Abstract
Focal adhesion kinase (FAK) has been implicated in tumorigenesis in various malignancies. We sought to examine the expression patterns of FAK and the activated form, phosphorylated FAK (pFAK), in human osteosarcoma and to investigate the correlation of FAK expression with clinicopathologic parameters and prognosis. In addition, the functional consequence of manipulating the FAK protein level was investigated in human osteosarcoma cell lines. Immunohistochemical staining was used to detect FAK and pFAK in pathologic archived materials from 113 patients with primary osteosarcoma. Kaplan-Meier survival and Cox regression analyses were performed to evaluate the prognoses. The role of FAK in the cytological behavior of MG63 and 143B human osteosarcoma cell lines was studied via FAK protein knock down with siRNA. Cell proliferation, migration, invasiveness and apoptosis were assessed using the CCK8, Transwell and Annexin V/PI staining methods. Both FAK and pFAK were overexpressed in osteosarcoma. There were significant differences in overall survival between the FAK-/pFAK- and FAK+/pFAK- groups (P = 0.016), the FAK+/pFAK- and FAK+/pFAK+ groups (P = 0.012) and the FAK-/pFAK- and FAK+/pFAK+ groups (P < 0.001). There were similar differences in metastasis-free survival between groups. The Cox proportional hazards analysis showed that the FAK expression profile was an independent indicator of both overall and metastasis-free survival. SiRNA-based knockdown of FAK not only dramatically reduced the migration and invasion of MG63 and 143B cells, but also had a distinct effect on osteosarcoma cell proliferation and apoptosis. These results collectively suggest that FAK overexpression and phosphorylation might predict more aggressive biologic behavior in osteosarcoma and may be an independent predictor of poor prognosis.
Highlights
Osteosarcoma is the most common malignant tumor in bone and leads to a large number of cancer-related deaths in children and young adults, mainly due to the development of lung metastases [1,2,3,4]
Focal adhesion kinase (FAK) was overexpressed in 61.95% (70/113) of osteosarcoma specimens with unequal intensity
The five-year metastasis-free survival rate was 55.0% for group A as compared with 27.6% and 16.9% for groups B and C, respectively. These results suggest that high FAK expression and FAK phosphorylation were associated with decreased overall survival and metastasisfree survival times
Summary
Osteosarcoma is the most common malignant tumor in bone and leads to a large number of cancer-related deaths in children and young adults, mainly due to the development of lung metastases [1,2,3,4]. The use of neoadjuvant chemotherapy began in the 1970s and has increased the five-year diseasefree survival rate from approximately 20% to 60% [2], www.impactjournals.com/oncotarget there have been only minimal improvements in the prognosis of osteosarcoma patients in the last two decades. It is of great importance to explore the mechanisms of osteosarcoma development in order to provide a basis for new therapies as alternatives to traditional chemotherapy and surgery. There are a limited number of predictors for patient prognosis in osteosarcoma. Other prognostic determinants have been insufficient to allow stratification of therapy, it is necessary to find novel prognostic indicators to stratify patients into low- and high-risk groups at initial diagnosis and to possibly indicate a role for effective targeted therapeutic agents [6,7,8]
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