Exploiting a novel miR-519c-HuR-ABCG2 regulatory pathway to overcome chemoresistance in colorectal cancer.

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.

To KK ，Leung WW ，Ng SS 《-》

Posttranscriptional Regulation of Human Antigen R by miR-133b Enhances Docetaxel Cytotoxicity Through the Inhibition of ATP-Binding Cassette Subfamily G Member 2 in Prostate Cancer Cells.

Liu H ，Song X ，Hou J ，Zhao Z ，Chang J ... -  《-》

Correlation between the promoter methylation status of ATP-binding cassette sub-family G member 2 and drug sensitivity in colorectal cancer cell lines.

Moon HH ，Kim SH ，Ku JL 《-》

A novel miR-203-DNMT3b-ABCG2 regulatory pathway predisposing colorectal cancer development.

Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. The majority of studies to date focused on genetic mutations and epigenetic changes that drive the CRC carcinogenesis process. Xenobiotic transporters play an important role in safeguarding our body from external toxic substances. These transporters lining the gastrointestinal tract protect us from dietary carcinogens. This study aimed to investigate the downregulation of an efflux transporter ABCG2 in CRC versus normal colon mucosa, so as to shed light on its relevance to CRC initiation and progression. We found that ABCG2 expression is at least 50-fold lower in adenomatous polyps and colon carcinoma specimens obtained from CRC patients than in their matched pair of adjacent normal colon mucosa. The underlying mechanism(s) for ABCG2 under-expression in CRC is currently not known. To this end, aberrant promoter methylation of ABCG2 has been reported to cause its repression in a few cancer types including renal carcinoma and multiple myeloma. In this study, miR-203 was found to be downregulated in all polyps and CRC specimens, relative to adjacent normal colon mucosa. We demonstrated that the de novo DNA methyltransferase DNMT3b is a direct target of miR-203. Importantly, by relieving the repression on DNMT3b, the lower expression of miR-203 in CRC caused ABCG2 promoter methylation and remarkable lower ABCG2 expression in colon cancer cell lines and the patient CRC specimens. The restoration of ABCG2 function via modulating this new microRNA-methylation mechanism in precancerous cells may represent an attractive strategy to delay the carcinogenesis process. © 2016 Wiley Periodicals, Inc.

To KK ，Leung WW ，Ng SS 《-》

Escape from hsa-miR-519c enables drug-resistant cells to maintain high expression of ABCG2.

To KK ，Robey RW ，Knutsen T ，Zhan Z ，Ried T ，Bates SE ... -  《-》