The significance of proline-rich tyrosine kinase2 (Pyk2) on hepatocellular carcinoma progression and recurrence

Abstract

Understanding the precise molecular mechanisms that trigger liver cancer cell migration and invasion could develop novel therapeutic strategies targeting cancer cell invasion to increase the sensitivity to current treatment modalities. In the current study, 49 patients with hepatocellular carcinoma (HCC) were included prospectively. Liver tumour and adjacent non-tumour tissues were detected for the expression of Proline-rich tyrosine kinase 2 (Pyk2), focal adhesion kinase (FAK), ezrin and fibronectin at protein and/or gene levels. Correlation between the expressions of Pyk2/FAK with the clinical pathological data was analysed. Protein expression of Pyk2 was also examined in a nude mice orthotopic liver tumour model with higher metastatic potential. There were 59% (29 out of 49) and 57% (28 out of 49) of HCC patients with higher levels of Pyk2 and FAK protein/gene expression, respectively. We observed a positive correlation between the protein and gene expression levels of Pyk2 and FAK (P ¼ 0.000, r ¼ 0.875). Overexpression of Pyk2 and FAK was significantly correlated with shorter disease-free survival. Patients with higher levels of Pyk2/FAK had larger tumour size and advanced Edmonson grading. In the animal studies, Pyk2 overexpression was found in infiltrative tumour cells and lung metastatic nodules. In conclusion, overexpression of Pyk2 and FAK was found in nearly 60% of HCC patients and was significantly correlated with poor prognosis. The significance of Pyk2 in HCC invasiveness was confirmed by animal studies. Understanding the precise molecular networks that trigger liver cancer cell migration and invasion could develop novel therapeutic strategies targeting cancer cell invasion to increase the sensitivity to current treatment modalities. Focal adhesion kinase (FAK) is an important mediator of cell proliferation, cell survival and migration. Recently, clinical evidences demonstrated that FAK was involved in liver tumour progression and had prognostic significance for hepatocellular carcinoma (HCC) patients (Fujii et al, 2004;Itoh et al, 2004). In addition to clinical relevance, animal experiments also demonstrated that FAK might play important roles in the regulation of metastatic adhesion of cancer cells with liver sinusoids and formation of organ-specific distant metastases. An in vitro study confirmed that FAK integrated growth-factor and integrin signals to promote cell migration (Sieg et al, 2000). An in vivo animal model also demonstrated that FAK is important for lung metastasis in a breast cancer model (van Nimwegen et al, 2005).Proline-rich tyrosine kinase 2 (Pyk2), also known as cell adhesion kinaseb (CAKb), is a tyrosine kinase that is structurally related to focal adhesion kinase (FAK) (Sasaki et al, 1995). Pyk2 has been demonstrated to be able to promote migration and invasion of glioma cells (Lipinski et al, 2005) as well as mediate angiogenesis of pulmonary vascular endothelial cells (Tang et al, 2002). Moreover, Pyk2 also mediated vascular endothelial cadherin-based cell -cell adhesion an...

Focal Adhesion Kinase-Related Proline-Rich Tyrosine Kinase 2 and Focal Adhesion Kinase Are Co-Overexpressed in Early-Stage and Invasive ErbB-2-Positive Breast Cancer and Cooperate for Breast Cancer Cell Tumorigenesis and Invasiveness

“…5 such a correlation between FAK levels and the invasive phenotype in breast cancer. 38 In a similar manner, elevated Pyk2 expression was found to correlate with the progression of hepatocellular carcinoma, 39 gastric carcinoma, 40 and astrocytomas. 41 In contrast, other studies reported rather decreased Pyk2 expression in advanced osteosacroma 42 and in high-grade prostate cancer compared with normal epithelial prostate tissue and benign prostatic hyperplasia.…”

PYK2 via S6K1 regulates the function of androgen receptors and the growth of prostate cancer cells

“…PYK2 is mainly expressed in the central nervous system and hematopoietic cells; however, lines of evidence indicated the elevated expression of PYK2 in malignant tumors of epithelial origin. In hepatocellular carcinoma and nonsmall cell lung cancer, overexpression of PYK2 is found in approximately 60% of tumors evaluated and is significantly correlated with poor prognosis or lymph node metastasis (Sun et al 2007, Zhang et al 2008. In breast and bladder cancers, the expression of PYK2 elevated in malignant lesions compared with benign tissues (Behmoaram et al 2008, Genua et al 2012.…”

Phosphoproteomic Analysis Identifies Focal Adhesion Kinase 2 (FAK2) as a Potential Therapeutic Target for Tamoxifen Resistance in Breast Cancer

“…As a member of the focal adhesion kinase family, FAK2 has been reported to be mainly localized at the focal adhesions and nuclei of cells (48). Autophosphorylation at tyrosine residue Y402 activates FAK2, which then functions as a docking site for the SH2 domain of Src (49).…”