Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama.
Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
Cancer Res. 2021 Apr 15;81(8):1942-1953. doi: 10.1158/0008-5472.CAN-20-2769. Epub 2021 Feb 8.
miRNA rarely possess pan-oncogenic or tumor-suppressive properties. Most miRNAs function under tissue-specific contexts, acting as either tumor suppressors in one tissue, promoting oncogenesis in another, or having no apparent role in the regulation of processes associated with the hallmarks of cancer. What has been less clear is the role of miRNAs within cell types of the same tissue and the ability within each cell type to contribute to oncogenesis. In this study, we characterize the role of one such tissue-specific miRNA, miR-31, recently identified as the most oncogenic miRNA in lung adenocarcinoma, across the histologic spectrum of human lung cancer. Compared with normal lung tissue, miR-31 was overexpressed in patient lung adenocarcinoma, squamous cell carcinoma, and large-cell neuroendocrine carcinoma, but not small-cell carcinoma or carcinoids. miR-31 promoted tumor growth in mice of xenografted human adenocarcinoma and squamous cell carcinoma cell lines, but not in large- or small-cell carcinoma lines. While miR-31 did not promote primary tumor growth of large- and small-cell carcinoma, it did promote spontaneous metastasis. Mechanistically, miR-31 altered distinct cellular signaling programs within each histologic subtype, resulting in distinct phenotypic differences. This is the first report distinguishing diverse functional roles for this miRNA across the spectrum of lung cancers and suggests that miR-31 has broad clinical value in human lung malignancy. SIGNIFICANCE: These findings demonstrate the oncogenic properties of miR-31 in specific subtypes of lung cancer and highlight it as a potential therapeutic target in these subtypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/1942/F1.large.jpg.
miRNA 很少具有泛癌基因或肿瘤抑制特性。大多数 miRNA 在组织特异性背景下发挥作用，在一种组织中作为肿瘤抑制剂，在另一种组织中促进肿瘤发生，或者在调节与癌症特征相关的过程中没有明显作用。不太清楚的是同一组织的细胞类型中的 miRNA 的作用，以及每个细胞类型在促进肿瘤发生中的能力。在这项研究中，我们描述了一种组织特异性 miRNA，miR-31 的作用，该 miRNA 最近被确定为肺腺癌中最致癌的 miRNA，跨越了人类肺癌的组织学谱。与正常肺组织相比，miR-31 在患者肺腺癌、鳞状细胞癌和大细胞神经内分泌癌中过度表达，但在小细胞癌或类癌中不表达。miR-31 促进了异种移植人腺癌和鳞状细胞癌细胞系的小鼠肿瘤生长，但不促进大细胞或小细胞癌系的肿瘤生长。虽然 miR-31 并没有促进大细胞和小细胞癌的原发性肿瘤生长，但它确实促进了自发性转移。从机制上讲，miR-31 在每种组织亚型内改变了不同的细胞信号转导程序，导致不同的表型差异。这是第一个在肺癌谱中区分该 miRNA 不同功能作用的报告，并表明 miR-31 在人类肺癌恶性肿瘤中有广泛的临床价值。意义：这些发现证明了 miR-31 在特定肺癌亚型中的致癌特性，并强调了它作为这些亚型潜在治疗靶点的可能性。
