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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

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 546

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

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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

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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

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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

Viewed by 1488

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 1 | Viewed by 1885

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

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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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