Identification of potential therapeutic target genes to suppress colon cancer liver metastasis

Abstract

Colorectal cancer is the third major cancer worldwide in both sexes. The survival of the colorectal cancer patients depends on the stage of the disease at the moment of initial diagnosis, and the 5-year survival rate of stage IV patients is only less than 15%. Therefore, development of therapeutic strategy targeting metastatic disease is necessary for improving the clinical outcomes of colorectal cancer. This study aims to identify the potential target genes to suppress liver metastasis of colon cancer and to suggest those genes to investigate the key pathways for colon cancer liver metastasis ultimately. First, we established colon cancer liver metastasis clones using HT-29 cell line as a parent cell via orthotropic mouse implantation. Then, next-generation sequencing was performed to identify differentially expressed genes among parent clone and metastatic clones. And several overexpressed genes were selected as target genes. Next, gene network analysis was performed to identify genes showing interactions with those target genes selected at the first step. Lastly, effect of those target genes on cancer cell growth was verified. In conclusion, this study showed overexpression of hTERT in liver metastatic clones. S100A4 and SNAI1, which are known to be related to epithelial-mesenchymal transition, were also overexpressed in liver metastatic clones. NCAM1, NHP2, and MTA3 were newly identified as a linkage between TERT and SNAI1 via gene network analysis, which is a new finding from this study. When those genes were silenced, cancer cell growth was inhibited in metastatic clones. Thus, we suggest these six genes as potential target genes to suppress colon cancer liver metastasis.