Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Aging (Albany NY). 2020 Dec 3;13(1):646-674. doi: 10.18632/aging.202171.
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 is dominantly expressed in the low-invasive CL1-0 lung adenocarcinoma cells and paired adjacent normal lung tissues. expression is significantly associated with better overall survival and disease-free survival in NSCLC and serves as an independent prognostic marker. Silencing promotes tumor cell migration, invasion and colony formation in lung adenocarcinoma cells. In xenograft mouse model, 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 , and . Moreover, silencing reduces the invasiveness that is promoted by silencing MITF. Strikingly, 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.
小眼相关转录因子（MITF）是黑素细胞分化过程中的关键介质，在黑色素瘤进展中发挥致癌作用。然而，MITF 在非小细胞肺癌（NSCLC）中的作用尚不清楚。我们发现， 在低侵袭性 CL1-0 肺腺癌细胞和配对的相邻正常肺组织中呈优势表达。 在 NSCLC 中， 的表达与更好的总生存期和无病生存期显著相关，是一个独立的预后标志物。沉默 可促进肺腺癌细胞的迁移、侵袭和集落形成。在异种移植小鼠模型中， 敲低可增强转移和肿瘤发生，但在 Matrigel 塞子测定中减少血管生成。肺腺癌中 MITF 调控的全转录组谱分析表明，MITF 参与细胞发育、细胞周期、炎症和 WNT 信号通路。染色质免疫沉淀试验显示，MITF 靶向 、 和 的启动子。此外，沉默 可降低 MITF 沉默所促进的侵袭性。引人注目的是， 在肺腺癌中与下游基因的表达呈显著负相关。总之，我们证明了 MITF 在肺癌进展中的抑制作用，这与 MITF 在黑色素瘤中的经典致癌作用相反。
