Gastric cancer (GC) is one of the leading causes of human mortality around the world. We have previously shown that Gαi1 (the inhibitory subunit 1 of the heterotrimeric guanine nucleotide-binding protein) recruitment to ligand-activated receptor tyrosine kinases (RTKs) is essential for signaling. Testing its role in GC cancer-promoting functions, we found that Gαi1 is upregulated in human GC, correlating with poor overall survival. In established and primary human GC cells, Gαi1 shRNA (small hairpin RNA) or knockout produced significant anti-GC cell activity, proliferation and migration was inhibited, and apoptosis was activated. Conversely, ectopic Gαi1 overexpression promoted proliferation and migration of GC cells in vitro. By examining the tumor-suppressive miRNA microRNA-200a (miR-200a), we found that miR-200a directly silenced Gαi1 to induce anti-GC cell activity. The expression of miR-200a was downregulated in human GC, correlating with upregulation of a novel miR-200a-targeting long non-coding RNA (LncRNA), PINK1 (PTEN Induced Kinase 1)-AS. RNA immunoprecipitation, RNA-pull down, and RNA fluorescence in situ hybridization assays confirmed that PINK1-AS directly binds to miR-200a. Silencing PINK1-AS in GC cells led to miR-200a accumulation, Gαi1 downregulation, and inhibition of GC cell progression in vitro, whereas PINK1-AS upregulation produced the converse results. Significantly, anti-GC cell activity induced by PINK1-AS shRNA was ameliorated by the expression of miR-200a antisense or the 3ʹ-UTR (untranslated region)-depleted Gαi1. In vivo, the growth of subcutaneous MGC-803 xenografts in nude mice was inhibited by PINK1-AS shRNA, but accelerated by PINK1-AS overexpression. Patient-derived GC xenograft growth in nude mice was largely inhibited after intratumoral injection of PINK1-AS shRNA lentivirus. In conclusion, PINK1-AS promotes Gαi1-driven GC progression by sponging miR-200a.
Subscribe to Journal
Get full journal access for 1 year
only $7.98 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA: a cancer J clinicians. 2020;70:7–30.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: a cancer J clinicians. 2019;69:7–34.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer J clinicians. 2018;68:7–30.
Shah MA. Gastrointestinal cancer: targeted therapies in gastric cancer-the dawn of a new era. Nat Rev Clin Oncol. 2014;11:10–11.
Wadhwa R, Song S, Lee JS, Yao Y, Wei Q, Ajani JA. Gastric cancer-molecular and clinical dimensions. Nat Rev Clin Oncol. 2013;10:643–55.
Cao C, Huang X, Han Y, Wan Y, Birnbaumer L, Feng GS, et al. Galpha(i1) and Galpha(i3) are required for epidermal growth factor-mediated activation of the Akt-mTORC1 pathway. Sci Signal. 2009;2:ra17.
Sun J, Huang W, Yang SF, Zhang XP, Yu Q, Zhang ZQ, et al. Galphai1 and Galphai3mediate VEGF-induced VEGFR2 endocytosis, signaling and angiogenesis. Theranostics. 2018;8:4695–709.
Marshall J, Zhou XZ, Chen G, Yang SQ, Li Y, Wang Y, et al. Antidepression action of BDNF requires and is mimicked by Galphai1/3 expression in the hippocampus. Proc Natl Acad Sci U.S.A. 2018;115:E3549–58.
Liu YY, Chen MB, Cheng L, Zhang ZQ, Yu ZQ, Jiang Q, et al. MicroRNA-200a downregulation in human glioma leads to Galphai1 over-expression, Akt activation, and cell proliferation. Oncogene. 2018;37:2890–902.
Niu ZS, Niu XJ, Wang WH. Long non-coding RNAs in hepatocellular carcinoma: potential roles and clinical implications. World J Gastroenterol. 2017;23:5860–74.
Huo X, Han S, Wu G, Latchoumanin O, Zhou G, Hebbard L, et al. Dysregulated long noncoding RNAs (lncRNAs) in hepatocellular carcinoma: implications for tumorigenesis, disease progression, and liver cancer stem cells. Mol cancer. 2017;16:165.
Yang X, Xie X, Xiao YF, Xie R, Hu CJ, Tang B, et al. The emergence of long non-coding RNAs in the tumorigenesis of hepatocellular carcinoma. Cancer Lett. 2015;360:119–24.
Ma L, Cao J, Liu L, Du Q, Li Z, Zou D, et al. LncBook: a curated knowledgebase of human long non-coding RNAs. Nucleic acids Res. 2019;47:D128–34.
Statello L, Guo CJ, Chen LL, Huarte M. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol cell Biol. 2021;22:96–118.
