A majority of the human genome is transcribed into noncoding RNAs, of which long noncoding RNAs (lncRNAs) form a large and heterogeneous fraction. While lncRNAs are mostly noncoding, recent evidence suggests that cryptic translation within some lncRNAs may produce proteins with important regulatory functions. In this issue of the JCI, Zheng, Wei, and colleagues used an integrative functional genomic strategy to systematically identify cryptic lncRNA-encoded ORFs that play a role in estrogen receptor–positive (ER⁺) breast cancer (BC). They identified 758 cryptic lncRNA-encoded ORFs undergoing active translation, of which 28 had potential functional and clinical relevance in ER⁺ BC. The LINC00992-encoded polypeptide GT3-INCP was upregulated in ER⁺ BC and drove tumor growth. GT3-INCP was regulated by estrogen and the ER and acted via the transcription factor GATA3 to regulate BC susceptibility and risk genes. These findings discern a largely unexplored class of molecules and have implications for many pathologies, including cancer.

中文翻译：

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隐蔽的 lncRNA 编码的 ORF：调节蛋白的隐藏来源

人类基因组的大部分被转录成非编码 RNA，其中长链非编码 RNA (lncRNA) 形成大量异质部分。虽然 lncRNA 大多是非编码的，但最近的证据表明，某些 lncRNA 中的隐蔽翻译可能会产生具有重要调节功能的蛋白质。在本期JCI中，Zheng、Wei 及其同事使用综合功能基因组策略系统地鉴定了在雌激素受体阳性 (ER ⁺ ) 乳腺癌 (BC)中起作用的隐性 lncRNA 编码的 ORF。他们确定了 758 个正在进行主动翻译的隐性 lncRNA 编码的 ORF，其中 28 个在 ER ⁺ BC 中具有潜在的功能和临床相关性。LINC00992 编码的多肽 GT3-INCP 在 ER ^{+中被上调}BC 并推动肿瘤生长。GT3-INCP 受雌激素和 ER 调节，并通过转录因子 GATA3 调节 BC 易感性和风险基因。这些发现辨别出一类很大程度上未被探索的分子，并对包括癌症在内的许多病理学产生影响。