Zhang Li, Singh Anand, Plaisier Christopher, Pruett Nathanael, Ripley R Taylor, Schrump David S, Hoang Chuong D
Thoracic Surgery Branch, NCI, National Institutes of Health, Bethesda, MD, USA.
School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA.
Transl Oncol. 2019 Jun;12(6):859-870. doi: 10.1016/j.tranon.2019.03.005. Epub 2019 May 1.
Therapies against malignant pleural mesothelioma (MPM) have yielded disappointing results, in part, because pathologic mechanisms remain obscure. In searching for rational molecular targets, we identified metadherin (MTDH), a multifunctional gene associated with several tumor types but previously unrecognized in MPM. Cox proportional hazards regression analysis delineated associations between higher MTDH expression and lower patient survival from three independent MPM cohorts (n = 349 patients). Through in vitro assays with overexpression and downregulation constructs in MPM cells, we characterized the role of MTDH. We confirmed in vivo the phenotype of altered MTDH expression in a murine xenograft model. Transcriptional regulators of MTDH were identified by chromatin immunoprecipitation. Overexpression of both MTDH mRNA (12-fold increased) and protein levels was observed in tumor tissues. MTDH stable overexpression significantly augmented proliferation, invasiveness, colony formation, chemoresistance, and an antiapoptosis phenotype, while its suppression showed opposite effects in MPM cells. Interestingly, NF-κB and c-Myc (in a feed-forward loop motif) contributed to modulating MTDH expression. Knockdown of MTDH expression profoundly retarded xenograft tumor growth. Thus, our findings support the notion that MTDH integrates upstream signals from certain transcription factors and mediates pathogenic interactions contributing to MPM traits. MTDH represents a new MPM-associated gene that can contribute to insights of MPM biology and, as such, suggest other treatment strategies.
针对恶性胸膜间皮瘤（MPM）的治疗效果令人失望，部分原因是病理机制仍不清楚。在寻找合理的分子靶点时，我们发现了黏附素（MTDH），这是一种与多种肿瘤类型相关的多功能基因，但此前在MPM中未被识别。Cox比例风险回归分析确定了三个独立的MPM队列（n = 349例患者）中较高的MTDH表达与较低的患者生存率之间的关联。通过在MPM细胞中使用过表达和下调构建体的体外试验，我们确定了MTDH的作用。我们在小鼠异种移植模型中在体内证实了MTDH表达改变的表型。通过染色质免疫沉淀确定了MTDH的转录调节因子。在肿瘤组织中观察到MTDH mRNA（增加12倍）和蛋白质水平的过表达。MTDH的稳定过表达显著增强了增殖、侵袭性、集落形成、化疗耐药性和抗凋亡表型，而其抑制在MPM细胞中显示出相反的效果。有趣的是，NF-κB和c-Myc（以前馈环基序）有助于调节MTDH表达。敲低MTDH表达可显著延缓异种移植肿瘤的生长。因此，我们的研究结果支持这样一种观点，即MTDH整合了来自某些转录因子的上游信号，并介导了导致MPM特征的致病相互作用。MTDH代表了一个新的与MPM相关的基因，它有助于深入了解MPM生物学，并因此提示其他治疗策略。
