Švec Jiří, Šťastná Monika, Janečková Lucie, Hrčkulák Dušan, Vojtěchová Martina, Onhajzer Jakub, Kříž Vítězslav, Galušková Kateřina, Šloncová Eva, Kubovčiak Jan, Pfeiferová Lucie, Hrudka Jan, Matěj Radoslav, Waldauf Petr, Havlůj Lukáš, Kolář Michal, Kořínek Vladimír
Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic.
Department of Oncology, Third Faculty of Medicine, Charles University, University Hospital Kralovské Vinohrady, Šrobárova 1150/50, 100 34 Prague, Czech Republic.
Cancers (Basel). 2022 Aug 26;14(17):4137. doi: 10.3390/cancers14174137.
Trophoblastic cell surface antigen 2 (TROP2) is a membrane glycoprotein overexpressed in many solid tumors with a poor prognosis, including intestinal neoplasms. In our study, we show that TROP2 is expressed in preneoplastic lesions, and its expression is maintained in most colorectal cancers (CRC). High TROP2 positivity correlated with lymph node metastases and poor tumor differentiation and was a negative prognostic factor. To investigate the role of TROP2 in intestinal tumors, we analyzed two mouse models with conditional disruption of the adenomatous polyposis coli () tumor-suppressor gene, human adenocarcinoma samples, patient-derived organoids, and TROP2-deficient tumor cells. We found that Trop2 is produced early after Apc inactivation and its expression is associated with the transcription of genes involved in epithelial-mesenchymal transition, the regulation of migration, invasiveness, and extracellular matrix remodeling. A functionally similar group of genes was also enriched in TROP2-positive cells from human CRC samples. To decipher the driving mechanism of TROP2 expression, we analyzed its promoter. In human cells, this promoter was activated by β-catenin and additionally by the Yes1-associated transcriptional regulator (YAP). The regulation of TROP2 expression by active YAP was verified by YAP knockdown in CRC cells. Our results suggest a possible link between aberrantly activated Wnt/β-catenin signaling, YAP, and TROP2 expression.
滋养层细胞表面抗原2（TROP2）是一种膜糖蛋白，在包括肠道肿瘤在内的许多预后不良的实体瘤中过表达。在我们的研究中，我们发现TROP2在肿瘤前病变中表达，并且在大多数结直肠癌（CRC）中持续表达。高TROP2阳性与淋巴结转移和肿瘤分化差相关，是一个负性预后因素。为了研究TROP2在肠道肿瘤中的作用，我们分析了两种条件性破坏腺瘤性息肉病（APC）肿瘤抑制基因的小鼠模型、人腺癌样本、患者来源的类器官以及TROP2缺陷的肿瘤细胞。我们发现Trop2在Apc失活后早期产生，其表达与参与上皮-间质转化、迁移、侵袭和细胞外基质重塑调控的基因转录相关。一组功能相似的基因在人CRC样本的TROP2阳性细胞中也富集。为了解析TROP2表达的驱动机制，我们分析了其启动子。在人细胞中，该启动子由β-连环蛋白激活，此外还由Yes1相关转录调节因子（YAP）激活。通过在CRC细胞中敲低YAP验证了活性YAP对TROP2表达的调控。我们的结果提示异常激活的Wnt/β-连环蛋白信号、YAP和TROP2表达之间可能存在联系。
