Hypoxia-Autophagy Axis Induces VEGFA by Peritoneal Mesothelial Cells to Promote Gastric Cancer Peritoneal Metastasis Through an Integrin α5-Fibronectin Pathway

Wang, Xiaoxun; Che, Xiaofang; Yu, Yang; Yu, Chongxiu; Bai, Ming; Yang, Zichang; Guo, Qiqiang; Xie, Xiaochen; Li, Danni; Guo, Min; Hou, Kezuo; Guo, Wendong; Qu, Xiujuan; Cao, Lei

doi:10.21203/rs.3.rs-49284/v1

Cited by 8 publications

(11 citation statements)

References 38 publications

(41 reference statements)

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“…An important subtype of the integrin α chain family, ITGA5, forms heterodimers together with integrin β1 (ITGB1). Previous studies have shown that ITGA5 is overexpressed in various cancer types, where it is involved in tumor progression [ 25 – 28 ]. Although its role in glioma has also been reported [ 29 – 31 ], the corresponding upstream and downstream mechanisms of action have not been fully clarified.…”

Section: Introductionmentioning

confidence: 99%

LncRNA NEAT1 Enhances Glioma Progression via Regulating the miR-128-3p/ITGA5 Axis

Chen

Wang

et al. 2021

Mol Neurobiol

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Accumulating evidences indicate that long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) promotes the progression of glioma. In this study, we postulated that NEAT1 may act as a miR-128-3p sponge. Relative levels of NEAT1 and miR-128-3p expression in human glioma samples and GBM cells were detected using quantitative real-time PCR. By means of CCK-8 assays, transwell assays, and flow cytometric analysis, the biological functions of miR-128-3p and NEAT1 were investigated in U87MG and U251MG human GBM cell lines with stable miR-128-3p and NEAT1 knockdown or overexpression. The luciferase reports, RNA pull-down assay, and RNA immunoprecipitation assay were conducted to determine the relevance of NEAT1 and miR-128-3p in glioma. As a result, high expression of NEAT1 and lack of miR-128-3p were observed in glioma specimens and cells. By binding to anti-oncogene miR-128-3p in the nucleus, NEAT1 enhanced tumorigenesis and glioma development. Further experiments suggested that ITGA5 expression was increased in glioma tissues and was found to be connected with miR-128-3p. Additionally, NEAT1 facilitated ITGA5 expression via competitively binding to miR-128-3p. For this reason, ITGA5 would not be decomposed by miR-128-3p and could activate FAK signaling pathway, thereby promoting cell growth. Collectively, these results indicated that the NEAT1/miR-128-3p/ITGA5 axis was involved in glioma initiation and progression, and might offer a potential novel strategy for treatment of glioma.

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Section: Introductionmentioning

confidence: 99%

LncRNA NEAT1 Enhances Glioma Progression via Regulating the miR-128-3p/ITGA5 Axis

Chen

Wang

et al. 2021

Mol Neurobiol

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“…The levels of ROS have been found to be significantly increased in patients with GC, and abnormally high levels of ROS to induce oxidative stress, which can damage the gastric mucosa and be an important factor in the development of GC [29]. In addition, hypoxia can induce autophagy and an acidic extracellular pH through intermediate components or modes, which are also associated with GC progression and chemoresistance [30][31][32][33][34].…”

Section: Introductionmentioning

confidence: 99%

Alteration and dysfunction of ion channels/transporters in a hypoxic microenvironment results in the development and progression of gastric cancer

Chen

Zhang

et al. 2021

Cell Oncol.

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Background Gastric cancer (GC) is one of the most common malignant cancers in the world and has only few treatment options and, concomitantly, a poor prognosis. It is generally accepted now that the tumor microenvironment, particularly that under hypoxia, plays an important role in cancer development. Hypoxia can regulate the energy metabolism and malignancy of tumor cells by inducing or altering various important factors, such as oxidative stress, reactive oxygen species (ROS), hypoxia-inducible factors (HIFs), autophagy and acidosis. In addition, altered expression and/or dysfunction of ion channels/transporters (ICTs) have been encountered in a variety of human tumors, including GC, and to play an important role in the processes of tumor cell proliferation, migration, invasion and apoptosis. Increasing evidence indicates that ICTs are at least partly involved in interactions between cancer cells and their hypoxic microenvironment. Here, we provide an overview of the different ICTs that regulate or are regulated by hypoxia in GC. Conclusions and perspectives Hypoxia is one of the major obstacles to cancer therapy. Regulating cellular responses and factors under hypoxia can inhibit GC. Similarly, altering the expression or activity of ICTs, such as the application of ion channel inhibitors, can slow down the growth and/or migration of GC cells. Since targeting the hypoxic microenvironment and/or ICTs may be a promising strategy for the treatment of GC, more attention should be paid to the interplay between ICTs and the development and progression of GC in such a microenvironment.

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“…Both HIF-1ɑ and HIF-2ɑ promote a more invasive phenotype [33], by activating the epithelial-mesenchymal transition (EMT) program [34][35][36] or cooperating with other strong pro-invasive factors such as Met receptor and soluble hepatocyte growth factor (HGF) [37], or VEGF receptor (VEGFR)/VEGF [38]. Notably, in triple negative breast cancer (TNBC) HIF-1ɑ stimulates the relase of the typical pro-inflammatory cytokine IL-1β that induces a metastatic attitude in both tumor cells and cancer associated fibroblasts (CAFs), creating a TME that strongly favors metastatization [39].…”

Section: Background: the Impact Of Hypoxia On Cancer And Its Microenvironmentmentioning

confidence: 99%

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

Akman

Belisario

Salaroglio

et al. 2021

J Exp Clin Cancer Res

100

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Solid tumors often grow in a micro-environment characterized by < 2% O2 tension. This condition, together with the aberrant activation of specific oncogenic patwhays, increases the amount and activity of the hypoxia-inducible factor-1α (HIF-1α), a transcription factor that controls up to 200 genes involved in neoangiogenesis, metabolic rewiring, invasion and drug resistance. Hypoxia also induces endoplasmic reticulum (ER) stress, a condition that triggers cell death, if cells are irreversibly damaged, or cell survival, if the stress is mild.Hypoxia and chronic ER stress both induce chemoresistance. In this review we discuss the multiple and interconnected circuitries that link hypoxic environment, chronic ER stress and chemoresistance. We suggest that hypoxia and ER stress train and select the cells more adapted to survive in unfavorable conditions, by activating pleiotropic mechanisms including apoptosis inhibition, metabolic rewiring, anti-oxidant defences, drugs efflux. This adaptative process unequivocally expands clones that acquire resistance to chemotherapy.We believe that pharmacological inhibitors of HIF-1α and modulators of ER stress, although characterized by low specificty and anti-cancer efficacy when used as single agents, may be repurposed as chemosensitizers against hypoxic and chemorefractory tumors in the next future.

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Hypoxia-Autophagy Axis Induces VEGFA by Peritoneal Mesothelial Cells to Promote Gastric Cancer Peritoneal Metastasis Through an Integrin α5-Fibronectin Pathway

Cited by 8 publications

References 38 publications

LncRNA NEAT1 Enhances Glioma Progression via Regulating the miR-128-3p/ITGA5 Axis

LncRNA NEAT1 Enhances Glioma Progression via Regulating the miR-128-3p/ITGA5 Axis

Alteration and dysfunction of ion channels/transporters in a hypoxic microenvironment results in the development and progression of gastric cancer

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

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