Loss of Trop2 promotes carcinogenesis and features of epithelial to mesenchymal transition in squamous cell carcinoma.
Loss of Trop2 promotes carcinogenesis and features of epithelial to mesenchymal transition in squamous cell carcinoma.
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DOI：
10.1158/1541-7786.mcr-11-0241
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发表时间：
2011-12
期刊：
影响因子：
--
通讯作者：
Michel LS
中科院分区：
文献类型：
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作者：
Wang J;Zhang K;Grabowska D;Li A;Dong Y;Day R;Humphrey P;Lewis J;Kladney RD;Arbeit JM;Weber JD;Chung CH;Michel LS
Trop 2是一种正在研究中的作为治疗靶点的致癌细胞表面蛋白，通常在几种上皮肿瘤类型中过表达，但其在肿瘤生物学中的功能仍然相对未被探索。为了研究Trop 2在上皮癌发生中的作用，我们产生了Trop 2 −/−小鼠，它们是可行的，具有正常的寿命。与预期相反，Trop 2缺失不能抑制角质形成细胞转化。相反，ras转化的Trop 2 −/−角质形成细胞优先通过上皮向间充质转化（EMT），并形成具有梭形细胞组织学的肿瘤。此外，Trop 2缺失使得Arf缺失小鼠在暴露于致癌物时易形成含有鳞状细胞和梭形细胞组分的双相肉瘤样癌，而在其他皮肤癌抗性品系（C57 B1/6）中。来源于Trop 2 −/−Arf−/−小鼠的永生化角质形成细胞在转化前表现出增强的增殖和迁移能力以及增加的MAPK和Src活化。这些发现的临床相关性得到了原发性头颈部鳞状细胞癌中Trop 2分子流行病学研究的支持。该分析显示，Trop 2 mRNA水平在具有EMT特征的肿瘤亚组中降低，并且在肉瘤样癌的梭形细胞组分中观察到Trop 2蛋白表达的完全丧失。因此，虽然以前的研究强调了Trop 2功能获得的潜在重要性，但这些结果揭示了Trop 2丢失在肿瘤发生和鳞状细胞癌亚群中观察到的间充质转分化中的作用。
Trop2, an oncogenic cell-surface protein under investigation as a therapeutic target, is commonly overexpressed in several epithelial tumor types yet its function in tumor biology remains relatively unexplored. To investigate the role of Trop2 in epithelial carcinogenesis, we generated Trop2−/− mice, which are viable and possess a normal lifespan. Contrary to expectations, Trop2 loss fails to suppress keratinocyte transformation. Instead, ras-transformed Trop2−/− keratinocytes preferentially pass through an epithelial to mesenchymal transition (EMT) and form tumors with spindle cell histology. Furthermore, Trop2 loss renders Arf null mice susceptible to the formation of biphasic sarcomatoid carcinomas containing both squamous and spindle cell components upon carcinogen exposure in an otherwise skin-cancer resistant strain (C57Bl/6). Immortalized keratinocytes derived from Trop2−/−Arf−/− mice exhibit enhanced proliferative and migratory capacity as well as increased activation of MAPK and Src prior to transformation. The clinical relevance of these findings was supported by studying the molecular epidemiology of Trop2 in primary head and neck squamous cell carcinomas. This analysis revealed that Trop2 mRNA levels are decreased in a subset of tumors with features of EMT, and total loss of Trop2 protein expression is observed in the spindle cell component of sarcomatoid carcinomas. Therefore, while previous studies have emphasized the potential importance of Trop2 gain-of-function, these results uncover a role for Trop2 loss in tumorigenesis and the mesenchymal transdifferentiation observed in a subset of squamous cell carcinomas.