Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Mol Cancer Ther. 2019 Jul;18(7):1243-1254. doi: 10.1158/1535-7163.MCT-18-0945. Epub 2019 May 7.
Human antigen R (HuR) is an RNA-binding protein that posttranscriptionally regulates many cancer-trait genes. CDC6, a central regulator of DNA replication, is regulated by HuR. In this study, we investigated the role of HuR in colorectal cancer tumorigenesis and oxaliplatin (L-OHP) resistance, as well as the underlying mechanisms involving CDC6. We detected increased HuR and CDC6 expression, along with a positive correlation between the two in human colorectal cancer tissues. HuR overexpression increased colorectal cancer cell proliferation and xenograft tumor growth , and induced resistance to L-OHP. In contrast, HuR knockdown sensitized colorectal cancer cells to L-OHP. CDC6 overexpression increased while CDC6 knockdown decreased colorectal cancer cell malignant behaviors (growth, DNA synthesis, EMT, migration, and invasion) and L-OHP resistance Moreover, L-OHP resistance induced by HuR overexpression was reversed by CDC6 knockdown. Mechanistically, the results from our luciferase reporter and ribonucleoprotein immunoprecipitation assays indicated that HuR upregulates CDC6 by binding to CDC6 3'-UTR. Taken together, our findings identified HuR's regulation of CDC6 as an essential mechanism driving colorectal cancer tumorigenesis and L-OHP resistance, and this mechanism may represent a potential target for overcoming drug resistance in colorectal cancer.
人抗原 R（HuR）是一种 RNA 结合蛋白，可在后转录水平调节许多癌症特征基因。CDC6 是 DNA 复制的中央调节剂，受 HuR 调控。在这项研究中，我们研究了 HuR 在结直肠癌发生和奥沙利铂（L-OHP）耐药中的作用，以及涉及 CDC6 的潜在机制。我们检测到人类结直肠癌组织中 HuR 和 CDC6 表达增加，且两者呈正相关。HuR 过表达增加结直肠癌细胞增殖和异种移植肿瘤生长，并诱导对 L-OHP 的耐药性。相反，HuR 敲低使结直肠癌细胞对 L-OHP 敏感。CDC6 过表达增加，而 CDC6 敲低减少结直肠癌细胞恶性行为（生长、DNA 合成、EMT、迁移和侵袭）和 L-OHP 耐药性。此外，HuR 过表达诱导的 L-OHP 耐药性被 CDC6 敲低逆转。从我们的荧光素酶报告基因和核糖核蛋白免疫沉淀测定的结果表明，HuR 通过结合 CDC6 3'-UTR 而上调 CDC6。总之，我们的研究结果确定了 HuR 对 CDC6 的调节是驱动结直肠癌发生和 L-OHP 耐药的重要机制，该机制可能代表克服结直肠癌耐药性的潜在靶点。
