MiR-30a-5p isoform -1|1 promotes the progression of gastric cancer by inhibiting TMEM66 and reducing intratumoral cytotoxic T cells.

ABSTRACT

Gastric cancer is histologically classified into the intestinal subtype, which forms tubular structures, and the aggressive diffuse subtype, characterized by rapid invasion and poor prognosis. The variety and quantity of miRNA isoforms between different histological subtypes of gastric cancer were unknown. Through systematic filtering, we found that more diverse miR-30a-5p isoforms was present in the diffuse subtype of gastric cancer, and was associated with patients' worse survival independent of tumor stage based on the TCGA miRNA-seq data. Among all nine isoforms of miR-30a-5p, miR-30a-5p -1|1 was more abundant than the archetype of miR-30a-5p. Higher expression of miR-30a-5p -1|1 was observed in patients with advanced tumor stage and poor survival. Furthermore, miR-30a-5p -1|1 could promote the metastasis of gastric cancer cells both in vitro and in vivo by down-regulating TMEM66. In clinical samples, decreased expression of TMEM66 was characteristic of gastric cancer, and the low level of TMEM66 correlated with deceased CD8 positive cells in the tumor microenvironment probably due to decreased cytokines production. In conclusion, the variety of miR-30a-5p isoforms correlates with worse survival in gastric cancer patients. Moreover, miR-30a-5p -1|1 could promote gastric cancer metastasis by inhibiting TMEM66 and the infiltration of intratumoral CD8 positive cells.