Role of Stathmin-1 in Colorectal Cancer Metastasis and Chemo-resistance

Abstract

CRC metastasis is a major cause of mortality worldwide. Stathmin-1 (STMN1) up-regulation correlates with CRC metastatic progression and predicts poor disease-free survival. This work demonstrates that high STMN1 expression is sufficient to initiate metastatic processes in vitro, through promoting metastatic protein expression, as well as modulating oncogenic and mesenchymal transcription. STMN1 silencing on the other hand reinstates the default cellular programme of metastatic inhibition, and significantly improves chemo-response to 5FU through a novel caspase 6-dependent mechanism. Moreover, STMN1 function in metastatic processes is further regulated at the expression level by chemo-attractant stimulation, at the interaction level through potential binding to RhoGAP8, and by phosphorylations at S25 or S38, which have profound consequences on migratory and invasive processes. These findings establish STMN1 as a potential target in anti-metastatic therapy, and demonstrate the power of an approach coupling proteomics and transcript analyses in the global assessment of treatment benefits and potential side-effects.