Abstract 791: The predictive value of a novel miR-519c-HuR-ABCG2 regulatory pathway in chemoresistance of colorectal cancer
Authors: Kenneth K.W. To, Wing Wa Leung, Simon S.M. Ng
Journal: Cancer Research (2012)

Abstract Colorectal carcinoma (CRC) is a major cause of mortality and morbidity worldwide. It is curable in early stages but recurrence and metastasis are very common in advanced tumors. While surgery remains the mainstay of treatment for CRC, adjuvant chemotherapy is usually given to reduce the risk of recurrence after colostomy. However, prognosis and response to chemotherapy for the more advanced stages of CRC remain dismal. An effective way to predict drug response could lead to better therapeutic outcome. Multidrug resistance (MDR) is a major unresolved obstacle to successful cancer treatment. It is often associated with increased ABC transporters-mediated efflux of substrate anticancer drugs out of the cell. Overexpression of ABCG2 in vitro has been shown to cause resistance to 5-FU and irinotecan, components of the most commonly adopted regimens for treating CRC. Moreover, elevated tumoral ABCG2 levels have also been shown to confer MDR in patients. Understanding ABCG2 regulation is crucial for targeting ABCG2-mediated MDR. MicroRNAs (miRNAs) represent a large class of short endogenous non-coding RNA that are capable of inducing mRNA degradation and translation repression by forming imperfect hybrids with the 3′untranslated region (3′UTR) of their target mRNAs. We and others have identified and validated three miRNAs (miR-519c, -520h and -328) targeting ABCG2. Interestingly, in ABCG2-overexpressing resistant cancer cell line models, the shortening of the ABCG2 3′UTR was found to be a common phenomenon, which as a result removes the miR-519c binding site and its repressive effects on ABCG2, thereby contributing to drug resistance. In our continuous investigation into this miR-519c-mediated ABCG2 regulation in clinical CRC specimens, we did obtain ABCG2 transcripts with predominantly long or short 3′UTR from ABCG2-overexpressing tumors. For tumors producing the short ABCG2 transcripts, high expression is presumably caused by the removal of miR-519c-mediated repression. On the other hand, a closer look at tumors bearing the long ABCG2 transcripts revealed a novel indirect pathway where low levels of miR-519c promote upregulation of a mRNA-binding protein HuR and subsequently leading to ABCG2 overexpression and increased drug resistance. Detailed mechanistic study confirmed the binding of HuR to the AU-rich elements on ABCG2 3′UTR, thereby enhancing ABCG2 transcript stability. More importantly, a good correlation was observed between low miR-519c expression, high levels of HuR and ABCG2 in the tumor, and poor patients’ response to chemotherapy. Collectively, our findings points to the clinical significance of this novel miR-519c-HuR-ABCG2 axis in determining the response of CRC patients to adjuvant chemotherapy. Besides being predictive biomarkers, miR-519c and HuR could also be potential “druggable” targets for modulating ABCG2-mediated MDR. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 791. doi:1538-7445.AM2012-791