Hypoxia: involved but not essential for endometrial breakdown in mouse menstural-like model

Menstruation is a specific physiological phenomenon that occurs in women. However, molecular mechanisms underlying this phenomenon are still unclear. According to the classical theory, tissue hypoxia resulting from vasoconstriction of the spiral arteries after progesterone (P4) withdrawal initiates the breakdown of the endometrium at the earliest stage of menstruation. However, this theory has been challenged by previous studies that have questioned the function and even the existence of hypoxia during menstruation. In this study, we not only provide convincing evidence that hypoxia exists during endometrial breakdown, but also further explore the role of hypoxia and hypoxia-inducible factor 1 (HIF1) in this process. Based on mouse menstrual-like model and experiments with human decidual stromal cells, we observed that P4 withdrawal induced both hypoxia and HIF1 activation; however, endometrial breakdown was triggered only by P4 withdrawal. Hypoxia significantly enhanced the mRNA expression of specific matrix metalloproteinases (MMPs) under the conditions of P4 withdrawal. In conclusion, hypoxia is involved but not an essential component of endometrial breakdown during menstruation.

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The Role of the Hypoxia-Inducible Factor 1 Binding Site in the Induction of Aquaporin-1 mRNA Expression by Hypoxia

DNA and Cell Biology ◽

10.1089/dna.2009.1014 ◽

2011 ◽

Vol 30 (8) ◽

pp. 539-544 ◽

Cited By ~ 14

Author(s):

Asami Tanaka ◽

Kenichi Sakurai ◽

Kentaro Kaneko ◽

Jun Ogino ◽

Kazuo Yagui ◽

...

Keyword(s):

Mrna Expression ◽

Binding Site ◽

Hypoxia Inducible Factor ◽

Aquaporin 1 ◽

Hypoxia Inducible Factor 1

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SEMAPHORINS and their receptors: focus on the crosstalk between melanoma and hypoxia

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01929-3 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Elisabetta Valentini ◽

Marta Di Martile ◽

Donatella Del Bufalo ◽

Simona D’Aguanno

Keyword(s):

Tumor Microenvironment ◽

Cancer Progression ◽

Stromal Cells ◽

Hypoxia Inducible Factor ◽

Cell Communication ◽

Hypoxic Condition ◽

Response To Therapy ◽

Hypoxia Inducible Factor 1 ◽

Shed Light

AbstractHypoxia, a condition of oxygen deprivation, is considered a hallmark of tumor microenvironment regulating several pathways and promoting cancer progression and resistance to therapy. Semaphorins, a family of about 20 secreted, transmembrane and GPI-linked glycoproteins, and their cognate receptors (plexins and neuropilins) play a pivotal role in the crosstalk between cancer and stromal cells present in the tumor microenvironment. Many studies reported that some semaphorins are involved in the development of a permissive tumor niche, guiding cell-cell communication and, consequently, the development and progression, as well as the response to therapy, of different cancer histotypes, including melanoma.In this review we will summarize the state of art of semaphorins regulation by hypoxic condition in cancer with different origin. We will also describe evidence about the ability of semaphorins to affect the expression and activity of transcription factors activated by hypoxia, such as hypoxia-inducible factor-1. Finally, we will focus our attention on findings reporting the role of semaphorins in melanocytes transformation, melanoma progression and response to therapy. Further studies are necessary to understand the mechanisms through which semaphorins induce their effect and to shed light on the possibility to use semaphorins or their cognate receptors as prognostic markers and/or therapeutic targets in melanoma or other malignancies.

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The Role of Chaperone-Mediated Autophagy in Cell Cycle Control and Its Implications in Cancer

Cells ◽

10.3390/cells9092140 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2140

Author(s):

Marina Andrade-Tomaz ◽

Izadora de Souza ◽

Clarissa Ribeiro Reily Rocha ◽

Luciana Rodrigues Gomes

Keyword(s):

Cell Cycle ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Cell Cycle Control ◽

Hypoxia Inducible Factor ◽

Cellular Processes ◽

Hypoxia Inducible Factor 1 ◽

Chaperone Mediated Autophagy ◽

Transformation Processes

The cell cycle involves a network of proteins that modulate the sequence and timing of proliferation events. Unregulated proliferation is the most fundamental hallmark of cancer; thus, changes in cell cycle control are at the heart of malignant transformation processes. Several cellular processes can interfere with the cell cycle, including autophagy, the catabolic pathway involved in degradation of intracellular constituents in lysosomes. According to the mechanism used to deliver cargo to the lysosome, autophagy can be classified as macroautophagy (MA), microautophagy (MI), or chaperone-mediated autophagy (CMA). Distinct from other autophagy types, CMA substrates are selectively recognized by a cytosolic chaperone, one-by-one, and then addressed for degradation in lysosomes. The function of MA in cell cycle control, and its influence in cancer progression, are already well-established. However, regulation of the cell cycle by CMA, in the context of tumorigenesis, has not been fully addressed. This review aims to present and debate the molecular mechanisms by which CMA can interfere in the cell cycle, in the context of cancer. Thus, cell cycle modulators, such as MYC, hypoxia-inducible factor-1 subunit alpha (HIF-1α), and checkpoint kinase 1 (CHK1), regulated by CMA activity will be discussed. Finally, the review will focus on how CMA dysfunction may impact the cell cycle, and as consequence promote tumorigenesis.

