Kiyoko Takane

Background Abnormal activation of Wnt/β‐catenin signaling is associated with various aspects of cancer development. This study explored the roles of novel target genes of the Wnt/β‐catenin signaling pathway in cancer cells. Methods Using the haploid chronic myelogenous leukemia cell line HAP1, RNA sequencing (RNA‐seq) was performed to identify genes whose expression was increased by APC disruption and reversed by β‐catenin knockdown (KD). The regulatory mechanism and function of one of the candidate genes was investigated in colorectal cancer (CRC) cells. Results In total, 64 candidate genes whose expression was regulated by Wnt/β‐catenin signaling were identified. Of these candidate genes, the expression levels of six were reduced by β‐catenin KD in HCT116 CRC cells in our previous microarray. One of these genes was Visinin‐like 1 ( VSNL1 ), which belongs to the neuronal calcium‐sensor gene family. The expression of VSNL1 was regulated by the β‐catenin/TCF7L2 complex via two TCF7L2‐binding elements in intron 1. VSNL1 KD‐induced apoptosis in VSNL1‐positive CRC cells. Additionally, forced expression of wild‐type VSNL1, but not a myristoylation, Ca 2+ ‐binding, or dimerization‐defective mutant, suppressed the apoptosis induced by camptothecin and doxorubicin in VSNL1‐negative CRC cells. Conclusion Our findings suggest that VSNL1 , a novel target gene of the Wnt/β‐catenin signaling pathway, is associated with apoptosis resistance in CRC cells.

The Wnt/β‐catenin signaling pathway plays a key role in development and carcinogenesis. Although some target genes of this signaling have been identified in various tissues and neoplasms, the comprehensive understanding of the target genes and their roles in the development of human cancer, including hepatoma and colorectal cancer remain to be fully elucidated. In this study, we searched for genes regulated by the Wnt signaling in liver cancer using HuH‐7 hepatoma cells. A comparison of the expression profiles between cells expressing an active form of mutant β‐catenin and cells expressing enhanced green fluorescent protein (EGFP) identified seven genes upregulated by the mutant β‐catenin gene ( CTNNB1 ). Among the seven genes, we focused in this study on ODAM , odontogenic, ameloblast associated, as a novel target gene. Interestingly, its expression was frequently upregulated in hepatocellular carcinoma, colorectal adenocarcinoma, and hepatoblastoma. We additionally identified a distant enhancer region that was associated with the β‐catenin/TCF7L2 complex. Further analyses revealed that ODAM plays an important role in the regulation of the cell cycle, DNA synthesis, and cell proliferation. These data may be useful for clarification of the main molecular mechanism(s) underlying these cancers.