Tan H, Zhang S, Zhang J, Zhu L, Chen Y, Yang H, et al. Long non-coding RNAs in gastric cancer: new emerging biological functions and therapeutic implications. Theranostics. 2020;10:8880–902.
Xie S, Chang Y, Jin H, Yang F, Xu Y, Yan X, et al. Non-coding RNAs in gastric cancer. Cancer Lett. 2020;493:55–70.
Hao NB, He YF, Li XQ, Wang K, Wang RL. The role of miRNA and lncRNA in gastric cancer. Oncotarget. 2017;8:81572–82.
Li H, Yu B, Li J, Su L, Yan M, Zhu Z, et al. Overexpression of lncRNA H19 enhances carcinogenesis and metastasis of gastric cancer. Oncotarget. 2014;5:2318–29.
Zhao J, Du P, Cui P, Qin Y, Hu C, Wu J, et al. LncRNA PVT1 promotes angiogenesis via activating the STAT3/VEGFA axis in gastric cancer. Oncogene. 2018;37:4094–109.
Li Y, Wu Z, Yuan J, Sun L, Lin L, Huang N, et al. Long non-coding RNA MALAT1 promotes gastric cancer tumorigenicity and metastasis by regulating vasculogenic mimicry and angiogenesis. Cancer Lett. 2017;395:31–44.
Sun M, Nie F, Wang Y, Zhang Z, Hou J, He D, et al. LncRNA HOXA11-AS promotes proliferation and invasion of gastric cancer by scaffolding the chromatin modification factors PRC2, LSD1, and DNMT1. Cancer Res. 2016;76:6299–310.
Peng W, Si S, Zhang Q, Li C, Zhao F, Wang F, et al. Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate gastric cancer progression. J Exp Clin cancer Res: CR. 2015;34:79.
Wei GH, Wang X. lncRNA MEG3 inhibit proliferation and metastasis of gastric cancer via p53 signaling pathway. Eur Rev Med Pharmacol Sci. 2017;21:3850–6.
Qi P, Xu MD, Shen XH, Ni SJ, Huang D, Tan C, et al. Reciprocal repression between TUSC7 and miR-23b in gastric cancer. Int J cancer. 2015;137:1269–78.
Dan J, Wang J, Wang Y, Zhu M, Yang X, Peng Z, et al. LncRNA-MEG3 inhibits proliferation and metastasis by regulating miRNA-21 in gastric cancer. Biomed Pharmacother. 2018;99:931–8.
Chen W, Chen M, Xu Y, Chen X, Zhou P, Zhao X, et al. Long non-coding RNA THOR promotes human osteosarcoma cell growth in vitro and in vivo. Biochemical biophysical Res Commun. 2018;499:913–9.
Feng L, Li H, Li F, Bei S, Zhang X. LncRNA KCNQ1OT1 regulates microRNA-9-LMX1A expression and inhibits gastric cancer cell progression. Aging. 2020;12:707–17.
Zhang X, Li J, Li F, Zhao Z, Feng L. LINC00682 inhibits gastric cancer cell progression via targeting microRNA-9-LMX1A signaling axis. Aging. 2019;11:11358–68.
Yang L, Zheng LY, Tian Y, Zhang ZQ, Dong WL, Wang XF, et al. C6 ceramide dramatically enhances docetaxel-induced growth inhibition and apoptosis in cultured breast cancer cells: a mechanism study. Exp Cell Res. 2015;332:47–59.
Wang W, Xu S, Yin M, Jin ZG. Essential roles of Gab1 tyrosine phosphorylation in growth factor-mediated signaling and angiogenesis. Int J Cardiol. 2015;181:180–4.
Zhang YM, Zhang ZQ, Liu YY, Zhou X, Shi XH, Jiang Q, et al. Requirement of Galphai1/3-Gab1 signaling complex for keratinocyte growth factor-induced PI3K-AKT-mTORC1 activation. J Invest Dermatol. 2015;135:181–91.
Li PH, Wu JX, Zheng JN, Pei DS. A sphingosine kinase-1 inhibitor, SKI-II, induces growth inhibition and apoptosis in human gastric cancer cells. Asian Pac J Cancer Prev. 2014;15:10381–5.
Ji D, Zhang Z, Cheng L, Chang J, Wang S, Zheng B, et al. The combination of RAD001 and MK-2206 exerts synergistic cytotoxic effects against PTEN mutant gastric cancer cells: involvement of MAPK-dependent autophagic, but not apoptotic cell death pathway. PloS ONE. 2014;9:e85116.
Shrestha S, Hsu SD, Huang WY, Huang HY, Chen W, Weng SL, et al. A systematic review of microRNA expression profiling studies in human gastric cancer. Cancer Med. 2014;3:878–88.
