Liu Rui, Huang Shan, Lei Yunlong, Zhang Tao, Wang Kui, Liu Bo, Nice Edouard C, Xiang Rong, Xie Ke, Li Jingyi, Huang Canhua
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, P. R. China.
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, P. R. China.
Oncotarget. 2015 Jan 20;6(2):935-52. doi: 10.18632/oncotarget.2822.
Colorectal cancer (CRC) is a major cause of cancer-related death worldwide. The poor prognosis of CRC is mainly due to uncontrolled tumor growth and distant metastases. In this study, we found that the level of FGF8 was elevated in the great majority of CRC cases and high FGF8 expression was significantly correlated with lymph nodes metastasis and worse overall survival. Functional studies showed that FGF8 can induce a more aggressive phenotype displaying epithelial-to-mesenchymal transition (EMT) and enhanced invasion and growth in CRC cells. Consistent with this, FGF8 can also promote tumor growth and metastasis in mouse models. Bioinformatics and pathological analysis suggested that YAP1 is a potential downstream target of FGF8 in CRC cells. Molecular validation demonstrated that FGF8 fully induced nuclear localization of YAP1 and enhanced transcriptional outcomes such as the expression of CTGF and CYR61, while decreasing YAP1 expression impeded FGF-8-induced cell growth, EMT, migration and invasion, revealing that YAP1 is required for FGF8-mediated CRC growth and metastasis. Taken together, these results demonstrate that FGF8 contributes to the proliferative and metastatic capacity of CRC cells and may represent a novel candidate for intervention in tumor growth and metastasis formation.
结直肠癌（CRC）是全球癌症相关死亡的主要原因。CRC预后不良主要归因于肿瘤生长失控和远处转移。在本研究中，我们发现绝大多数CRC病例中FGF8水平升高，且FGF8高表达与淋巴结转移及较差的总生存期显著相关。功能研究表明，FGF8可诱导CRC细胞呈现更具侵袭性的表型，表现为上皮-间质转化（EMT）以及侵袭和生长能力增强。与此一致的是，FGF8在小鼠模型中也可促进肿瘤生长和转移。生物信息学和病理学分析表明，YAP1是CRC细胞中FGF8潜在的下游靶点。分子验证表明，FGF8可完全诱导YAP1核定位，并增强诸如CTGF和CYR61表达等转录结果，而降低YAP1表达则会阻碍FGF-8诱导的细胞生长、EMT、迁移和侵袭，这表明YAP1是FGF8介导的CRC生长和转移所必需的。综上所述，这些结果表明FGF8有助于CRC细胞的增殖和转移能力，可能是干预肿瘤生长和转移形成的新候选靶点。
