, and altering signaling pathways. Activation of matrix metalloproteinases (MMPs) further degrades the extracellular matrix and enhances tumor invasion and metastasis. This process also involves hypoxia-induced angiogenesis, regulated by HIF-1α. A comprehensive understanding of the mechanisms of hypoxia-driven tumor adaptation is essential for developing effective therapeutic strategies. Furthermore, this review examines current treatments aimed at targeting HIF-1α and explores future directions to enhance treatment efficacy and improve patient outcomes. Full article

(This article belongs to the Special Issue Molecular Biology of Hypoxia)

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28 pages, 6331 KiB

Open AccessReview

The Hippo Pathway in Breast Cancer: The Extracellular Matrix and Hypoxia

by Hanyu Yang, Jiaxin Yang, Xiang Zheng, Tianshun Chen, Ranqi Zhang, Rui Chen, Tingting Cao, Fancai Zeng and Qiuyu Liu

Int. J. Mol. Sci. 2024, 25(23), 12868; https://doi.org/10.3390/ijms252312868 - 29 Nov 2024

Cited by 5 | Viewed by 2216

Abstract

As one of the most prevalent malignant neoplasms among women globally, the optimization of therapeutic strategies for breast cancer has perpetually been a research hotspot. The tumor microenvironment (TME) is of paramount importance in the progression of breast cancer, among which the extracellular [...] Read more.

As one of the most prevalent malignant neoplasms among women globally, the optimization of therapeutic strategies for breast cancer has perpetually been a research hotspot. The tumor microenvironment (TME) is of paramount importance in the progression of breast cancer, among which the extracellular matrix (ECM) and hypoxia are two crucial factors. The alterations of these two factors are predominantly regulated by the Hippo signaling pathway, which promotes tumor invasiveness, metastasis, therapeutic resistance, and susceptibility. Hence, this review focuses on the Hippo pathway in breast cancer, specifically, how the ECM and hypoxia impact the biological traits and therapeutic responses of breast cancer. Moreover, the role of miRNAs in modulating ECM constituents was investigated, and hsa-miR-33b-3p was identified as a potential therapeutic target for breast cancer. The review provides theoretical foundations and potential therapeutic direction for clinical treatment strategies in breast cancer, with the aspiration of attaining more precise and effective treatment alternatives in the future. Full article

(This article belongs to the Special Issue Molecular Biology of Hypoxia)

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18 pages, 577 KiB

Open AccessReview

mTOR in the Development of Hypoxic Pulmonary Hypertension Associated with Cardiometabolic Risk Factors

by Karen Flores, Carlo Almeida, Karem Arriaza, Eduardo Pena and Samia El Alam

Int. J. Mol. Sci. 2024, 25(20), 11023; https://doi.org/10.3390/ijms252011023 - 14 Oct 2024

Viewed by 2136

Abstract

The pathophysiology of pulmonary hypertension is complex and multifactorial. It is a disease characterized by increased pulmonary vascular resistance at the level due to sustained vasoconstriction and remodeling of the pulmonary arteries, which triggers an increase in the mean pulmonary artery pressure and [...] Read more.

The pathophysiology of pulmonary hypertension is complex and multifactorial. It is a disease characterized by increased pulmonary vascular resistance at the level due to sustained vasoconstriction and remodeling of the pulmonary arteries, which triggers an increase in the mean pulmonary artery pressure and subsequent right ventricular hypertrophy, which in some cases can cause right heart failure. Hypoxic pulmonary hypertension (HPH) is currently classified into Group 3 of the five different groups of pulmonary hypertensions, which are determined according to the cause of the disease. HPH mainly develops as a product of lung diseases, among the most prevalent causes of obstructive sleep apnea (OSA), chronic obstructive pulmonary disease (COPD), or hypobaric hypoxia due to exposure to high altitudes. Additionally, cardiometabolic risk factors converge on molecular mechanisms involving overactivation of the mammalian target of rapamycin (mTOR), which correspond to a central axis in the development of HPH. The aim of this review is to summarize the role of mTOR in the development of HPH associated with metabolic risk factors and its therapeutic alternatives, which will be discussed in this review. Full article

(This article belongs to the Special Issue Molecular Biology of Hypoxia)

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