MITF functions as a tumor suppressor in non-small cell lung cancer beyond the canonically oncogenic role.

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.

• Authors: Yi-Jing Hsiao, Wen-Hsin Chang, Hsuan-Yu Chen, Yin-Chen Hsu, Su-Chin Chiu, Ching-Cheng Chiang, Gee-Chen Chang, Yi-Ju Chen, Chia-Yu Wang, Yan-Ming Chen, Chien-Yu Lin, Yu-Ju Chen, Pan-Chyr Yang, Jeremy J W Chen, Sung-Liang Yu
• Journal: Aging (Aging (Albany NY)) Vol. 13 Issue 1 Pg. 646-674 (12 03 2020) ISSN: 1945-4589 [Electronic] United States
• PMID: 33293474 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ANXA1 protein, human
• Annexin A1
• FZD7 protein, human
• Frizzled Receptors
• MITF protein, human
• Microphthalmia-Associated Transcription Factor
• Alcohol Oxidoreductases
• leukotriene B4 12-hydroxydehydrogenase

Topics

• Adenocarcinoma of Lung (blood supply, genetics, pathology)
• Aged
• Alcohol Oxidoreductases (genetics)
• Animals
• Annexin A1 (genetics)
• Carcinogenesis
• Carcinoma, Non-Small-Cell Lung (blood supply, genetics, pathology)
• Cell Line, Tumor
• Cell Movement
• Female
• Frizzled Receptors (genetics)
• Gene Knockdown Techniques
• Genes, Tumor Suppressor
• Humans
• Lung Neoplasms (blood supply, genetics, pathology)
• Male
• Mice
• Microphthalmia-Associated Transcription Factor (genetics)
• Middle Aged
• Neoplasm Metastasis
• Neoplasm Transplantation
• Neovascularization, Pathologic
• Tumor Stem Cell Assay
• Exome Sequencing
• Wnt Signaling Pathway