RASAL2 promotes tumor progression through LATS2/YAP1 axis of hippo signaling pathway in colorectal cancer

作者：Yi Pan, Joanna H.M. Tong, Raymond Wai Ming Lung, Wei Kang, Johnny Sheung Him Kwan, Wing Po Chak, Ka Yee Tin, Lau Ying Chung, Feng Wu, Simon S.M. Ng, Tony Wing Chung Mak, Jun Yu, Kwok Wai Lo, Anthony W.H. Chan, Ka‐Fai To · 发表于：Molecular Cancer · 年份：2018 · DOI：10.1186/s12943-018-0853-6 · 被引用次数：78 · 研究领域：Hippo pathway signaling and YAP/TAZ、RNA Research and Splicing、Hereditary Neurological Disorders

BACKGROUND: Patients with colorectal cancer (CRC) have a high incidence of regional and distant metastases. Although metastasis is the main cause of CRC-related death, its molecular mechanisms remain largely unknown. METHODS: Using array-CGH and expression microarray analyses, changes in DNA copy number and mRNA expression levels were investigated in human CRC samples. The mRNA expression level of RASAL2 was validated by qRT-PCR, and the protein expression was evaluated by western blot as well as immunohistochemistry in CRC cell lines and primary tumors. The functional role of RASAL2 in CRC was determined by MTT proliferation assay, monolayer and soft agar colony formation assays, cell cycle analysis, cell invasion and migration and in vivo study through siRNA/shRNA mediated knockdown and overexpression assays. Identification of RASAL2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays. RESULTS: Integrated genomic analysis identified copy number gains and upregulation of RASAL2 in metastatic CRC. RASAL2 encodes a RAS-GTPase-activating protein (RAS-GAP) and showed increased expression in CRC cell lines and clinical specimens. Higher RASAL2 expression was significantly correlated with lymph node involvement and distant metastasis in CRC patients. Moreover, we found that RASAL2 serves as an independent prognostic marker of overall survival in CRC patients. In vitro and in vivo functional...