Abstract
Identification of cancer-specific target molecules and biomarkers may be useful in the development of novel treatment and immunotherapeutic strategies. We have recently demonstrated that the expression of long noncoding (lnc) RNAs can be cancer-type specific due to abnormal chromatin remodeling and alternative splicing. Furthermore, we identified and determined that the functional small protein C20orf204-189AA encoded by long intergenic noncoding RNA Linc00176 that is expressed predominantly in hepatocellular carcinoma (HCC), enhances transcription of ribosomal RNAs and supports growth of HCC. In this study we combined RNA-sequencing and polysome profiling to identify novel micropeptides that originate from HCC-specific lncRNAs. We identified nine lncRNAs that are expressed exclusively in HCC cells but not in the liver or other normal tissues. Here, DNase-sequencing data revealed that the altered chromatin structure plays a key role in the HCC-specific expression of lncRNAs. Three out of nine HCC-specific lncRNAs contain at least one open reading frame (ORF) longer than 50 amino acid (aa) and enriched in the polysome fraction, suggesting that they are translated. We generated a peptide specific antibody to characterize one candidate, NONHSAT013026.2/Linc013026. We show that Linc013026 encodes a 68 amino acid micropeptide that is mainly localized at the perinuclear region. Linc013026-68AA is expressed in a subset of HCC cells and plays a role in cell proliferation, suggesting that Linc013026-68AA may be used as a HCC-specific target molecule. Our finding also sheds light on the role of the previously ignored ’dark proteome’, that originates from noncoding regions in the maintenance of cancer.
Highlights
Hepatocellular carcinoma (HCC) is one of the most prevalent tumor types worldwide [1]; current treatment options are limited, and precise and effective medical strategies for therapy do not exist [2]
We show that Linc013026 encodes a 68 amino acid micropeptide that is mainly localized at the perinuclear region
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Summary
Hepatocellular carcinoma (HCC) is one of the most prevalent tumor types worldwide [1]; current treatment options are limited, and precise and effective medical strategies for therapy do not exist [2]. HCC typically occurs on a background of chronic liver disease, with risk factors including viral or autoimmune hepatitis, chronic alcohol abuse, and nonalcoholic fatty liver disease [3] These risk factors trigger aberrant liver regeneration, which initiates the formation of HCC. 28% of altered gene products are involved in a chromatin-remodeling complex, suggesting that HCC expresses unique genes that are not expressed in normal hepatocytes. In this context, we have previously shown that a subset of lncRNAs that are predominantly expressed in HCC plays a role as fine tuners in cancer formation and/or maintenance [7,8]. A potential strategy for cancer therapy may be to target multiple cancer type-specific fine tuners including noncoding RNA
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