Role of PAK4 in extracellular matrix (ECM) degradation

Abstract

Extra Cellular Matrix (ECM) Degradation is one of the properties of metastatic cancer cells. A membrane structure called invadopodia is thought to be responsible to this property in cancer cells. It has been found in some invasive cancer cell but not yet in hepatocellular carcinoma (HCC). PAK4 belongs to the p21-associated kinases family. It has been found to be overexpressed in various carcinoma. It has also been shown to be participating in cell survival and cytoskeleton dynamic pathways so as to promote the proliferation and migration of cancer cells. PAK4 has also been found to promote podosomes formation, a homolog of invadopodia in macrophage. This research aims to investigate the role of PAK4 in the ECM degrading properties of HCC. HCC cell lines were tested by ECM degradation assay. Among those, only Hep3B exhibited invadopodia-like degradation. A MMP dependent, gelatin degradation pattern, characterized by large patches around cell peripheral, was observed in 2 HCC cell lines, SMMC-7721 (SMMC) and MHCC-97L. PAK4 overexpression in SMMC has been shown to promote the new degradation pattern and these cells have also shown a faster recovery of ECM degradation after removal of MMPs inhibitor. Q-PCR analysis showed PAK4 overexpression promoted MMP-9 transcription, one of the gelatin-degrading MMPs. These results suggested that PAK4 promotes the newly observed ECM degradation pattern in SMMC. This promotion is probably signaled through induction of MMP-9 transcription.