Babu Kamesh R, Muckenthaler Martina U
Department of Pediatric Hematology, Oncology, and Immunology, University of Heidelberg, Heidelberg, Germany.
Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany.
J Mol Med (Berl). 2016 Mar;94(3):347-59. doi: 10.1007/s00109-015-1362-3. Epub 2015 Nov 12.
Ferroportin (FPN) exports iron from duodenal enterocytes, macrophages, and hepatocytes to maintain systemic iron homeostasis. In addition, FPN is expressed in various cancer cells. Here, we show that in lung cancer, FPN expression is regulated by miR-20a. Within the FPN-3'-untranslated region (3'UTR), we identify and experimentally validate three evolutionarily conserved target sites for the microRNA (miRNA) members of the miR-17 seed family, including miR-20a. Our analysis of RNA sequencing data from patients with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) revealed that FPN messenger RNA (mRNA) levels are significantly decreased in tumor compared to matched healthy tissue, while miR-20a levels are increased. A significant negative correlation of miR-20a and FPN expression was observed. Functional studies further demonstrate that FPN is post-transcriptionally regulated by miR-20a in non-small cell lung cancer (NSCLC) cells and that overexpression or knockdown of miR-20a or FPN affects NSCLC proliferation and colony formation. Taken together, our data suggest that increased expression of miR-20 in lung cancer may decrease iron export, leading to intracellular iron retention, which, in turn, favors cell proliferation.
miR-20a controls expression of the iron exporter ferroportin (FPN) by binding to highly conserved target sites in its 3'UTR. Expression of miR-20a is inversely correlated to FPN in lung cancer. Low FPN expression stimulates proliferation and colony formation of non-small cell lung cancer (NSCLC) cells, possibly by increasing iron availability for cancer cell proliferation.
铁转运蛋白（FPN）将铁从十二指肠肠上皮细胞、巨噬细胞和肝细胞中输出，以维持全身铁稳态。此外，FPN在多种癌细胞中表达。在此，我们表明在肺癌中，FPN的表达受miR-20a调控。在FPN的3'非翻译区（3'UTR），我们鉴定并通过实验验证了miR-17种子家族的微小RNA（miRNA）成员（包括miR-20a）的三个进化保守靶位点。我们对肺腺癌（LUAD）和肺鳞状细胞癌（LUSC）患者的RNA测序数据的分析显示，与匹配的健康组织相比，肿瘤中FPN信使核糖核酸（mRNA）水平显著降低，而miR-20a水平升高。观察到miR-20a与FPN表达呈显著负相关。功能研究进一步证明，在非小细胞肺癌（NSCLC）细胞中，FPN在转录后受miR-20a调控，miR-20a或FPN的过表达或敲低会影响NSCLC的增殖和集落形成。综上所述，我们的数据表明肺癌中miR-20表达增加可能会减少铁输出，导致细胞内铁潴留，进而有利于细胞增殖。
miR-20a通过与其3'UTR中的高度保守靶位点结合来控制铁输出蛋白铁转运蛋白（FPN）的表达。在肺癌中，miR-20a的表达与FPN呈负相关。低FPN表达可能通过增加癌细胞增殖的铁可用性来刺激非小细胞肺癌（NSCLC）细胞的增殖和集落形成。
