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Cells
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Hypoxia Signaling and Hormonal Signaling in Cancer Progression
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Hypoxia Signaling and Hormonal Signaling in Cancer Progression

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 8199

Special Issue Editor

Dr. David Qian

E-Mail Website
Guest Editor
OHSU Knight Cancer Institute, Prostate Cancer Program, Oregon Health & Science University, Portland, OR 97239, USA
Interests: oxygen/hypoxia sensing and signal transduction; translational cancer research; single-cell-based sequencing and functions; protein post-translational modification; transcriptional regulation; epigenetics; solid tumor

Special Issue Information

Dear Colleagues,

In this Special Issue, we seek in-depth reviews and original research articles addressing the roles and interactions of hormonal signaling and hypoxia signaling in the development and therapy-resistance of human cancers. Cancer development and therapy-resistance are driven by multiple mechanisms. Hormonal and hypoxia signaling are two independent and significant contributors. While their individual contributions have been extensively studied, the interactions between hormone and hypoxia—and the biological significance of the interactions—are less understood. For example, sex hormone receptors (SHRs; e.g. estrogen, progesterone, and androgen receptors) promote hormone-related cancers such as breast, endometrium, ovary, prostate, and osteosarcoma by serving as critical transcription factors and turning on gene expression. Hypoxia-inducible factors (HIFs), especially HIF1, are master regulators of gene expression for cells under low oxygen or oncogenic stress.

Currently, the interaction and the functional consequences of these two transcriptional programs are unclear. Thus, we encourage expert reviews and original studies to understand: 1) how SHR and HIF interact at the transcription level, leading to measurable and significant changes in SHR and hypoxia target gene expressions or novel gene expression; 2) how hormone and hypoxia signaling interact at the cellular level, impacting tumor growth, angiogenesis, and immunity; and 3) how the interactions between hormone and hypoxia signaling modify the efficacies of anticancer therapies, targeting hormone and hypoxia signaling and immune checkpoints.

Dr. David Qian
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hypoxia
  • hormone
  • cancer
  • signaling interaction
  • therapy resistance

Published Papers (3 papers)

