Protumorigenic stathmin expression in liver cancer is linked to karyopherin alpha 2-dependent import of E2F1 and TFDP1

Alterations of the nuclear transport machinery including the functional and mechanistic consequences represent a promising field in liver cancer research. Karyopherin alpha 2 (KPNA2) serves as a key factor of nuclear protein import and is overexpressed in different malignancies including HCC. In this study we combined large scale proteomics (LC-MS/MS), cell based assays, co-transfection and co-immunoprecipitation experiments with data derived from murine and human liver cancer samples to explore the role of KPNA2 in HCC. By this approach we uncovered a functionally relevant link between KPNA2 and the oncogenic microtubule interacting protein stathmin (STMN1). More specifically, we could show that KPNA2 is required for full expression of stathmin and thereby maintains the migratory and clonogenic capacity of HCC cells. As the underlying mechanism we identified the transcription factors E2F1 and TFDP1 as transport substrates of KPNA2 controlling stathmin expression. Significant correlations between the aforementioned players in murine and human HCC samples as well as with an aggressive disease course highlight the in vivo relevance of our findings.

Our study suggests a KPNA2-dependent regulation of STMN1 by import of its transcription factors E2F1/TFDP1 and thereby provides a novel link between the nuclear transport system and microtubuli-interacting proteins in HCC with potential therapeutic implications.