MicroRNA-106a-3p Induces Apatinib Resistance and Activates Janus-Activated Kinase 2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) by Targeting the SOCS System in Gastric Cancer
Wei Guo, Wenyuan Li, Li Yuan, Xianghuang Mei, Wenqing Hu
Department of Gastrointestinal Surgery, Affiliated Heji Hospital of Changzhi Medical College, Changzhi, Shanxi, China (mainland)
Med Sci Monit 2019; 25:10122-10128
MicroRNA (miR)-106a was involved in the tumorigenesis and highly expressed in gastric cancer. Required apatinib resistance greatly limits its efficacy in patients. Thus, the aim of the present study was to investigate the potential role of miR-106a-3p in gastric cancer cells with apatinib-resistance.
MATERIAL AND METHODS: The expression of miR-106a-3p was quantified by real-time quantitative polymerase chain reaction (RT-qPCR). Cell Counting Kit-8 (CCK-8) assay was performed to analyze the sensitivity of gastric cancer cells to apatinib. The expression of relevant drug-resistant proteins was detected by western blot. We searched Targetscan6.2 to find out the target gene of miR-106a-3p. Luciferase reporter assay was used to analyze whether miR-106a-3p bound to relevant gene of SOCS family. The SOCS2, SOCS4, and SOCS5 were qualified by western blot, and their mRNA levels were detected by RT-qPCR. Further, JAK2, STAT3, and their phosphorylation levels were detected by western blot.
RESULTS: The results showed that the expression of miR-106a-3p was increased in apatinib‑resistant gastric cancer, while miR-106a-3p inhibitor reduced the drug-resistance of SGC-7901-AP cells to apatinib. Dual luciferase reporter gene assay suggested that SOCS2, SOCS4, and SOCS5 were target genes of miR-106a-3p. The relevant SOCS genes silencing reversed the effects of miR-106a-3p inhibitor on decreasing the apatinib resistance of SGC-7901-AP cells, while the phosphorylation level of JAK and STAT reduced by miR-106a-3p inhibitor were increased.
CONCLUSIONS: miR-106a-3p induces apatinib resistance and activates JAK2/STAT3 by targeting SOCS system in gastric cancer. miR-106a-3p/SOCS plays a potent role in gastric cancer cell resistance to apatinib.
Keywords: Drug Resistance, Janus Kinase 2, MicroRNAs, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins