Li Jindong, Feng Qingchuan, Wei Xudong, Yu Yongkui
Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, No.127, Dongming Road, Zhengzhou, Henan, 450003, China.
Department of Cell Biology and Medical Genetics, Basical Medical College, Zhengzhou, Henan, 450008, China.
Tumour Biol. 2016 Nov;37(11):15221-15228. doi: 10.1007/s13277-016-5347-9. Epub 2016 Sep 28.
Lung cancer remains a leading cause of cancer-related mortality, with metastatic progression remaining the single largest cause of lung cancer mortality. Hence, it is imperative to determine reliable biomarkers of lung cancer prognosis. MicroRNA-490-3p has been previously reported to be a positive prognostic biomarker for hepatocellular cancer. However, its role in human lung cancer has not yet been elucidated. Here, we report that hsa-miR-490-3p expression is significantly higher in human lung cancer tissue specimens and cell line. Gain- and loss-of-function studies of hsa-miR-490-3p showed that it regulates cell proliferation and is required for induction of in vitro migration and invasion-the latter being a hallmark of epithelial to mesenchymal transition. In situ analysis revealed that hsa-miR-490-3p targets poly r(C)-binding protein 1 (PCBP1), which has been previously shown to be a negative regulator of lung cancer metastasis. Reporter assays confirmed PCBP1 as a bona fide target of miR-490-3p, and metagenomic analysis revealed an inverse relation between expression of miR-490-3p and PCBP1 in metastatic lung cancer patients. In fact, PCBP1 expression, as detected by immunohistochemistry, was undetectable in advanced stages of lung cancer patients' brain and lymph node tissues. Xenograft tail vein colonization assays proved that high expression of miR-490-3p is a prerequisite for metastatic progression of lung cancer. Our results suggest that hsa-miR-490-3p might be a potential biomarker for lung cancer prognosis. In addition, we can also conclude that the lung cancer cells have evolved refractory mechanisms to downregulate the expression of the metastatic inhibitor, PCBP1.
肺癌仍然是癌症相关死亡的主要原因，转移进展是肺癌死亡的单一最大原因。因此，确定可靠的肺癌预后生物标志物势在必行。此前有报道称MicroRNA-490-3p是肝细胞癌的一种阳性预后生物标志物。然而，其在人类肺癌中的作用尚未阐明。在此，我们报告hsa-miR-490-3p在人类肺癌组织标本和细胞系中的表达显著更高。对hsa-miR-490-3p进行功能获得和功能缺失研究表明，它调节细胞增殖，并且是体外迁移和侵袭诱导所必需的——后者是上皮-间质转化的一个标志。原位分析显示hsa-miR-490-3p靶向聚r(C)结合蛋白1（PCBP1），此前已证明该蛋白是肺癌转移的负调节因子。报告基因检测证实PCBP1是miR-490-3p的真正靶点，宏基因组分析揭示了转移性肺癌患者中miR-490-3p和PCBP1表达之间的负相关关系。事实上，通过免疫组织化学检测，在肺癌患者脑和淋巴结组织的晚期阶段未检测到PCBP1表达。异种移植尾静脉定植试验证明miR-490-3p的高表达是肺癌转移进展的先决条件。我们的结果表明hsa-miR-490-3p可能是肺癌预后的一个潜在生物标志物。此外，我们还可以得出结论，肺癌细胞已经进化出难治机制来下调转移抑制因子PCBP1的表达。
