Abstract
BackgroundGallbladder cancer (GBC) is a leading cause of cancer-related death worldwide, and its prognosis remains poor, with 5-year survival of approximately 5%. In this study, we analyzed the involvement of a novel proteoglycan, Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1), in the tumor progression and prognosis of human GBC.MethodsSPOCK1 expression levels were measured in fresh samples and stored specimens of GBC and adjacent nontumor tissues. The effect of SPOCK1 on cell growth, DNA replication, migration and invasion were explored by Cell Counting Kit-8, colony formation, EdU retention assay, wound healing, and transwell migration assays, flow cytometric analysis, western blotting, and in vivo tumorigenesis and metastasis in nude mice.ResultsSPOCK1 mRNA and protein levels were increased in human GBC tissues compared with those in nontumor tissues. Immunohistochemical analysis indicated that SPOCK1 levels were increased in tumors that became metastatic, compared with those that did not, which was significantly associated with histological differentiation and patients with shorter overall survival periods. Knockdown of SPOCK1 expression by lentivirus-mediated shRNA transduction resulted in significant inhibition of GBC cell growth, colony formation, DNA replication, and invasion in vitro. The knockdown cells also formed smaller xenografted tumors than control GBC cells in nude mice. Overexpression of SPOCK1 had the opposite effects. In addition, SPOCK1 promoted cancer cell migration and epithelial-mesenchymal transition by regulating the expression of relevant genes. We found that activation of the PI3K/Akt pathway was involved in the oncogenic functions of SPOCK1 in GBC.ConclusionsSPOCK1 activates PI3K/Akt signaling to block apoptosis and promote proliferation and metastasis by GBC cells in vitro and in vivo. Levels of SPOCK1 increase with the progression of human GBC. SPOCK1 acts as an oncogene and may be a prognostic factor or therapeutic target for patients with GBC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-014-0276-y) contains supplementary material, which is available to authorized users.
Highlights
Gallbladder cancer (GBC) is a leading cause of cancer-related death worldwide, and its prognosis remains poor, with 5-year survival of approximately 5%
With a focus on its antiapoptotic and epithelial-mesenchymal transition (EMT) functions, we demonstrated that SPOCK1 acts as a potential oncogene, which in turn contributes to the initiation and progression of GBC
SPOCK1 inhibits apoptosis in GBC cells To explore the molecular mechanism by which SPOCK1 regulated the proliferation and metastasis of GBC cells, we investigated the effect of SPOCK1 on apoptosis
Summary
Gallbladder cancer (GBC) is a leading cause of cancer-related death worldwide, and its prognosis remains poor, with 5-year survival of approximately 5%. We analyzed the involvement of a novel proteoglycan, Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1), in the tumor progression and prognosis of human GBC. Despite the relatively low incidence rate, GBC-associated mortality is higher than that of other cancers [2]. The prognosis of advanced gallbladder carcinoma is very poor, and the 5-year survival rate is only approximately 5% [3]. This poor survival rate is because of the early spread of tumors via lymphatic, perineural, and hematogenous routes as well as direct invasion into the liver [4]. Patient prognoses may be improved by identifying novel and effective therapeutic targets for the treatment of this disease and increasing our understanding of biomarkers that can predict therapeutic responses
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