Microphthalamia-associated transcription factor (MITF) is a critical mediator in melanocyte differentiation and exerts oncogenic functions in melanoma progression. However, the role of MITF in non-small cell lung cancer (NSCLC) is still unknown. We found that MITF is dominantly expressed in the low-invasive CL1-0 lung adenocarcinoma cells and paired adjacent normal lung tissues. MITF expression is significantly associated with better overall survival and disease-free survival in NSCLC and serves as an independent prognostic marker. Silencing MITF promotes tumor cell migration, invasion and colony formation in lung adenocarcinoma cells. In xenograft mouse model, MITF knockdown enhances metastasis and tumorigenesis, but decreases angiogenesis in the Matrigel plug assay. Whole transcriptome profiling of the landscape of MITF regulation in lung adenocarcinoma indicates that MITF is involved in cell development, cell cycle, inflammation and WNT signaling pathways. Chromatin immunoprecipitation assays revealed that MITF targets the promoters of FZD7, PTGR1 and ANXA1. Moreover, silencing FZD7 reduces the invasiveness that is promoted by silencing MITF. Strikingly, MITF has significantly inverse correlations with the expression of its downstream genes in lung adenocarcinoma. In summary, we demonstrate the suppressive role of MITF in lung cancer progression, which is opposite to the canonical oncogenic function of MITF in melanoma.

中文翻译：

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MITF在非小细胞肺癌中起着典型的致癌作用以外的肿瘤抑制作用

Microphthalamia相关转录因子（MITF）是黑色素细胞分化的关键介质，并在黑色素瘤进展中发挥致癌作用。但是，MITF在非小细胞肺癌（NSCLC）中的作用仍然未知。我们发现MITF在低侵袭性CL1-0肺腺癌细胞和配对的正常肺组织中占优势。MITF表达与NSCLC中更好的总体生存率和无病生存率显着相关，并且可以作为独立的预后指标。沉默MITF可以促进肺腺癌细胞中肿瘤细胞的迁移，侵袭和集落形成。在异种移植小鼠模型中，MITF组合剔除可增强转移和肿瘤发生，但在Matrigel塞测定法中可降低血管生成。肺腺癌中MITF调控的全转录组图谱分析表明MITF参与细胞发育，细胞周期，炎症和WNT信号通路。染色质免疫沉淀实验表明，MITF靶向FZD7，PTGR1和ANXA1的启动子。而且，沉默FZD7降低了通过沉默MITF促进的侵袭性。惊人的是MITF与下游基因在肺腺癌中的表达显着负相关。总之，我们证明了MITF在肺癌进展中的抑制作用，这与MITF在黑素瘤中的典型致癌功能相反。