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The Role of Hypoxia-Inducible Factor 1 in Mild Cognitive Impairment

Cellular and Molecular Neurobiology ◽

10.1007/s10571-016-0440-6 ◽

2016 ◽

Vol 37 (6) ◽

pp. 969-977 ◽

Cited By ~ 12

Author(s):

Osigbemhe Iyalomhe ◽

Sabina Swierczek ◽

Ngozi Enwerem ◽

Yuanxiu Chen ◽

Monica O. Adedeji ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1

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Hypoxia-inducible factor–1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma

Neurosurgical FOCUS ◽

10.3171/2014.9.focus14496 ◽

2014 ◽

Vol 37 (6) ◽

pp. E8 ◽

Cited By ~ 18

Author(s):

Matthew Womeldorff ◽

David Gillespie ◽

Randy L. Jensen

Keyword(s):

Cellular Response ◽

Treatment Options ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1 ◽

Poor Patient ◽

Growth Development ◽

The Relationship ◽

Insight Into ◽

Upstream Regulators

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

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Long-Noncoding RNA (lncRNA) in the Regulation of Hypoxia-Inducible Factor (HIF) in Cancer

Non-Coding RNA ◽

10.3390/ncrna6030027 ◽

2020 ◽

Vol 6 (3) ◽

pp. 27 ◽

Cited By ~ 3

Author(s):

Dominik A. Barth ◽

Felix Prinz ◽

Julia Teppan ◽

Katharina Jonas ◽

Christiane Klec ◽

...

Keyword(s):

Noncoding Rna ◽

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Protein Coding ◽

Rna Molecules ◽

Von Hippel Lindau ◽

Hypoxic Conditions ◽

Main Regulator ◽

Upstream Regulators

Hypoxia is dangerous for oxygen-dependent cells, therefore, physiological adaption to cellular hypoxic conditions is essential. The transcription factor hypoxia-inducible factor (HIF) is the main regulator of hypoxic metabolic adaption reducing oxygen consumption and is regulated by gradual von Hippel-Lindau (VHL)-dependent proteasomal degradation. Beyond physiology, hypoxia is frequently encountered within solid tumors and first drugs are in clinical trials to tackle this pathway in cancer. Besides hypoxia, cancer cells may promote HIF expression under normoxic conditions by altering various upstream regulators, cumulating in HIF upregulation and enhanced glycolysis and angiogenesis, altogether promoting tumor proliferation and progression. Therefore, understanding the underlying molecular mechanisms is crucial to discover potential future therapeutic targets to evolve cancer therapy. Long non-coding RNAs (lncRNA) are a class of non-protein coding RNA molecules with a length of over 200 nucleotides. They participate in cancer development and progression and might act as either oncogenic or tumor suppressive factors. Additionally, a growing body of evidence supports the role of lncRNAs in the hypoxic and normoxic regulation of HIF and its subunits HIF-1α and HIF-2α in cancer. This review provides a comprehensive update and overview of lncRNAs as regulators of HIFs expression and activation and discusses and highlights potential involved pathways.

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Normoxic Tumour Extracellular Vesicles Modulate the Response of Hypoxic Cancer and Stromal Cells to Doxorubicin In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms21175951 ◽

2020 ◽

Vol 21 (17) ◽

pp. 5951

Author(s):

Laura Patras ◽

Marcel H. A. M. Fens ◽

Pieter Vader ◽

Arjan Barendrecht ◽

Alina Sesarman ◽

...

Keyword(s):

Drug Resistance ◽

Extracellular Vesicles ◽

Hypoxia Inducible Factor ◽

B Cell Lymphoma ◽

Tumour Microenvironment ◽

Hypoxia Inducible Factor 1 ◽

Apoptotic Protein ◽

Donor Cells

Extracellular vesicles (EV) secreted in the tumour microenvironment (TME) are emerging as major antagonists of anticancer therapies by orchestrating the therapeutic outcome through altering the behaviour of recipient cells. Recent evidence suggested that chemotherapeutic drugs could be responsible for the EV-mediated tumour–stroma crosstalk associated with cancer cell drug resistance. Here, we investigated the capacity of tumour EV (TEV) secreted by normoxic and hypoxic (1% oxygen) C26 cancer cells after doxorubicin (DOX) treatment to alter the response of naïve C26 cells and RAW 264.7 macrophages to DOX. We observed that C26 cells were less responsive to DOX treatment under normoxia compared to hypoxia, and a minimally cytotoxic DOX concentration that mounted distinct effects on cell viability was selected for TEV harvesting. Homotypic and heterotypic pretreatment of naïve hypoxic cancer and macrophage-like cells with normoxic DOX-elicited TEV rendered these cells slightly less responsive to DOX treatment. The observed effects were associated with strong hypoxia-inducible factor 1-alpha (HIF-1α) induction and B-cell lymphoma–extra-large anti-apoptotic protein (Bcl-xL)-mediated anti-apoptotic response in normoxic DOX-treated TEV donor cells, being also tightly connected to the DOX-TEV-mediated HIF-1α induction, as well as Bcl-xL levels increasing in recipient cells. Altogether, our results could open new perspectives for investigating the role of chemotherapy-elicited TEV in the colorectal cancer TME and their modulatory actions on promoting drug resistance.

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