Peptide SMIM30 promotes HCC development by inducing SRC/YES1 membrane anchoring and MAPK pathway activation.

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A substantial proportion of non-coding RNAs (ncRNAs) with small open reading frames (smORFs) are indeed translated to short peptides. It is unclear where and how short peptides promote hepatocellular carcinoma (HCC) development.We performed RNA-immunoprecipitation followed by high-throughput sequencing (RIP-seq) assay with an antibody against ribosomal protein S6 (RPS6) on four cancer cell lines. Focusing on one lncRNA, LINC00998, we used qPCR and public databases to evaluate its expression level in HCC patients. Special vectors were constructed to confirm its coding potential. We also explored the function and mechanism of LINC00998-encoded peptide in tumor growth and metastasis.We discovered lots of lncRNAs binding to RPS6 in cancer cells. One of these lncRNAs, LINC00998, encoded one small endogenous peptide, termed SMIM30. SMIM30, rather than the RNA itself, promoted the HCC tumorigenesis by modulating cell proliferation and migration and its level was correlated with the poor survival rate of HCC patients. Furthermore, SMIM30 was transcribed by c-Myc and then drove the membrane anchoring of non-receptor tyrosine kinases-SRC/YES1. Moreover, the downstream MAPK signaling pathway was activated by SRC/YES1.Our results not only unravel a new mechanism of HCC tumorigenesis promoted by ncRNA-encoded peptides, but also suggest that the peptides can serve as a new target for HCC cancer therapy and a new biomarker for HCC diagnosis and prognosis.

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