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LncRNA PINK1-AS promotes Gαi1-driven gastric cancer tumorigenesis by sponging microRNA-200a

Abstract

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.

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Fig. 1: Gαi1 overexpression in GC.
Fig. 2: Gαi1 promotes GC cell progression in vitro.
Fig. 3: Gαi1 silencing by miR-200a produces significant anti-GC cell activity.
Fig. 4: PINK1-AS sponges miR-200a to promote Gαi1 expression.
Fig. 5: PINK1-AS expedites malignant behaviors of GC cells.
Fig. 6: PINK1-AS silencing provokes apoptosis activation in GC cells.
Fig. 7: PINK1-AS shRNA-induced anti-GC cell activity is due to regulating miR-200a-Gαi1 cascade.
Fig. 8: PINK1-AS is required for MGC-803 xenograft growth in nude mice.
Fig. 9: Patient-derived GC xenograft growth is inhibited after intratumoral injection of sh-PINK1-AS lentivirus.

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Funding

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.

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Correspondence to Jin Yao or Li-na Zhou or Zhuo-yan Ling or Cong Cao.

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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

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