HMGA2 functions as a competing endogenous RNA to promote lung cancer progression.
HMGA2 functions as a competing endogenous RNA to promote lung cancer progression.
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作者：
非小细胞肺癌（NSCLC）是全球最常见的组织学癌症亚型。由于大多数患者呈现侵袭性、转移性疾病，了解肺癌进展的基础至关重要。高迁移率族蛋白A2（Hmga2）在转移性肺腺癌中高度表达，它促进癌症进展和转移。在此我们表明，Hmga2通过作为let - 7微小RNA（miRNA）家族的竞争性内源RNA（ceRNA）来促进肺癌进展。Hmga2能够促进肺癌细胞的转化，这种转化不依赖于蛋白质编码功能，但依赖于let - 7位点的存在；这一过程中let - 7异构体的水平没有变化，表明Hmga2通过改变miRNA靶向作用来影响let - 7的活性。这些效应在体内进一步得到观察，其中Hmga2的ceRNA活性驱动肺癌的生长、侵袭和扩散。对miRNA靶标预测算法和转移性肺癌基因表达数据的综合分析显示，转化生长因子 - β共受体Tgfbr3是Hmga2的ceRNA功能的一个假定靶标。Tgfbr3的表达受Hmga2的ceRNA通过对Argonaute - 2（Ago2）的差异募集来调节，并且由Tgfbr3驱动的转化生长因子 - β信号通路对于Hmga2促进肺癌进展在很大程度上是必需的。最后，对非小细胞肺癌患者基因表达数据的分析显示，HMGA2和TGFBR3在非小细胞肺癌患者样本中是协同调节的，这是ceRNA功能的一个重要推论。综上所述，这些结果表明Hmga2作为一个蛋白质编码基因和一个非编码RNA促进肺癌发生；这种基因表达网络的双重功能调节反映了癌基因促进疾病进展的一种新方式。
Non-small cell lung cancer (NSCLC) is the most prevalent histological cancer subtype worldwide. As the majority of patients present with invasive, metastatic disease, it is vital to understand the basis for lung cancer progression. Hmga2 is highly expressed in metastatic lung adenocarcinoma where it contributes to cancer progression and metastasis. Here we show that Hmga2 promotes lung cancer progression by operating as a competing endogenous RNA (ceRNA) for the let-7 microRNA (miRNA) family. Hmga2 can promote the transformation of lung cancer cells independent of protein-coding function but dependent upon the presence of let-7 sites; this occurs without changes in the levels of let-7 isoforms, suggesting that Hmga2 affects let-7 activity by altering miRNA targeting. These effects are further observed in vivo, where Hmga2 ceRNA activity drives lung cancer growth, invasion and dissemination. Integrated analysis of miRNA target prediction algorithms and metastatic lung cancer gene expression data reveals the TGF-β co-receptor Tgfbr3 as a putative target of Hmga2 ceRNA function. Tgfbr3 expression is regulated by the Hmga2 ceRNA via differential recruitment to Argonaute-2 (Ago2), and TGF-β signalling driven by Tgfbr3 is largely necessary for Hmga2 to promote lung cancer progression. Finally, analysis of NSCLC patient gene expression data reveals that HMGA2 and TGFBR3 are co-ordinately regulated in NSCLC patient material, a vital corollary to ceRNA function. Taken together, these results suggest that Hmga2 promotes lung carcinogenesis as both a protein-coding gene and a non-coding RNA; such dual-function regulation of gene expression networks reflects a novel means by which oncogenes promote disease progression.
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DOI：
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发表时间：
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期刊：
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