title: Exploiting a novel miR-519c-HuR-ABCG2 regulatory pathway to overcome chemoresistance in colorectal cancer.
abstract: Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. While surgery remains the mainstay of treatment for early stage CRC, adjuvant chemotherapy is usually given to reduce the risk of recurrence after colectomy. Overexpression of a multidrug resistance (MDR) transporter ABCG2 in vitro has been shown to cause resistance to 5-fluorouracil (5-FU) and irinotecan, components of the most commonly adopted regimens for treating CRC. Both anticancer drugs are known ABCG2 substrates. An effective way to predict drug response may provide guidance for better cancer treatment. We investigated the effect of ABCG2 dysregulation on cancer cell sensitivity to chemotherapy using pairs of snap-frozen paraffin-embedded archival blocks of human colorectal cancer tissues and their matched non-cancerous colon tissues from CRC patients. In CRC patients responding to chemotherapy, the tumors were found to have remarkable lower ABCG2 expression than the adjacent normal colon tissues. On the contrary, the tumors from patients not responding to 5-FU-based chemotherapy have higher ABCG2 level than the adjacent normal tissues. The high ABCG2 expression in the tumor is associated with the concomitant overexpression of the mRNA binding protein HuR but a low expression of miR-519c because miR-519c is known to target both ABCG2 and HuR. Further investigation in CRC cell lines revealed that the ABCG2 overexpression was caused by an interplay between miR-519c, HuR and the length of the 3' untranslated region (UTR) of ABCG2. These parameters may be further developed as useful biomarkers to predict patient response to adjuvant chemotherapy. Besides being predictive biomarkers, the microRNAs and mRNA binding protein identified may also be potential drug targets for modulating ABCG2 to combat resistance in CRC chemotherapy.
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Lo Kwee-Seong Integrated Biomedical Sciences Building, Room 801N, Area 39, Shatin, New Territories, Hong Kong SAR, China. Electronic address: kennethto@cuhk.edu.hk.
authors.forename: Kenneth K W
authors.initials: KK
authors.lastname: To
authors.affiliation: Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: W W
authors.initials: WW
authors.lastname: Leung
authors.affiliation: Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: simonng@surgery.cuhk.edu.hk.
authors.forename: Simon S M
authors.initials: SS
authors.lastname: Ng
mesh_terms: D020413:3' Untranslated Regions / Q000187:drug effects / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D018938:Caco-2 Cells; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000067780:ELAV-Like Protein 1 / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D019073:HT29 Cells; D006801:Humans; D000077146:Irinotecan; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C546194:MIRN519 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin
keywords: ABCG2; Chemoresistance; Colorectal cancer; HuR; MicroRNA