The p53-inducible CLDN7 regulates colorectal tumorigenesis and has prognostic significance

Abstract

Most colorectal cancer (CRC) are characterized by allele loss of the genes located on the short arm of chromosome 17 (17p13.1), including the tumor suppressor p53 gene. Although important, p53 is not the only driver of chromosome 17p loss. In this study, we explored the biological and prognostic significance of genes around p53 on 17p13.1 in CRC. The Cancer Genome Atlas (TCGA) were used to identify differentially expressed genes located between 1000 kb upstream and downstream of p53 gene. The function of CLDN7 was evaluated by both in vitro and in vivo experiments. Quantitative real-time PCR, western blot, and promoter luciferase activity, immunohistochemistry were used to explore the molecular drivers responsible for the development and progression of CRC. The results showed that CLDN7, located between 1000 kb upstream and downstream of p53 gene, were remarkably differentially expressed in tumor and normal tissues. CLDN7 expression also positively associated with p53 level in different stages of the adenoma-carcinoma sequence. Both in vitro and in vivo assays showed that CLDN7 inhibited cell proliferation in p53 wild type CRC cells, but had no effects on p53 mutant CRC cells. Mechanistically, p53 could bind to CLDN7 promoter region and regulate its expression. Clinically, high CLDN7 expression was negatively correlated with tumor size, invasion depth, lymphatic metastasis and AJCC III/IV stage, but was positively associated with favorable prognosis of CRC patients. Collectively, our work uncovers the tumor suppressive function for CLDN7 in a p53-dependent manner, which may mediate colorectal tumorigenesis induced by p53 deletion or mutation.

Androgen receptor variant 7 exacerbates hepatocarcinogenesis in a c-MYC-driven mouse HCC model

“…Claudin 7 is a member of the claudin family that is involved in wide variety of biological processes including tight junction formation, cell polarity, signal transduction, transcription regulation, and mRNA stability [ 39 , 40 ]. Recent studies revealed that the human CLDN7 is upregulated by the p53 signaling pathway and suppresses cell proliferation in various cancer types [ 41 , 42 ]. Hence, we investigated further the expression and function of Cldn7 in the c-MYC-driven HCC mouse model.…”

Is High Expression of Claudin-7 in Advanced Colorectal Carcinoma Associated with a Poor Survival Rate? A Comparative Statistical and Artificial Intelligence Study

“…Consistent with our results, Hou et al who conducted a study to explore the role of Claudin-7, a p53 regulated gene, in tumorigenesis and progression of CRC through quantitative real-time PCR, Western blot, a luciferase reporter assay, and immunohistochemistry, found no correlation between clinicopathological parameters (tumor size, invasion depth, lymphatic metastasis, stage III/IV) and Claudin-7 high expression. In addition, Claudin-7’s high expression was significantly correlated with a favorable prognosis [ 36 ]. However, in contrast with these findings, in our study, the Kaplan–Meier univariate survival analysis, by using the log-rank test and the scatter plots, showed a significant correlation between survival and Claudin-7 intensity in the invasive front ( p = 0.00), where a higher expression was associated with a worse prognosis.…”

Analyses of the expression and prognosis of ILDR1 in human gastric cancer

“…Finally, we used the LinkedOmics web tool to determine the co-altered genes, pathways, and gene ontology associated with ILDR1 in gastric cancer. CLDN7 and CLDN3, which are members of the claudin family and are among the most significantly co-expressed genes, are integral membrane proteins and components of tight junction strands, and genes have been associated with multiple malignancies [ 29 , 30 , 31 ]. The most significantly positively correlated KEGG pathway was steroid hormone biosynthesis, a complex process in which cholesterol is converted into steroid hormones with the participation of various enzymes and cofactors [ 32 ].…”