Fagoonee Sharmila, Picco Gabriele, Orso Francesca, Arrigoni Arrigo, Longo Dario L, Forni Marco, Scarfò Irene, Cassenti Adele, Piva Roberto, Cassoni Paola, Silengo Lorenzo, Tolosano Emanuela, Aime Silvio, Taverna Daniela, Pandolfi Pier Paolo, Brancaccio Mara, Medico Enzo, Altruda Fiorella
Institute of Biostructure and Bioimaging, CNR, Department of Molecular Biotechnology and Health Sciences, University of Turin, Italy.
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Italy.
Oncotarget. 2017 Feb 7;8(6):10007-10024. doi: 10.18632/oncotarget.14318.
Epithelial splicing regulatory protein 1 (ESRP1) is an epithelial cell-specific RNA binding protein that controls several key cellular processes, like alternative splicing and translation. Previous studies have demonstrated a tumor suppressor role for this protein. Recently, however, a pro-metastatic function of ESRP1 has been reported. We thus aimed at clarifying the role of ESRP1 in Colorectal Cancer (CRC) by performing loss- and gain-of-function studies, and evaluating tumorigenesis and malignancy with in vitro and in vivo approaches. We found that ESRP1 plays a role in anchorage-independent growth of CRC cells. ESRP1-overexpressing cells grown in suspension showed enhanced fibroblast growth factor receptor (FGFR1/2) signalling, Akt activation, and Snail upregulation. Moreover, ESRP1 promoted the ability of CRC cells to generate macrometastases in mice livers. High ESRP1 expression may thus stimulate growth of cancer epithelial cells and promote colorectal cancer progression. Our findings provide mechanistic insights into a previously unreported, pro-oncogenic role for ESRP1 in CRC, and suggest that fine-tuning the level of this RNA-binding protein could be relevant in modulating tumor growth in a subset of CRC patients.
上皮剪接调节蛋白1（ESRP1）是一种上皮细胞特异性RNA结合蛋白，可控制多种关键细胞过程，如可变剪接和翻译。先前的研究已证明该蛋白具有肿瘤抑制作用。然而，最近有报道称ESRP1具有促转移功能。因此，我们旨在通过进行功能缺失和功能获得研究，并采用体外和体内方法评估肿瘤发生和恶性程度，来阐明ESRP1在结直肠癌（CRC）中的作用。我们发现ESRP1在CRC细胞的非锚定依赖性生长中起作用。悬浮培养的ESRP1过表达细胞显示出增强的成纤维细胞生长因子受体（FGFR1/2）信号传导、Akt激活和Snail上调。此外，ESRP1促进CRC细胞在小鼠肝脏中产生大转移灶的能力。因此，ESRP1高表达可能刺激癌上皮细胞生长并促进结直肠癌进展。我们的研究结果为ESRP1在CRC中以前未报道的促癌作用提供了机制性见解，并表明微调这种RNA结合蛋白的水平可能与调节一部分CRC患者肿瘤生长有关。
