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Original Article | Open Access

MiR-378a-3p acts as a tumor suppressor in gastric cancer via directly targeting RAB31 and inhibiting the Hedgehog pathway proteins GLI1/2

Xinxin Xu1,2,*, Yang Li1,2,*, Guoxiao Liu1,2, Kai Li1,2, Peng Chen3, Yunhe Gao2, Wenquan Liang2, Hongqing Xi2, Xinxin Wang2, Bo Wei2, Hongtao Li3 ( ), Lin Chen2 ( )
Medical School of Chinese PLA, Beijing 100853, China
Senior Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of People’s Liberation Army, Lanzhou 730050, China

*These authors contributed equally to this work.

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Abstract

Objective

To improve the prognosis of patients with gastric cancer (GC), more effective therapeutic targets are urgently needed. Increasing evidence indicates that miRNAs are involved in the progression of various tumors, and RAS-associated protein in the brain 31 (RAB31) is upregulated and promotes the progression of multiple malignant tumors. Here, we focused on identifying RAB31-targeted miRNAs and elucidating their potential mechanism in the progression of GC.

Methods

RAB31 and miR-378a-3p expression levels were detected in paired fresh GC tissues and GC cell lines. Bioinformatics analysis was used to predict the miRNAs targeting RAB31 and the relationships between RAB31 and other genes. Dual-luciferase reporter assays were applied to verify the targeted interaction relationship. CCK-8, colony formation, flow cytometry, wound healing, and Transwell assays were performed to assess the proliferation, apoptosis, migration, and invasion of GC cells. Tumorsphere formation assays were performed to assess the stemness of gastric cancer stem cells. Related proteins were detected by Western blot. Xenograft assays in nude mice were performed to explore the effect of miR-378a-3p in vivo.

Results

We report the first evidence that miR-378a-3p is downregulated in GC, whereas its overexpression inhibits proliferation, invasion, and migration as well as promotes apoptosis in GC cells. Mechanistically, miR-378a-3p inhibits the progression of GC by directly targeting RAB31. Restoring RAB31 expression partially offsets the inhibitory effect of miR-378a-3p. Further research revealed that miR-378a-3p inhibits GLI1/2 in the Hedgehog signaling pathway and attenuates the stemness of gastric cancer stem cells. Finally, xenograft assays showed that miR-378a-3p inhibits GC tumorigenesis in vivo.

Conclusions

MiR-378a-3p inhibits GC progression by directly targeting RAB31 and inhibiting the Hedgehog signaling pathway proteins GLI1/2.

Keywords

cancer stem cellsGastric cancerHedgehogRAB31miR-378a-3p

Electronic Supplementary Material

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Cancer Biology & Medicine
Volume 19 Issue 12,
December 2022
Pages 1662-1682
DOI: 10.20892/j.issn.2095-3941.2022.0337
Cite this article:
Xu X, Li Y, Liu G, et al. MiR-378a-3p acts as a tumor suppressor in gastric cancer via directly targeting RAB31 and inhibiting the Hedgehog pathway proteins GLI1/2. Cancer Biology & Medicine, 2022, 19(12): 1662-1682. https://doi.org/10.20892/j.issn.2095-3941.2022.0337

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Received: 17 June 2022
Accepted: 22 September 2022
Published: 12 December 2022
©2022 Cancer Biology & Medicine.

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