DJ-1 promotes survival of human colon cancer cells under hypoxia by modulating HIF-1α expression through the PI3K-AKT pathway
Authors Zheng H, Zhou C, Lu X, Liu Q, Liu M, Chen G, Chen W, Wang S, Qiu Y
Received 23 April 2018
Accepted for publication 13 July 2018
Published 16 October 2018 Volume 2018:10 Pages 4615—4629
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Colin Mak
Peer reviewer comments 3
Editor who approved publication: Professor Nakshatri
Hong Zheng,1,* Chao Zhou,2,* Xiao Lu,1 Quanxing Liu,1 Minqiang Liu,2 Guoqing Chen,2 Weigang Chen,2 Shuai Wang,2 Yuan Qiu2
1Department of Thoracic Surgery of Xinqiao Hospital, The Third Military Medical University, Shapingba, 400037, Chongqing, People’s Republic of China; 2Department of General Surgery of Xinqiao Hospital, The Third Military Medical University, Shapingba, 400037, Chongqing, People’s Republic of China
*These authors contributed equally to this work
Background: 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.
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-p110α, phosphorylated Akt (p-AKT), and HIF-1α 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-1α 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-p110α, p-AKT, and HIF-1α expression in CRC. HIF-1α 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-1α was partially preserved after treatment with PI3K inhibitors. We also show that DJ-1 is necessary for the transcriptional ability of HIF-1α 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-1α pathway.
Keywords: DJ-1, hypoxia-inducible factor-1α, phosphatidylinositol 3-kinase, phosphorylated Akt, colorectal cancer
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