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.

中文翻译：

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胚胎中胚层因子MESP1的异常表达促进肿瘤发生。

背景技术中胚层后壁1（MESP1）属于基本螺旋-环-螺旋转录因子家族。它是中胚层发育的主要调节剂，可导致心脏和肺等器官的形成。然而，其在成人病理生理中的作用仍然未知。在这里，我们首次报告了MESP1与非小细胞肺癌（NSCLC）的先前未知的关联。方法分别采用qPCR和免疫印迹法检测NSCLC来源的细胞中MESP1的mRNA和蛋白水平。使用菌落形成测定，比色细胞增殖测定和软琼脂菌落形成测定来评估MESP1敲除和过表达的体外作用。RNA测序和染色质免疫沉淀（ChIP）-qPCR用于确定MESP1的直接靶基因。在免疫受损的小鼠中皮下注射了MESP1耗尽的NSCLC细胞，以研究MESP1介导的体内肿瘤形成的作用。结果我们发现，MESP1表达与NSCLC患者的不良预后相关，并且对于NSCLC衍生细胞的增殖和存活至关重要，因此暗示MESP1是肺癌的癌基因。异位MESP1表达与肿瘤抑制因子ARF的丧失协同作用来转化鼠成纤维细胞。来自耗尽MESP1细胞的异种移植物显示体内肿瘤生长减少。全球转录组分析揭示了与癌症的各种特征相关的MESP1 DNA结合依赖性基因签名，表明MESP1的转录活性最可能是其致癌能力的原因。