Abstract
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 in vitro and xenograft tumor growth in vivo, 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 in vitro 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.
Highlights
Colorectal carcinoma is one of the most common malignancies and a leading cause of cancer-related deaths worldwide [1]
We investigated the role of Human antigen R (HuR) in colorectal cancer tumorigenesis and oxaliplatin (L-OHP) resistance, as well as the underlying mechanisms involving Cell division cycle 6 (CDC6)
We found that HuR promotes colorectal cancer tumorigenesis and L-OHP resistance by upregulating CDC6
Summary
Colorectal carcinoma is one of the most common malignancies and a leading cause of cancer-related deaths worldwide [1]. If the cancer is diagnosed at a very early stage, surgery is curative in >90% of cases. The diagnosis often occurs at stages II/III or later, and neoadjuvant chemotherapy and radiotherapy are sometimes used to shrink the tumor before surgery. Because of the high risk of recurrence and metastasis in advanced cancers, chemotherapy is maintained after colectomy [2]. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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