Chen Z, Saad R, Jia P, Peng D, Zhu S, Washington MK, et al. Gastric adenocarcinoma has a unique microRNA signature not present in esophageal adenocarcinoma. Cancer. 2013;119:1985–93.
Mirzaei S, Baghaei K, Parivar K, Hashemi M, Asadzadeh, Aghdaei H. The expression level changes of microRNAs 200a/205 in the development of invasive properties in gastric cancer cells through epithelial-mesenchymal transition. Eur J Pharmacol. 2019;857:172426.
Guo T, Zhang Y, Qu X, Che X, Li C, Fan Y, et al. miR-200a enhances TRAIL-induced apoptosis in gastric cancer cells by targeting A20. Cell Biol Int. 2018;42:506–14.
Li D, Wang J, Zhang M, Hu X, She J, Qiu X, et al. LncRNA MAGI2-AS3 is regulated by BRD4 and promotes gastric cancer progression via maintaining ZEB1 overexpression by sponging miR-141/200a. Mol Ther Nucleic acids. 2020;19:109–23.
Gu Y, Chen T, Li G, Yu X, Lu Y, Wang H, et al. LncRNAs: emerging biomarkers in gastric cancer. Future Oncol. 2015;11:2427–41.
Sun M, Nie FQ, Wang ZX, De W. Involvement of lncRNA dysregulation in gastric cancer. Histol Histopathol. 2016;31:33–9.
Yuan L, Xu ZY, Ruan SM, Mo S, Qin JJ, Cheng XD. Long non-coding RNAs towards precision medicine in gastric cancer: early diagnosis, treatment, and drug resistance. Mol cancer. 2020;19:96.
Liu HT, Liu S, Liu L, Ma RR, Gao P. EGR1-mediated transcription of lncRNA-HNF1A-AS1 promotes cell-cycle progression in gastric cancer. Cancer Res. 2018;78:5877–90.
Zhang G, Li S, Lu J, Ge Y, Wang Q, Ma G, et al. LncRNA MT1JP functions as a ceRNA in regulating FBXW7 through competitively binding to miR-92a-3p in gastric cancer. Mol cancer. 2018;17:87.
Sun TT, He J, Liang Q, Ren LL, Yan TT, Yu TC, et al. LncRNA GClnc1 promotes gastric carcinogenesis and may act as a modular scaffold of WDR5 and KAT2A complexes to specify the histone modification pattern. Cancer Discov. 2016;6:784–801.
He W, Liang B, Wang C, Li S, Zhao Y, Huang Q, et al. MSC-regulated lncRNA MACC1-AS1 promotes stemness and chemoresistance through fatty acid oxidation in gastric cancer. Oncogene. 2019;38:4637–54.
Hedner C, Borg D, Nodin B, Karnevi E, Jirstrom K, Eberhard J. Expression and prognostic significance of human epidermal growth factor receptors 1 and 3 in gastric and esophageal adenocarcinoma. PloS ONE. 2016;11:e0148101.
Satoh T, Lee KH, Rha SY, Sasaki Y, Park SH, Komatsu Y, et al. Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second-line therapy for patients with advanced gastric cancer. Gastric Cancer. 2015;18:824–32.
Satoh T, Xu RH, Chung HC, Sun GP, Doi T, Xu JM, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN-a randomized, phase III study. J Clin Oncol. 2014;32:2039–49.
Wong H, Yau T. Molecular targeted therapies in advanced gastric cancer: does tumor histology matter? Therapeutic Adv Gastroenterol. 2013;6:15–31.
Park CK, Park JS, Kim HS, Rha SY, Hyung WJ, Cheong JH, et al. Receptor tyrosine kinase amplified gastric cancer: clinicopathologic characteristics and proposed screening algorithm. Oncotarget. 2016;7:72099–112.
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–97.
Bai JY, Li Y, Xue GH, Li KR, Zheng YF, Zhang ZQ, et al. Requirement of Galphai1 and Galphai3 in interleukin-4-induced signaling, macrophage M2 polarization and allergic asthma response. Theranostics. 2021;11:4894–909.
This work was generously supported by grants from the National Natural Science Foundation of China (81922025, 81802386, 81970823, 81974388, 81302195, 31371139, 81571282, 81771457, and 81670878), and the Natural Science Foundation of Jiangsu Province (BK20170060), a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, Suzhou People’s Livelihood Science and Technology project (sysd2018205). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the paper.
Conflict of interest
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Lv, Y., Wang, Y., Song, Y. et al. LncRNA PINK1-AS promotes Gαi1-driven gastric cancer tumorigenesis by sponging microRNA-200a. Oncogene 40, 3826–3844 (2021). https://doi.org/10.1038/s41388-021-01812-7