Microtubule-associated protein 4 is an important regulator of cell invasion/migration and a potential therapeutic target in esophageal squamous cell carcinoma

Y-Y Jiang, L Shang, Z-Z Shi1, T-T Zhang, S Ma, C-C Lu, Y Zhang, J-J Hao, C Shi, F Shi, X Xu, Y Cai, X-M Jia, Q–M Zhan and M-R Wang

Oncogene 2016 35, 4846–4856

Speaker: Chun-I Li (李俊毅)                                               Time: 15:00~16:00, Apr. 05, 2017

Commentator: Dr. Bei-Chang Yang (楊倍昌 老師)            Place: Room 601

Abstract:

Extensive local invasion and distant metastasis are the major cause of deaths in cancer patients including esophageal squamous cell carcinoma (ESCC), a predominant type of esophageal cancer occurring in Chinese population¹. Cortactin (CTTN) is an oncogene which promotes ESCC metastasis². CTTN localizes in the cytoplasm and the cell-substratum contacts to regulate the interaction of the components of adherens-type junctions and to organize the cytoskeleton and cell adhesion structures of epithelia and carcinoma cells. In the preasent study, the authors found that microtubule-associated protein 4 (MAP4) is a regulator which interactes with CTTN. MAP4 protein is a member of microtubule-associate proteins (MAPs) family. MAP proteins interacts with the microtubules of the cellular cytoskeleton, and is responsible for stabilization of microtubules in human cancers. Here, the authors showed that knockdown of MAP4 suppressed the invasion and migration ability of the cells with MAP4 overexpression. When MAP4 expression was restored by transfecting with the GV230-MAP4-expression plasmid, the inhibition on cell invasion and migration could be rescued. The authors reveal that MAP4 promotes vascular endothelial growth factor A (VEGFA) expression through ERK1/2-c-Jun signaling pathway. The stable ESCC cell line expressing lentivirus sh-MAP4 showed suppression of tumor growth and metastasis compared with sh-scramble cells in the mouse model. The authors further confirmed that the tumor volume of the mice received MAP4-siRNA complex was smaller than the mice received non-silencing-siRNA complex. A combination of MAP4-siRNA and Bevacizumab, a recombinant humanized monoclonal antibody and can inhibit the binding of VEGF to its receptors, significantly enhanced the inhibitory effect. Multivariate Cox regression analysis showed that MAP4 is an independent prognostic indicator. Taken together, this study suggests that MAP4 is probably a useful prognostic biomarker and a potential therapeutic target for the ESCC development.

References:

1     Mengb H-XJ, Chenb C (2005). Decrease in the esophageal cancer incidence rate in mountainous but not level parts of Cixian County, China, over 29 years. Asian Pac J Cancer Prev 6: 510-514.

2     Luo M-L, Shen X-M, Zhang Y, Wei F, Xu X, Cai Y et al (2006). Amplification and overexpression of CTTN (EMS1) contribute to the metastasis of esophageal squamous cell carcinoma by promoting cell migration and anoikis resistance. Cancer Res 66: 11690-11699.