Identification of NCK1 as a novel downstream effector of STAT3 in colorectal cancer metastasis and angiogenesis

• Published in: Cellular signalling 2017-08, Vol.36, p.67-78
• Main Authors: Zhang, Fan, Lu, Yan-xia, Chen, Qing, Zou, Hui-mei, Zhang, Jian-ming, Hu, Yu-han, Li, Xiao-min, Zhang, Wen-juan, Zhang, Wei, Lin, Chun, Li, Xue-nong
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Angiogenesis; Animals; Cell Movement; Chickens; Colorectal cancer; Colorectal Neoplasms - blood supply; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Focal Adhesion Kinase 2 - metabolism; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Human Umbilical Vein Endothelial Cells; Humans; Lymphatic Metastasis - pathology; Male; Metastasis; Mice, Nude; Middle Aged; NCK1; Neovascularization, Pathologic - metabolism; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; STAT3; STAT3 Transcription Factor - metabolism; Transcription, Genetic
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2017.04.020

Signal transducer and activator of transcription 3 (STAT3) is known to activate targets associated with invasion, proliferation, and angiogenesis in a wide variety of cancers. The adaptor protein NCK1 is involved in cytoskeletal movement and was identified as a STAT3-associated target in human tumors. However, the underlying molecular mechanism associated with colorectal cancer (CRC) metastasis is not yet completely understood. In this study, we report a novel STAT3 to NCK1 signaling pathway in colorectal cancer (CRC). We investigated the expression of NCK1 and its potential clinical and biological significance in CRC. NCK1 was noticeably up-regulated in human CRC tissues. NCK1 was also significantly associated with serosal invasion, lymph metastasis, and tumor-node-metastasis classification but was inversely correlated with differentiation. Gain-of-function and loss-of-function studies have shown that ectopic expression of NCK1 enhanced metastasis and angiogenesis in CRC cells. By gene expression analyses, we revealed a high co-overexpression of STAT3 and NCK1 in CRC tissues. Ectopic overexpression of STAT3 in CRC cells induced the expression of NCK1, whereas STAT3 knockdown decreased the expression of NCK1. Promoter activation and binding analyses demonstrated that STAT3 promoted the expression of NCK1 via direct action on the NCK1 promoter. The knock down of NCK1 partially reduced the CRC cell metastasis and angiogenesis promoted by STAT3. Additionally, by co-immunoprecipitation assays, we verified that NCK1 interacted with PAK1, which resulted in the activation of the PAK1/ERK pathway. STAT3 induced the transcription of NCK1 and triggered a PAK1/ERK cascade in CRC. These findings suggest a novel STAT3 to NCK1 to PAK1/ERK signaling mechanism that is potentially critical for CRC metastasis and angiogenesis. •Overexpression of NCK1 correlates with colorectal cancer metastasis•NCK1 promotes CRC metastasis and enhances CRC-induced angiogenesis•NCK1 activates PAK1/ERK signaling in CRC cells•PYK2 is critical for the activation of the PAK1/ERK pathway induced by NCK1•STAT3 activation of the PAK1/ERK axis partially depends on the transcriptional regulation of NCK1