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

Overview

Journal Med Sci Monit

Specialties General Medicine
Pathology

Date 2019 Dec 30

PMID 31884511

Citations 12

Authors

Wei Guo

Wenyuan Li

Li Yuan

Xianghuang Mei

Wenqing Hu

Affiliations

Soon will be listed here.

Abstract

BACKGROUND 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.

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References

Yang X, Leslie G, Gentry-Maharaj A, Ryan A, Intermaggio M, Lee A . Evaluation of polygenic risk scores for ovarian cancer risk prediction in a prospective cohort study. J Med Genet. 2018; 55(8):546-554. PMC: 6073911. DOI: 10.1136/jmedgenet-2018-105313. View

Hu H, Zhang Q, Chen W, Wu T, Liu S, Li X . MicroRNA-301a promotes pancreatic cancer invasion and metastasis through the JAK/STAT3 signaling pathway by targeting SOCS5. Carcinogenesis. 2019; 41(4):502-514. DOI: 10.1093/carcin/bgz121. View

Zhou X, Xia Y, Li L, Zhang G . MiR-101 inhibits cell growth and tumorigenesis of Helicobacter pylori related gastric cancer by repression of SOCS2. Cancer Biol Ther. 2015; 16(1):160-9. PMC: 4622743. DOI: 10.4161/15384047.2014.987523. View

Fu M, Wang B, Chen X, He Z, Wang Y, Li X . MicroRNA gga-miR-130b Suppresses Infectious Bursal Disease Virus Replication via Targeting of the Viral Genome and Cellular Suppressors of Cytokine Signaling 5. J Virol. 2017; 92(1). PMC: 5730774. DOI: 10.1128/JVI.01646-17. View

Li W, Tibben M, Wang Y, Lebre M, Rosing H, Beijnen J . P-glycoprotein (MDR1/ABCB1) controls brain accumulation and intestinal disposition of the novel TGF-β signaling pathway inhibitor galunisertib. Int J Cancer. 2019; 146(6):1631-1642. DOI: 10.1002/ijc.32568. View

Chan M, Chu E, To K, Leung W . Quantitative detection of methylated SOCS-1 , a tumor suppressor gene, by a modified protocol of quantitative real time methylation-specific PCR using SYBR green and its use in early gastric cancer detection. Biotechnol Lett. 2004; 26(16):1289-93. DOI: 10.1023/B:BILE.0000044922.43572.2d. View

Xiao B, Guo J, Miao Y, Jiang Z, Huan R, Zhang Y . Detection of miR-106a in gastric carcinoma and its clinical significance. Clin Chim Acta. 2008; 400(1-2):97-102. DOI: 10.1016/j.cca.2008.10.021. View

Bartel D . MicroRNAs: target recognition and regulatory functions. Cell. 2009; 136(2):215-33. PMC: 3794896. DOI: 10.1016/j.cell.2009.01.002. View

Menheniott T, Judd L, Giraud A . STAT3: a critical component in the response to Helicobacter pylori infection. Cell Microbiol. 2015; 17(11):1570-82. DOI: 10.1111/cmi.12518. View

10.

Souma Y, Nishida T, Serada S, Iwahori K, Takahashi T, Fujimoto M . Antiproliferative effect of SOCS-1 through the suppression of STAT3 and p38 MAPK activation in gastric cancer cells. Int J Cancer. 2011; 131(6):1287-96. DOI: 10.1002/ijc.27350. View

11.

Torre L, Bray F, Siegel R, Ferlay J, Lortet-Tieulent J, Jemal A . Global cancer statistics, 2012. CA Cancer J Clin. 2015; 65(2):87-108. DOI: 10.3322/caac.21262. View

12.

Tian S, Quan H, Xie C, Guo H, Lu F, Xu Y . YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci. 2011; 102(7):1374-80. PMC: 11158267. DOI: 10.1111/j.1349-7006.2011.01939.x. View

13.

Kabir N, Sun J, Ronnstrand L, Kazi J . SOCS6 is a selective suppressor of receptor tyrosine kinase signaling. Tumour Biol. 2014; 35(11):10581-9. DOI: 10.1007/s13277-014-2542-4. View

14.

Yu H, Lee H, Herrmann A, Buettner R, Jove R . Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer. 2014; 14(11):736-46. DOI: 10.1038/nrc3818. View

15.

Wu Q, Yang Z, Xia L, Nie Y, Wu K, Shi Y . Methylation of miR-129-5p CpG island modulates multi-drug resistance in gastric cancer by targeting ABC transporters. Oncotarget. 2014; 5(22):11552-63. PMC: 4294356. DOI: 10.18632/oncotarget.2594. View

16.

Dong S, Zhang X, Liu D . Overexpression of long noncoding RNA GAS5 suppresses tumorigenesis and development of gastric cancer by sponging miR-106a-5p through the Akt/mTOR pathway. Biol Open. 2019; 8(6). PMC: 6602335. DOI: 10.1242/bio.041343. View

17.

Petrocca F, Visone R, Onelli M, Shah M, Nicoloso M, De Martino I . E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell. 2008; 13(3):272-86. DOI: 10.1016/j.ccr.2008.02.013. View

18.

Shang Y, Zhang Z, Liu Z, Feng B, Ren G, Li K . miR-508-5p regulates multidrug resistance of gastric cancer by targeting ABCB1 and ZNRD1. Oncogene. 2013; 33(25):3267-76. DOI: 10.1038/onc.2013.297. View

19.

Kazi J, Kabir N, Flores-Morales A, Ronnstrand L . SOCS proteins in regulation of receptor tyrosine kinase signaling. Cell Mol Life Sci. 2014; 71(17):3297-310. PMC: 11113172. DOI: 10.1007/s00018-014-1619-y. View

20.

Galm O, Yoshikawa H, Esteller M, Osieka R, Herman J . SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma. Blood. 2002; 101(7):2784-8. DOI: 10.1182/blood-2002-06-1735. View