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DJ-1 promotes survival of human colon cancer cells under hypoxia by modulating HIF-1? expression through the PI3K-AKT pathway.

ABSTRACT: Background:Protein/nucleic acid deglycase (DJ-1) and hypoxia-inducible factor-1? (HIF-1?) play significant roles in the progression of various types of cancer and are associated with the phosphatidylinositol 3-kinase (PI3K) pathway. However, their functions in colorectal cancer (CRC) have not been identified. The aim of this study was to analyze the putative signaling pathway encompassing DJ-1, PI3K, and HIF-1? in a series of CRC tissues and cell lines. Purpose:This study aimed at exploring the expression status of DJ-1 in colon cancer and its role in survival of cancer cell lines. Methods:The expression and localization of DJ-1, PI3K-p110?, phosphorylated Akt (p-AKT), and HIF-1? were determined by immunohistochemistry in 73 resected CRC tissues. The effect of DJ-1 on cell activity was explored by in vitro knockdown and overexpression experiments in SW480 and HT-29 cells. The cells were treated with a PI3K inhibitor (LY294002 or wortmannin), and p-AKT and HIF-1? protein expression were then analyzed. Apoptosis was analyzed by flow cytometry. The expression levels of several HIF-1 target genes were assessed under hypoxic conditions by reverse transcription-PCR and Western blot. Xenograft tumor growth studies were conducted in DJ-1 knockdown or overexpression cells. Results:High DJ-1 expression was found in 68.49% (50/73) of CRC tissues and associated with larger tumor size and advanced clinical stages. DJ-1 expression was positively associated with PI3K-p110?, p-AKT, and HIF-1? expression in CRC. HIF-1? and p-AKT protein levels were lower in SW480 and HT-29 cells with stable DJ-1 knockdown than in those with DJ-1 overexpression. PI3K inhibitors almost completely blocked DJ-1-induced AKT phosphorylation. However, the expression of HIF-1? was partially preserved after treatment with PI3K inhibitors. We also show that DJ-1 is necessary for the transcriptional ability of HIF-1? and CRC cell survival after hypoxic stress. Moreover, DJ-1 promoted the growth of established tumor xenografts in nude mice. Conclusion:Our findings are the first to show that DJ-1 is overexpressed in CRC. We suggest a model in which DJ-1 mediates CRC cell survival by regulating the PI3K-AKT-HIF-1? pathway.

SUBMITTER: Zheng H

PROVIDER: S-EPMC6199970 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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DJ-1 promotes survival of human colon cancer cells under hypoxia by modulating HIF-1α expression through the PI3K-AKT pathway.

Zheng Hong H Zhou Chao C Lu Xiao X Liu Quanxing Q Liu Minqiang M Chen Guoqing G Chen Weigang W Wang Shuai S Qiu Yuan Y

Cancer management and research 20181016

<h4>Background</h4>Protein/nucleic acid deglycase (DJ-1) and hypoxia-inducible factor-1α (HIF-1α) play significant roles in the progression of various types of cancer and are associated with the phosphatidylinositol 3-kinase (PI3K) pathway. However, their functions in colorectal cancer (CRC) have not been identified. The aim of this study was to analyze the putative signaling pathway encompassing DJ-1, PI3K, and HIF-1α in a series of CRC tissues and cell lines.<h4>Purpose</h4>This study aimed at ...[more]

PMID: 30410397

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Dataset Information

DJ-1 promotes survival of human colon cancer cells under hypoxia by modulating HIF-1? expression through the PI3K-AKT pathway.

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DJ-1 promotes survival of human colon cancer cells under hypoxia by modulating HIF-1α expression through the PI3K-AKT pathway.

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