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

Abstract

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.

• Authors: Bing Liu, Yanfeng Liu, Lifen Zhao, Yue Pan, Yujia Shan, Yang Li, Li Jia
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 56 Issue 12 Pg. 2669-2680 (Dec 2017) ISSN: 1098-2744 [Electronic] United States
• PMID: 28767179 (Publication Type: Journal Article)
• Copyright: © 2017 Wiley Periodicals, Inc.

Chemical References

• 3' Untranslated Regions
• Antimetabolites, Antineoplastic
• MIRN135 microRNA, human
• MicroRNAs
• Mirn182 microRNA, human
• ST6GALNAC2 protein, human
• Sialyltransferases
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Fluorouracil

Topics

• 3' Untranslated Regions (genetics)
• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Apoptosis (drug effects, genetics)
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Colorectal Neoplasms (drug therapy, genetics, metabolism)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Fluorouracil (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Humans
• Mice, Nude
• MicroRNAs (genetics)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Sialyltransferases (genetics, metabolism)
• Signal Transduction (drug effects, genetics)
• Up-Regulation
• Xenograft Model Antitumor Assays