Abstract
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.
Highlights
Lung cancer is the leading cause of cancer-related death worldwide [1]
The results showed that Microphthalamia-associated transcription factor (MITF) expression was significantly associated with overall survival (OS) and progressionfree survival (PFS) in lung adenocarcinoma (p-value 0.047 was for OS and 0.034 for PFS, log-rank test) (Supplementary Figure 1B, 1C)
MITF contains several isoforms generated through differential use of alternative promoters that are controlled by tissue specificity, leading to MITF isoforms having distinct N-termini with a range of 419526 amino acids [10]
Summary
Lung cancer is the leading cause of cancer-related death worldwide [1]. Approximately 85% of lung cancers are non-small cell lung cancer (NSCLC) including adenocarcinoma, squamous cell carcinoma and large cell carcinoma, and lung adenocarcinoma accounts for the majority of all lung cancer cases [2]. The 5-year survival rate of early stage NSCLC ranges from 41% to 90%, whereas tumor metastasis or recurrence leads to the high mortality of stage I patients after surgery [2, 3]. Lymph node metastasis is a prognostic predictor for NSCLC survival [4]. Metastasis involves oncogenic cell transformation, cell motility and invasion and angiogenesis [5, 6]. Through functional genomics studies and an isogenic metastasis cell model in CL1-0, CL1-1 and CL1-5 lung adenocarcinoma cell lines, we discovered several metastasis-related genes [7,8,9]. A comprehensive understanding of the role of these novel genes in lung metastasis is critical for the development of prognostic markers and therapeutic strategies
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