Aberrant expression of embryonic mesendoderm factor MESP1 promotes tumorigenesis.
BACKGROUND
Mesoderm Posterior 1 (MESP1) belongs to the family of basic helix-loop-helix transcription factors. It is a master regulator of mesendoderm development, leading to formation of organs such as heart and lung. However, its role in adult pathophysiology remains unknown. Here, we report for the first time a previously-unknown association of MESP1 with non-small cell lung cancer (NSCLC).


METHODS
MESP1 mRNA and protein levels were measured in NSCLC-derived cells by qPCR and immunoblotting respectively. Colony formation assay, colorimetric cell proliferation assay and soft agar colony formation assays were used to assess the effects of MESP1 knockdown and overexpression in vitro. RNA-sequencing and chromatin immunoprecipitation (ChIP)-qPCR were used to determine direct target genes of MESP1. Subcutaneous injection of MESP1-depleted NSCLC cells in immuno-compromised mice was done to study the effects of MESP1 mediated tumor formation in vivo.


FINDINGS
We found that MESP1 expression correlates with poor prognosis in NSCLC patients, and is critical for proliferation and survival of NSCLC-derived cells, thus implicating MESP1 as a lung cancer oncogene. Ectopic MESP1 expression cooperates with loss of tumor suppressor ARF to transform murine fibroblasts. Xenografts from MESP1-depleted 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 transcription activity of MESP1 is most likely responsible for its oncogenic abilities.


INTERPRETATION
Our study demonstrates MESP1 as a previously-unknown lineage-survival oncogene in NSCLC which may serve as a potential prognostic marker and therapeutic target for lung cancer in the future.
['Tandon|Neha|N|', 'Goller|Kristina|K|', 'Wang|Fan|F|', 'Soibam|Benjamin|B|', 'Gagea|Mihai|M|', 'Jain|Abhinav K|AK|', 'Schwartz|Robert J|RJ|', 'Liu|Yu|Y|']
D000818:Animals D051792:Basic Helix-Loop-Helix Transcription Factors D002289:Carcinoma, Non-Small-Cell Lung D045744:Cell Line, Tumor D049109:Cell Proliferation D002471:Cell Transformation, Neoplastic D019295:Computational Biology D004195:Disease Models, Animal D020869:Gene Expression Profiling D005786:Gene Expression Regulation D064593:Heterografts D006801:Humans D008175:Lung Neoplasms D051379:Mice
Mesp1 Lung cancer ARF Lineage-survival oncogene