CREB5 promotes invasiveness and metastasis in colorectal cancer by directly activating MET
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(2020) 39:168
RESEARCH
Open Access
CREB5 promotes invasiveness and metastasis in colorectal cancer by directly activating MET Shuyang Wang1,2,3†, Junfeng Qiu1,2,3†, Lei Liu1,2,3†, Cailin Su1,2,3, Lu Qi1,2,3, Chengmei Huang1,2,3, Xiaoning Chen1,2,3, Yaxin Zhang1,2,3, Yaping Ye1,2,3, Yanqing Ding1,2,3, Li Liang1,2,3* and Wenting Liao1,2,3,4*
Abstract Background: cAMP responsive element binding protein 5 (CREB5) is a transcriptional activator in eukaryotic cells that can regulate gene expression. Previously, we found that CREB5 was involved in the occurrence and development of colorectal cancer (CRC) using bioinformatics analysis. However, the biological roles and underlying regulatory mechanism of CREB5 in CRC remain unclear. Methods: Real-time PCR, western blotting, and immunohistochemistry were used to examine CREB5 expression. In vitro experiments including migration assay, wound-healing assay, chicken chorioallantoic membrane assay, and human umbilical vein endothelial cells tube formation assay were used to investigate the effects of CREB5 on CRC cell migration and tumor angiogenesis ability. Additionally, an orthotopic implantation assay was performed in nude mice to confirm the effects of CREB5 in vivo. Furthermore, gene set enrichment analysis was performed to explore the potential mechanism of CREB5 in CRC. Results: We found that CREB5 expression was highly upregulated in CRC. CREB5 overexpression was positively correlated with advanced WHO stages and TNM stages and shorter survival in CRC patients. Moreover, CREB5 overexpression promoted while CREB5 silencing reduced the invasiveness and metastatic capacity of CRC cells both in vitro and in vivo. Furthermore, CREB5 directly interacted with the MET promoter and activated the hepatocyte growth factor-MET signalling pathway. Importantly, inhibition of MET reduced the invasion and metastasis of CREB5-overexpressing CRC cells, suggesting that CREB5 promotes metastasis mainly through activation of MET signalling. Conclusion: Our study demonstrates a crucial role for CREB5 in CRC metastasis by directly upregulating MET expression. CREB5 may be both a potential prognostic marker and a therapeutic target to effectively overcome metastasis in CRC. Keywords: Colorectal cancer, CREB5, Invasion, Metastasis, MET
* Correspondence: [email protected]; [email protected] † Shuyang Wang, Junfeng Qiu and Lei Liu contributed equally to this work. 1 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the a
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