Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 14, 2015; 21(34): 9887-9899
Published online Sep 14, 2015. doi: 10.3748/wjg.v21.i34.9887
Dexamethasone inhibits hypoxia-induced epithelial-mesenchymal transition in colon cancer
Jung Ho Kim, You-Jin Hwang, Sang Hoon Han, Young Eun Lee, Saerom Kim, Yoon Jae Kim, Jae Hee Cho, Kwang An Kwon, Ju Hyun Kim, Se-Hee Kim
Jung Ho Kim, Young Eun Lee, Saerom Kim, Yoon Jae Kim, Jae Hee Cho, Kwang An Kwon, Ju Hyun Kim, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 405-760, South Korea
You-Jin Hwang, Division of Biological Science, Gachon University of Medicine and Science, Incheon 406-799, South Korea
Sang Hoon Han, Department of Internal Medicine, Jeju National University School of Medicine, Jeju-si 890-716, South Korea
Se-Hee Kim, Gachon Medical Research Institute, Gachon University Gil Medical Center, Incheon 405-760, South Korea
Author contributions: Kim JH performed the research and wrote the manuscript; Han SH, Lee YE, and Kim S edited and provided critical revisions of the manuscript; Hwang YJ, Kim YJ, and Cho JH analyzed the data; Kim JH and Kim SH coordinated and supervised this work; Kim JH and Kim SH contributed equally to this work and were corresponding authors.
Supported by A grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea, No. HI13C-1602-010014); and grants of the Gachon University Gil Medical Center, No. 2013-01, 2014-11 and 2014-25.
Conflict-of-interest statement: The authors have declared that no competing interests exist.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Se-Hee Kim, PhD, Gachon Medical Research Institute, Gachon University Gil Medical Center, 21 Namdong-daero 774 beon-gil, Namdong-gu, Incheon 405-760, South Korea. sehee0423@gilhospital.com
Telephone: +82-32-4608470 Fax: +82-32-4608470
Received: March 20, 2015
Peer-review started: March 21, 2015
First decision: April 13, 2015
Revised: May 16, 2015
Accepted: July 8, 2015
Article in press: July 8, 2015
Published online: September 14, 2015
Processing time: 178 Days and 6 Hours
Abstract

AIM: To elucidate the effects of dexamethasone on hypoxia-induced epithelial-to-mesenchymal transition (EMT) in colon cancer.

METHODS: Human colon cancer HCT116 and HT29 cells were exposed to normoxic (21%) and hypoxic (1%) conditions. First, the effect of dexamethasone on cell viability was examined by MTT cell proliferation assay. In order to measure the expression levels of EMT markers (Snail, Slug, Twist, E-cadherin, and integrin αVβ6) and hypoxia-related genes [Hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF)] by dexamethasone, quantitative real-time polymerase chain reaction and western blot analysis were performed. Furthermore, the morphological changes of colon cancer cells and the expression pattern of E-cadherin by dexamethasone were detected through immunocytochemistry. Finally, the effects of dexamethasone on the invasiveness and migration of colon cancer cells were elucidated using matrigel invasion, migration, and wound healing migration assays.

RESULTS: Under hypoxia, dexamethasone treatment inhibited HIF-1α protein level and its downstream gene, VEGF mRNA level in the colon cancer cell lines, HCT116 and HT29. In addition, the presence of dexamethasone down-regulated the mRNA levels of hypoxia-induced Snail, Slug, and Twist, all transcriptional factors of EMT, as well as hypoxia-induced integrin αVβ6 protein level, a well-known EMT marker for colon cancer cells. Furthermore, reduced E-cadherin in hypoxic condition was found to be recoverable by treating with dexamethasone in both colon cancer cell lines. Similarly, under hypoxic conditions, dexamethasone restored the growth pattern and morphological phenotype reminiscent of colon cancer cells grown under normoxic conditions; dexamethasone blocked the migration and invasion of both colorectal cancer cell lines in hypoxia.

CONCLUSION: Our study suggested that dexamethasone has inhibitory effects on cell migration and invasion by suppressing EMT of colon cancer cell lines in hypoxic condition.

Keywords: Dexamethasone; Colon cancer; Hypoxia; Hypoxia-inducible factor-1α; Epithelial-mesenchymal transition

Core tip: In solid tumors, the heightened metabolism of cancer cells often leads to areas of hypoxia that can drive epithelial-mesenchymal transition (EMT). Dexamethasone is often given to patients with colon cancer to limit the negative side effects of chemotherapy. Our study investigated the effects of dexamethasone on hypoxia-induced EMT and found that it was sufficient to block the propensity for cells to undergo EMT by repressing the hypoxia-induced expression of Hypoxia-inducible factor-1α, vascular endothelial growth factor and other EMT markers. This evidence suggests that dexamethasone co-treatment may limit the migratory properties of colorectal cancer cells that subsist in the hypoxic regions of colorectal cancers.