Dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p) coordinately targeted MTDH in lung squamous cell carcinoma.
Dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p) coordinately targeted MTDH in lung squamous cell carcinoma.
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DOI：
10.18632/oncotarget.12290
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发表时间：
2016-11-01
期刊：
影响因子：
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通讯作者：
Inoue H
中科院分区：
文献类型：
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作者：
Mataki H;Seki N;Mizuno K;Nohata N;Kamikawaji K;Kumamoto T;Koshizuka K;Goto Y;Inoue H
肺腺癌患者可能受益于最近发展起来的分子靶向治疗。然而，类似的高级治疗并不适用于肺鳞状细胞癌(肺SCC)患者。晚期肺鳞状细胞癌患者的生存率仍然很低。探索新的肺鳞状细胞癌致癌途径可能会导致新的治疗方案。基于这一概念，我们已经确定了microRNA-(MiRNA)介导的肺鳞状细胞癌的致癌途径。众所周知，miR-145-5p(导向链)在几种类型的癌症中发挥肿瘤抑制作用。然而，miR-145-3P(客体链)对癌细胞的影响仍然不明确。MiR-145-5p和miR-145-3p在肿瘤组织中的表达水平显著降低，异位表达抑制了癌细胞的侵袭性，提示miR-145-3p和miR-145-5p均具有抗肿瘤作用。我们发现了7个在肺鳞状细胞癌中受miR-145-5p和miR-145-3p协同调控的靶基因(MTDH、EPN3、TPD52、CYP27B1、LMAN1、STAT1和TXNDC12)。在这七个基因中，我们发现胃粘附素(MTDH)是这些miRNAs的直接靶标。Kaplan-Meier生存曲线显示，MTDH的高表达预示着肺鳞状细胞癌患者生存率的降低。我们通过全基因组的基因表达分析研究了MTDH下游的途径。我们的数据显示，在肺鳞状细胞癌中，几个抗凋亡和促增殖基因参与了MTDH下游的通路。综上所述，miR-145、miR-145-5p和miR-145-3p的两条链都具有功能，在肺鳞状细胞癌中发挥着关键的抗肿瘤miRNAs作用。
Patients with lung adenocarcinoma may benefit from recently developed molecular targeted therapies. However, analogous advanced treatments are not available for patients with lung squamous cell carcinoma (lung SCC). The survival rate of patients with the advanced stage of lung SCC remains poor. Exploration of novel lung SCC oncogenic pathways might lead to new treatment protocols for the disease. Based on this concept, we have identified microRNA- (miRNA) mediated oncogenic pathways in lung SCC. It is well known that miR-145-5p (the guide strand) functions as a tumor suppressor in several types of cancer. However, the impact of miR-145-3p (the passenger strand) on cancer cells is still ambiguous. Expression levels of miR-145-5p and miR-145-3p were markedly reduced in cancer tissues, and ectopic expression of these miRNAs inhibited cancer cell aggressiveness, suggesting that both miR-145-3p as well as miR-145-5p acted as antitumor miRNAs. We identified seven putative target genes (MTDH, EPN3, TPD52, CYP27B1, LMAN1, STAT1 and TXNDC12) that were coordinately regulated by miR-145-5p and miR-145-3p in lung SCC. Among the seven genes, we found that metadherin (MTDH) was a direct target of these miRNAs. Kaplan–Meier survival curves showed that high expression of MTDH predicted reduced survival of lung SCC patients. We investigated pathways downstream from MTDH by using genome-wide gene expression analysis. Our data showed that several anti-apoptosis and pro-proliferation genes were involved in pathways downstream from MTDH in lung SCC. Taken together, both strands of miR-145, miR-145-5p and miR-145-3p are functional and play pivotal roles as antitumor miRNAs in lung SCC.