Lung adenocarcinoma is one of the most common forms of lung cancer with a low five-year survival rate. The roles of the novel proteins and peptides encoded by circular RNAs (circRNAs) in cancer are emerging. However, the functions and underlying molecular mechanisms of the peptides that affect lung adenocarcinoma progression are yet to be elucidated. In this study, we characterized a lung-adenocarcinoma-associated small peptide (SCAPEP) encoded by circRNA_0065214 via the IRES element. Tumors with a large diameter, lymphatic metastasis, or advanced stage have high SCAPEP levels. Furthermore, modulation of SCAPEP expression can regulate cell proliferation, metastasis, and autophagy in vitro or in vivo. We found that the up-regulation of methionine synthase reductase (MTRR) by regulating the phosphorylation of vimentin Ser56 in SCAPEP is a key mechanism driving the aggressiveness of SCAPEP -high lung adenocarcinoma. Consistent with these findings, MTRR overexpression reversed the effects of SCAPEP depletion. Altogether, our observations provide novel insights into how oncogenic peptides crosstalk with autophagy and contribute to lung adenocarcinoma tumorigenesis.
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