MicroRNA-494 sensitizes colon cancer cells to fluorouracil through regulation of DPYD.

Chemoresistance of colon cancer cells to the chemotherapeutics is still a main obstacle in treatment of this malignancy. The microRNA (miRNA) mediated chemosensitivity regulation in colon cancer cells is still largely unknown. Here we constructed a fluorouracil (5-Fu) resistant SW480 cell line (SW480/5-Fu) and discovered that miRNA miR-494 was down-regulated in the drug resistant cells compared with the parental cells. miR-494 level was found to be correlated with 5-Fu sensitivity in colon cancer cells, and artificial alteration of miR-494 affects the sensitivity of colon cancer cell lines to 5-Fu. miR-494 also promoted apoptosis of colon cancer cells at present of 5-Fu. Importantly, as a regulatory enzyme in the 5-Fu catabolic pathway, DPYD was confirmed to be a direct target of miR-494 through the interaction of miR-494 and its binding site within DPYD 3' untranslated region (3'UTR). miR-494 also negatively regulated endogenous DPYD expression in SW480 cells. Overexpression or knockdown of DPYD could attenuate miR-494 mediated 5-Fu sensitivity regulation, suggesting the dependence of DPYD regulation in miR-494 activity. miR-494 inhibited SW480/5-Fu derived xenograft tumors growth in vivo at present of 5-Fu. Thus, we concluded that in colon cancer cells, tumor suppressor miR-494 enhanced 5-Fu sensitivity via regulation of DPYD expression.

Chai J ，Dong W ，Xie C ，Wang L ，Han DL ，Wang S ，Guo HL ，Zhang ZL ... -  《-》

Inhibition of lactate dehydrogenase A by microRNA-34a resensitizes colon cancer cells to 5-fluorouracil.

Li X ，Zhao H ，Zhou X ，Song L ... -  《-》

Targeting miR-21 enhances the sensitivity of human colon cancer HT-29 cells to chemoradiotherapy in vitro.

5-Fluorouracil (5-FU) is a classic chemotherapeutic drug that has been widely used for colorectal cancer treatment, but colorectal cancer cells are often resistant to primary or acquired 5-FU therapy. Several studies have shown that miR-21 is significantly elevated in colorectal cancer. This suggests that this miRNA might play a role in this resistance. In this study, we investigated this possibility and the possible mechanism underlying this role. We showed that forced expression of miR-21 significantly inhibited apoptosis, enhanced cell proliferation, invasion, and colony formation ability, promoted G1/S cell cycle transition and increased the resistance of tumor cells to 5-FU and X radiation in HT-29 colon cancer cells. Furthermore, knockdown of miR-21 reversed these effects on HT-29 cells and increased the sensitivity of HT-29/5-FU to 5-FU chemotherapy. Finally, we showed that miR-21 targeted the human mutS homolog2 (hMSH2), and indirectly regulated the expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). These results demonstrate that miR-21 may play an important role in the 5-FU resistance of colon cancer cells.

Deng J ，Lei W ，Fu JC ，Zhang L ，Li JH ，Xiong JP ... -  《-》

Upregulation of microRNA-135b and microRNA-182 promotes chemoresistance of colorectal cancer by targeting ST6GALNAC2 via PI3K/AKT pathway.

MicroRNAs (miRNAs) are increasingly involved in the development of drug resistance, including 5-fluorouracil (5-FU) resistance in colorectal cancer (CRC). Aberrant sialylation is correlated with human CRC. The study was to explore whether miR-135b and miR-182 modulated 5-FU chemoresistance of CRC by targeting ST6GALNAC2 via PI3K/AKT pathway. MiR-135b and miR-182 were found to be up-regulated in CRC tissues and 5-FU resistant CRC cell lines. Forced miR-135b and miR-182 expression also affected ST6GALNAC2 levels. Using reporter-gene assay, ST6GALNAC2 was identified as direct target of miR-135b and miR-182, while ST6GALNAC2 expression exhibited patterns opposite to that of miR-135b and miR-182 in CRC samples and cell lines. Interestingly, up-regulation of miR-135b or miR-182 increased drug resistance and proliferation, but decreased apoptosis in 5-FU resistant CRC cell lines. Suppression of these miRNAs implicated an inverse function, while altered expression of ST6GALNAC2 mediated CRC progression upon transfection with miR-135b/-182 mimic or inhibitor. Furthermore, miR-135b and miR-182 were clarified to regulate the activity of phosphoinositide-3 kinase (PI3K)/AKT pathway. Inhibition of the PI3K/AKT pathway enhanced the chemosensitivity to 5-FU in HCT-8/5-FU and LoVo/5-FU. Taken together, miR-135b and miR-182 may reverse the resistance to 5-FU in CRC cells by targeting ST6GALNAC2 via PI3K/AKT pathway, which render potential chemotherapy targets for the treatment of CRC.

Liu B ，Liu Y ，Zhao L ，Pan Y ，Shan Y ，Li Y ，Jia L ... -  《-》

Overexpressing microRNA-34a overcomes ABCG2-mediated drug resistance to 5-FU in side population cells from colon cancer via suppressing DLL1.

Colon cancer side population (SP) cells are a small subset of cancer cells that have cancer stemness capacity and enhanced drug resistance. ABCG2 is a multidrug resistance-related protein in SP cells and has been demonstrated to be regulated by Notch signalling pathway. Recently, microRNAs are reported to play a critical role in SP cell fate. However, their role in ABCG2-mediated drug resistance in colon cancer SP cells remains unclear. In the current study, the different expressions of miR-552, miR-611, miR-34a and miR-5000-3p were compared within SP and non-SP cells, which were separated from human colon cancer cell lines (SW480 and LoVo). We found that miR-34a was significantly down-regulated in SP cells and that overexpressing miR-34a overcame drug resistance to 5-fluorouracil (5-FU). The luciferase reporter assay indicated that miR-34a negatively regulated DLL1, a ligand of Notch signalling pathway, via binding with 3'-untranslated region of its messenger RNA. In addition, overexpressing miR-34a overcame ABCG2-mediated resistance to 5-FU via DLL1/Notch pathway in vitro, and suppressed tumour growth under 5-FU treatment in vivo. In conclusion, our findings suggest that miR-34a acts as a tumour suppressor via enhancing chemosensitivity to 5-FU in SP cells, which provides a novel therapeutic target in chemotherapy-resistant colon cancer.

Xie ZY ，Wang FF ，Xiao ZH ，Liu SF ，Tang SL ，Lai YL ... -  《-》