A Novel Mechanism of Doxorubicin Resistance and Tumorigenesis Mediated by MicroRNA-501-5p-Suppressed BLID

作者：Xu, Yun-chao; Liu, Xu; Li, Min; Li, Yan; Li, Chun-yan; Lu, Ying; Sanches, Jaceline; Wang, Lu; Du, Yue; Mao, Li-min; Zuo, Si-bo; Liu, Hui-ting; Shen, Jie; Wang, Bo; Hou, Li; Li, Lian-hong; Tang, Jian-wu; Ju, Jing-fang; Guan, Hong-wei^*; Song, Bo^*

来源：Molecular Therapy - Nucleic Acids, 2018, 12: 578-590.

DOI：10.1016/j.omtn.2018.06.011

• PROMOTES CELL-PROLIFERATION
• TUMOR-SUPPRESSOR FUNCTION
• ADVANCED GASTRIC-CANCER
• HEPATOCELLULAR-CARCINOMA
• MULTIDRUG-RESISTANCE
• SIGNALING PATHWAY
• UP-REGULATION
• EXPRESSION
• CHEMORESISTANCE
• METHYLATION

Doxorubicin is a widely used anthracycline-based anti-tumor agent for both solid and liquid tumors. Mounting evidence has demonstrated that microRNAs (miRNAs) are involved in chemoresistance and tumorigenesis. However, the roles of microRNA-501-5p (miR-501) in doxorubicin resistance and gastric cancer cell proliferation and invasion are still not fully understood. In this study, we identified that BLID (BH3-like motif-containing protein, cell death inducer) was directly regulated by miR-501 at the post-transcriptional level in multiple gastric cancer cell lines. Endogenous miR-501 was higher, whereas BLID was lower, in doxorubicin-resistant gastric cancer SGC7901/ADR cells compared with their parental SGC7901 cells. miR-501 suppressed gastric cancer cell apoptosis, induced resistance to doxorubicin, and enhanced cell proliferation, migration, and invasion. Subcutaneous injection of miR-501 lentivirus-infected SGC7901 cells resulted in rapid growth of xenograft tumors and resistance to doxorubicin treatment, unlike injection of negative miRNA lentivirus-infected SGC7901 cells. This is achieved at least partially by directly targeting BLID and subsequent inactivation of caspase-9 and caspase-3 and phosphorylation of Akt. Taken together, miR-501 induces doxorubicin resistance and enhances the tumorigenesis of gastric cancer cells by suppressing BLID. miR-501 might be a potential target for doxorubicin resistance and gastric cancer therapy.

• 出版日期2018-9-7
• 单位大连医科大学