在胶质母细胞瘤中，非典型的Cadherin-FAT1通过抑制PDCD10通过RelA/miR221-3p/222-3p轴的表达发挥促肿瘤作用。
Protumorigenic role of the atypical cadherin FAT1 by the suppression of PDCD10 via RelA/miR221-3p/222-3p axis in glioblastoma.
发表日期：2023 Aug 22
作者：
Nargis Malik, Archismita Kundu, Yakhlesh Gupta, Khushboo Irshad, Manvi Arora, Sanjeev Goswami, Swati Mahajan, Chitra Sarkar, Vaishali Suri, Ashish Suri, Parthaprasad Chattopadhyay, Subrata Sinha, Kunzang Chosdol
来源：
Cell Death & Disease
摘要：
非典型钙粘蛋白FAT1在不同组织起源的肿瘤中可能具有促癌或抗癌的功能。我们的研究小组先前在胶质母细胞瘤（GBM）中证明了FAT1信号通路的促癌性质。在本研究中，我们调查了FAT1如何影响GBM中聚集的致癌miRs（miR-221-3p/miR-222-3p）的表达及其下游效应。通过进行多个实验，包括测量特定基因/微RNA表达、基因沉默、蛋白质和细胞评估，我们证明了FAT1介导的一条新的钉子突变信号通路在胶质瘤中的致癌作用。这些结果已经通过使用抗甲基RNA和miR模拟实验得到验证。最初，在胶质瘤衍生的细胞系（U87MG和LN229）中，我们观察到FAT1作为转录因子NFκB-RelA的新的上调调节因子。RelA随后促进了聚集致癌miRs miR-221-3p/miR-222-3p的表达，而这些miRs进一步抑制了肿瘤抑制基因（TSG）PDCD10（编程性细胞死亡蛋白10）的表达。由miR-221-3p/miR-222-3p抑制PDCD10和其他已知TSG靶点（PTEN/PUMA），导致胶质瘤细胞的增加的克隆潜能、迁移和侵袭能力。与我们的体外实验结果一致，我们在GBM组织样本中观察到了FAT1与miR-221-3p的正相关表达，以及FAT1与miR靶点（PDCD10/PTEN/PUMA）的负相关表达。这些发现也得到了公开可用的GBM数据库（癌症基因组图谱[TCGA]和分子脑肿瘤数据库[Rembrandt]）的支持。具有高水平FAT1和miR-221-3p表达（分别为50%和65%）的肿瘤患者的整体生存期较短。类似的结果在TCGA-GBM数据库中观察到。因此，我们的研究结果显示了一条新的FAT1/RelA/miR-221/miR-222致癌效应通路，在GBM中下调了TSG PDCD10，可以特异性地成为治疗靶点。© 2023 Wiley Periodicals LLC.
The atypical cadherin FAT1 function either as a pro or antitumorigenic in tumors of different tissue origins. Our group previously demonstrated the protumorigenic nature of FAT1 signaling in glioblastoma (GBM). In this study, we investigated how FAT1 influences the expression of clustered oncomiRs (miR-221-3p/miR-222-3p) and their downstream effects in GBM. Through several experiments involving the measurement of specific gene/microRNA expression, gene knockdowns, protein and cellular assays, we have demonstrated a novel oncogenic signaling pathway mediated by FAT1 in glioma. These results have been verified using antimiRs and miR-mimic assays. Initially, in glioma-derived cell lines (U87MG and LN229), we observed FAT1 as a novel up-regulator of the transcription factor NFκB-RelA. RelA then promotes the expression of the clustered-oncomiRs, miR-221-3p/miR-222-3p, which in turn suppresses the expression of the tumor suppressor gene (TSG), PDCD10 (Programmed cell death protein10). The suppression of PDCD10, and other known TSG targets (PTEN/PUMA), by miR-221-3p/miR-222-3p, leads to increased clonogenicity, migration, and invasion of glioma cells. Consistent with our in-vitro findings, we observed a positive expression correlation of FAT1 and miR-221-3p, and an inverse correlation of FAT1 and the miR-targets (PDCD10/PTEN/PUMA), in GBM tissue-samples. These findings were also supported by publicly available GBM databases (The Cancer Genome Atlas [TCGA] and The Repository of Molecular Brain Neoplasia Data [Rembrandt]). Patients with tumors displaying high levels of FAT1 and miR-221-3p expression (50% and 65% respectively) experienced shorter overall survival. Similar results were observed in the TCGA-GBM database. Thus, our findings show a novel FAT1/RelA/miR-221/miR-222 oncogenic-effector pathway that downregulates the TSG, PDCD10, in GBM, which could be targeted therapeutically in a specific manner.© 2023 Wiley Periodicals LLC.