Voutsadakis Ioannis A
Algoma District Cancer Program, Sault Area Hospital, Sault Ste Marie, ON P6B 0A8, Canada.
Division of Clinical Sciences, Section of Internal Medicine, Northern Ontario School of Medicine, Sudbury, ON P3E 2C6, Canada.
Curr Issues Mol Biol. 2023 Oct 28;45(11):8670-8686. doi: 10.3390/cimb45110545.
Metastatic colon cancer remains incurable despite improvements in survival outcomes. New therapies based on the discovery of colon cancer genomic subsets could improve outcomes. Colon cancers from genomic studies with publicly available data were examined to define the expression and regulation of the major tight junction proteins claudins and occludin in genomic groups. Putative regulations of the promoters of tight junction genes by colon-cancer-deregulated pathways were evaluated in silico. The effect of claudin mRNA expression levels on survival of colon cancer patients was examined. Common mutations in colon-cancer-related genes showed variable prevalence in genomically identified groups. Claudin genes were rarely mutated in colon cancer patients. Genomically identified groups of colon cancer displayed distinct regulation of claudins and occludin at the mRNA level. Claudin gene promoters possessed clustered sites of binding sequences for transcription factors TCF4 and SMADs, consistent with a key regulatory role of the WNT and TGFβ pathways in their expression. Although an effect of claudin mRNA expression on survival of colon cancer patients as a whole was not prominent, survival of genomic subsets was significantly influenced by claudin mRNA expression. mRNA expression of the main tight junction genes showed differential regulation in various genomically defined subgroups of colon cancer. These data pinpoint a distinct role of claudins and pathways that regulate them in these subgroups and suggest that subgroups of colon cancer should be considered in future efforts to therapeutically target claudins.
尽管生存结局有所改善，但转移性结肠癌仍然无法治愈。基于结肠癌基因组亚群发现的新疗法可能会改善治疗效果。我们研究了来自基因组研究且有公开数据的结肠癌，以确定基因组组中主要紧密连接蛋白claudin和occludin的表达及调控情况。通过计算机模拟评估了结肠癌失调通路对紧密连接基因启动子的假定调控。研究了claudin mRNA表达水平对结肠癌患者生存的影响。结肠癌相关基因的常见突变在基因组鉴定的组中显示出不同的患病率。在结肠癌患者中，claudin基因很少发生突变。基因组鉴定的结肠癌组在mRNA水平上对claudin和occludin表现出不同的调控。claudin基因启动子具有转录因子TCF4和SMADs的结合序列聚类位点，这与WNT和TGFβ通路在其表达中的关键调控作用一致。尽管claudin mRNA表达对总体结肠癌患者生存的影响并不显著，但基因组亚群的生存受到claudin mRNA表达的显著影响。主要紧密连接基因的mRNA表达在结肠癌的各种基因组定义亚组中表现出差异调控。这些数据明确了claudin及其调控通路在这些亚组中的独特作用，并表明在未来针对claudin进行治疗的努力中应考虑结肠癌亚组。
