Cancer Management and Research (Apr 2019)
CLDN8 promotes colorectal cancer cell proliferation, migration, and invasion by activating MAPK/ERK signaling
Abstract
Bo Cheng,1 Aimei Rong,2 Quanbo Zhou,3 Wenlu Li4 1Department of Emergency Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China; 2Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan 450000, China; 3Department of Anus and Intestine Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China; 4Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China Background: Claudin 8 (CLDN8), an integral membrane protein that constitutes tight junctions in cell membranes, was recently implicated in tumor progression. However, its roles in colorectal cancer (CRC) progression and metastasis remain unknown. Methods: In this study, we examined the effect of CLDN8 on the progression of CRC, including cell proliferation, migration, and invasion, and determines its underlying molecular mechanism using in vitro CRC cell lines and in vivo mouse xenograft models. Results: We found that CLDN8 expression in human CRC tissues was significantly higher than that in adjacent normal tissues. The knockdown of CLDN8 markedly suppressed the proliferation, migration, and invasion of SW480 and HT-29 CRC cells, whereas the overexpression of CLDN8 notably promoted tumor progression in SW480 and HT-29 CRC cells. Mechanistic studies revealed that CLDN8 upregulated p-ERK (p-PKB/AKT) and MMP9 in CRC cells. Notably, the MAPK/ERK inhibitor PD98095 dramatically attenuated the effects of CLDN8 on p-ERK and MMP9. Moreover, PD98095 remarkably blocked the tumor-promoting activity of CLDN8. The knockdown of CLDN8 also inhibited the in vivo tumor growth in a nude mouse xenograft model. Collectively, CLDN8 promoted CRC cell proliferation, migration, and invasion, at least in part, by activating the MAPK/ERK signaling pathway. Conclusion: These findings suggest that CLDN8 exhibits an oncogenic effect in human CRC progression. Keywords: CLDN8, colorectal cancer, MAPK/ERK signaling
