Functional And Mechanistic Links Between Oncoprotein P28^GANK, Proline-rich Tyrosine Kinase-2(Pyk2) And Hepatocellular Carcinoma Recurrence And Metastasis

Partâ… Oncoprotein p28GANK Promotes Hepatocellular Carcinoma Progression and MetastasisPrimary liver cancer (PLC) is one of most prevalent malignant digestive cancers, the fifth most common cancer worldwide and the third most common cause of cancer-related death.90% PLC is hepacocellular carcinoma (HCC). PLC is most prevalent in our country and the second most common cause of cancer-related death, second only to lung cancer. The death cause of 90% HCC patients is related to tumor recurrence and metastasis after hepatectomy. Therefore, many biomarkers for prediction and intervention, mainly HCC metastasis-related chromosomes, genes, and proteins have been tried.It has been previously demonstrated that oncoprotein p28GANK (Gankyrin, PSMD10 or p28), commonly amplified in HCC, plays an important role in hepatocarcinogenesis by destabilizing Rb and p53, but its functional role in HCC metastases has remained unexplored. Here we reported that increased p28GANK in clinical samples of human HCC tissues after hepatohectomy predicted marked poorer survival and disease recurrence profiles. Analysis of tumor samples revealed that HCC patients with large tumors, vascular invasion, intrahepatic metastatic and distant metastatic tumor were prone to have higher p28GANK expression. Subsequent investigation revealed that tumors overexpressing p28GANK were more invasive, and exhibited increased angiogenesis associated with VEGF activation, whereas silencing endogenous p28GANK expression reduced motility/invasion. Taken together, it suggests that p28GANK plays an important role in recurrence and metastasis process. Partâ…¡The Role of Proline-rich Tyrosine Kinase 2 (Pyk2) in Hepatocellular Carcinoma Recurrence and MetastasisPyk2 (proline-rich tyrosine kinase-2), also known as RAFTK, CAK, and CADTK, is a non-receptor, proline-rich protein tyrosine kinase that is expressed in the cytoplasm of different cell types including brain cells, fibroblasts, platelets, and other hemopoietic cells. As a new member of focal adhesion kinase family, Pyk2 exhibits a high level (45% amino acid sequence) of sequence homology and similar structural organization to FAK. FAK has been reported to play a role on regulation of proliferation, survival, migration, invasion, metastasis and angiopoiesis in cancer cells. Pyk2 is an important signaling protein, serving as a upstream mediator of the JNK (c-Jun N-terminal kinase) signaling pathway as well as the Ras-MAPK (mitogen-activated protein kinase) signaling pathway. Overexpression or altered activity of Pyk2 has been linked to changes in cell adhesion, as well as invasion and metastasis of various malignancies, such as glioma or prostate cancers. However, the role of Pyk2 in HCCs has been unclear.In current study, we found that increased expression of Pyk2 in human HCC predicts poor survival and disease recurrence after surgery. HCC patients having large tumors, with vascular invasion and intrahepatic or distant metastasis, expressed high levels of Pyk2. Invasive tumors expressing Pyk2 exhibited increased vascular endothelia growth factor (VEGF) overexpression. Furthermore, Pyk2 activates AKT to promote VEGF promotion. Consistently, we detected a significant correlation between Pyk2 and VEGF levels in a cohort of HCC biopsie. Therefore, we proposed that Pyk2 plays a key role in HCC recurrence and metastasis via PI3K/AKT signaling pathway to induce VEGF expression.