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17 pages, 2310 KiB  
Article
Hypoxia-Inducible Expression of Annexin A6 Enhances the Resistance of Triple-Negative Breast Cancer Cells to EGFR and AR Antagonists
by Stephen D. Williams, Tunde M. Smith, LaMonica V. Stewart and Amos M. Sakwe
Cells 2022, 11(19), 3007; https://doi.org/10.3390/cells11193007 - 27 Sep 2022
Cited by 2 | Viewed by 2189
Abstract
Physiological changes such as hypoxia in the tumor microenvironment (TME) endow cancer cells with malignant properties, leading to tumor recurrence and rapid progression. Here, we assessed the effect of hypoxia (1% Oxygen) on the tumor suppressor Annexin A6 (AnxA6) and the response of [...] Read more.
Physiological changes such as hypoxia in the tumor microenvironment (TME) endow cancer cells with malignant properties, leading to tumor recurrence and rapid progression. Here, we assessed the effect of hypoxia (1% Oxygen) on the tumor suppressor Annexin A6 (AnxA6) and the response of triple-negative breast cancer (TNBC) cells to epidermal growth factor receptor (EGFR) and androgen receptor (AR) targeted therapies. We demonstrate that brief exposure of TNBC cells to hypoxia (within 24 h) is associated with down regulation of AnxA6 while > 24 h exposure cell type dependently stimulated the expression of AnxA6. Hypoxia depicted by the expression and stability of HIF-1/2α led to up regulation of the HIF target genes SLC2A1, PGK1 as well as AR and the AR target genes FABP-4 and PPAR-γ, but the cellular levels of AnxA6 protein decreased under prolonged hypoxia. Down regulation of AnxA6 in TNBC cells inhibited, while AnxA6 over expression enhanced the expression and cellular levels of HIF-1/2α, SLC2A1 and PGK1. RNAi mediated inhibition of hypoxia induced AnxA6 expression also strongly inhibited glucose uptake and ROS production in AnxA6 expressing TNBC cells. Using a luciferase reporter assay, we confirm that short-term exposure of cells to hypoxia inhibits while prolonged exposure of cells to hypoxia enhances AnxA6 promoter activity in HEK293T cells. Compared to cells cultured under normoxia, TNBC cells were more resistant to lapatinib under hypoxic conditions, and the downregulation of AnxA6 sensitized the cells to EGFR as well as AR antagonists. These data suggest that AnxA6 is a hypoxia inducible gene and that targeting AnxA6 upregulation may be beneficial in overcoming TNBC resistance to EGFR and/or AR targeted therapies. Full article
(This article belongs to the Special Issue Hypoxia Signaling and Hormonal Signaling in Cancer Progression)
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13 pages, 3412 KiB  
Article
GPT2 Is Induced by Hypoxia-Inducible Factor (HIF)-2 and Promotes Glioblastoma Growth
by Bo Zhang, Yan Chen, Lei Bao and Weibo Luo
Cells 2022, 11(16), 2597; https://doi.org/10.3390/cells11162597 - 20 Aug 2022
Cited by 7 | Viewed by 3566
Abstract
Hypoxia-inducible factor (HIF) directly activates the transcription of metabolic enzymes in response to hypoxia to reprogram cellular metabolism required for tumor cell proliferation. Through analyzing glutamate-linked aminotransferases, we here identified glutamate pyruvate transaminase 2 (GPT2) as a direct HIF-2 target gene [...] Read more.
Hypoxia-inducible factor (HIF) directly activates the transcription of metabolic enzymes in response to hypoxia to reprogram cellular metabolism required for tumor cell proliferation. Through analyzing glutamate-linked aminotransferases, we here identified glutamate pyruvate transaminase 2 (GPT2) as a direct HIF-2 target gene in human glioblastoma (GBM). Hypoxia upregulated GPT2 mRNA and protein levels in GBM cells, which required HIF-2 but not HIF-1. HIF-2 directly bound to the hypoxia response element of the human GPT2 gene, leading to its transcription in hypoxic GBM cells. GPT2 located at the nucleus and mitochondria and reduced α-ketoglutarate levels in GBM cells. Genetic or pharmacological inhibition of GPT2 decreased GBM cell growth and migration under normoxia and hypoxia. Knockout of GPT2 inhibited GBM tumor growth in mice. Collectively, these findings uncover a hypoxia-inducible aminotransferase GPT2 required for GBM progression. Full article
(This article belongs to the Special Issue Hypoxia Signaling and Hormonal Signaling in Cancer Progression)
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14 pages, 1499 KiB  
Brief Report
The Paracrine Effect of Hypoxic and Normoxic Cancer Secretion on the Proliferation of Brain Endothelial Cells (bEnd.3)
by Mariam Rado and David Fisher
Cells 2022, 11(7), 1197; https://doi.org/10.3390/cells11071197 - 2 Apr 2022
Viewed by 1914
Abstract
Background: This study aimed to investigate the disruption of cell cycle phases of bEnd.3 cells exposed to cancer paracrine secretion. Cancer cells have been reported to use the secretion of paracrine factors to compromise the endothelial barrier to prepare for their passage into [...] Read more.
Background: This study aimed to investigate the disruption of cell cycle phases of bEnd.3 cells exposed to cancer paracrine secretion. Cancer cells have been reported to use the secretion of paracrine factors to compromise the endothelial barrier to prepare for their passage into the parenchyma. As cancer cells are known to act differently under conditions of hypoxia, we investigated how conditional media (CM) derived from breast and glioblastoma cells incubated under conditions of normoxia and hypoxia would affect proliferation of brain endothelial cells (bEnd.3). Methods: Brain endothelial cells (bEnd.3) were cultivated with normoxic and hypoxic CM generated from breast cancer MCF7 cells and glioblastoma U-87 cells. Cell proliferation was evaluated using the trypan blue exclusion assay and phases of the cell cycle were evaluated using flow cytometry. Results: bEnd.3 proliferations was suppressed more aggressively with hypoxic CM after 72 and 96 h; cell cycle analysis showed that paracrine treatment tended to prevent BECs from entering the G2 phase, thus suppressing cell division. Conclusions: MCF7 and U-87 cells induce suppressed proliferation of BECs deferentially under hypoxia by blocking cell cycle progression to the G2 phase. Full article
(This article belongs to the Special Issue Hypoxia Signaling and Hormonal Signaling in Cancer Progression)
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