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

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.

Exploring the regulatory role of FBXL19‐AS1 in triple‐negative breast cancer through the miR‐378a‐3p/OTUB2 axis

“…22 miR-378a-3p restrains gastric cancer proliferation by directly targeting RAB31 and blocking GLI1/2. 23 Consistent with this finding, we found that miR-378a-3p serves as a tumor suppressor in TNBC. miR-378a-3p upregulation prevented TNBC cell proliferation and metastasis and increased the proportion of apoptotic cells.…”

“…By sponging miR‐378a‐3p, lncRNA SLC2A1‐AS1 promotes cancer cell metabolism and development 22 . miR‐378a‐3p restrains gastric cancer proliferation by directly targeting RAB31 and blocking GLI1/2 23 . Consistent with this finding, we found that miR‐378a‐3p serves as a tumor suppressor in TNBC.…”

Positive GLI1/INHBA feedback loop drives tumor progression in gastric cancer

“…Previous reports have shown that the activated canonical Hh signaling pathway is involved in the carcinogenesis of GC 5,36–39 . In addition to the canonical activation of GLI by Smoothened (SMO), increasing evidence suggests that GLI transcription factors are also activated by epidermal growth factor (EGF), 40 insulin‐like growth factor (IGF), 41 TGF‐β, 42,43 mTOR, 44 RAS, 45 Notch 46 and PKC 47 .…”

Synthetic RNA Therapeutics in Cancer

“…circRNAs can be generated using a cell-free system via in vitro transcription followed by ligation. Unlike linear RNAs which are susceptible to degradation by exonucleases and hydrolysis, circRNA is covalently closed and more resistant to degradation by enzymes displaying extended half-lives relative to linear RNA (Enuka et al, 2016;X Liu et al, 2022). Owing to its stability, circRNAs are more applicable than linear RNAs in therapeutic modalities.…”