Aberrant Expression of Embryonic Mesendoderm Factor MESP1 Promotes Tumorigenesis

Date

2019-08

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Abstract

Lung cancer is the leading cause of cancer-related deaths in the United States, with KRAS and EGFR known as driver oncogenes for the disease. Adding to these are “lineage-survival oncogenes” where tumor survival depends on the aberrant expression of master transcriptional regulators of cell-lineages. Here, by integrating various patient gene expression datasets, we identified that basic helix- loop-helix transcription factor MESP1, a master regulator of mesendoderm development, has a previously-unknown association with Non-Small Cell Lung Cancer (NSCLC). We found that MESP1 expression correlates with poor prognosis in NSCLC patients, and is critical for proliferation and survival of NSCLC-derived cell lines, thus, implicating MESP1 as a lung cancer oncogene. Ectopic MESP1 expression cooperates with the loss of tumor suppressor ARF to transform murine fibroblasts. Xenografts of MESP1-knockdown cells showed decreased tumor growth in vivo. Global transcriptome analysis revealed a MESP1 DNA-binding dependent gene signature associated with various hallmarks of cancer, suggesting that the transcription activity of MESP1 is most likely responsible for its oncogenic abilities. These observations demonstrate MESP1 as a previously-unknown lineage survival oncogene in NSCLC.

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Keywords

MESP1, Lung cancer, ARF, EMT

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