Abstract
BackgroundSonic hedgehog (SHH) plays critical roles in cell growth and development. Tumor cells express SHH, which can promote cell proliferation and epithelial-to-mesenchymal transition. However, the autocrine SHH pathway has not been described in gastric cancer. The aim of this study was to explore molecular mechanisms underlying autocrine SHH signaling in gastric cancer cells.MethodsSHH expression was assessed using immunohistochemistry and the results were compared with clinicopathologic parameters, including survival. Using gastric cancer cell lines, we measured SHH mRNA and protein expression, and studied the effects of SHH signaling on cell proliferation and SHH secretion. We also studied the effects of an inhibitor of PLC-γ1 on phosphorylation of phospholipase Cγ1 and extracellular signal-regulated kinases (ERK)1/2.ResultsSHH protein expression in gastric cancer tissue was significantly higher compared with that in normal gastric tissue (P < 0.001), and the increased expression was significantly associated with pT staging (P = 0.004), pN staging (P = 0.018), pM staging (P = 0.006), and pTNM staging (P < 0.001). In multivariate analyses, overall survival in gastric cancer was significantly shorter in cases with high SHH expression (HR = 1.734, 95 % CI: 1.109–2.713, P = 0.016). The AGS and SGC-7901 gastric cancer cell lines expressed SHH mRNA and protein. In these cell lines, SHH promoted carcinogenesis through activation of the PLCγ1-ERK1/2 pathway, resulting in increased cell proliferation and survival.ConclusionsIncreased SHH expression is associated with shorter survival in gastric cancer patients, and SHH could represent a useful biomarker or therapeutic target for this disease.
Highlights
Sonic hedgehog (SHH) plays critical roles in cell growth and development
Increased SHH expression is associated with shorter survival in gastric cancer patients, and SHH could represent a useful biomarker or therapeutic target for this disease
We found that compared with tumor tissues, 9 patients (9/30) have low SHH expression in tumor tissues, and 21 patients (21/30) have high SHH expression in tumor tissues
Summary
Sonic hedgehog (SHH) plays critical roles in cell growth and development. Tumor cells express SHH, which can promote cell proliferation and epithelial-to-mesenchymal transition. The autocrine SHH pathway has not been described in gastric cancer. The aim of this study was to explore molecular mechanisms underlying autocrine SHH signaling in gastric cancer cells. Despite advances in chemotherapy and surgery, the prognosis of patients with advanced GC remains poor. Targeted molecular therapy provides greater specificity and selectivity than traditional treatments, decreasing the likelihood of drug resistance and chemotherapy-associated side effects [4]. Despite their superior efficacy against many tumors, the effects of targeted drugs on GC remain unsatisfactory. It is necessary to further understand the molecular mechanism underlying GC development and to design new targeted drugs for improving the prognosis and treatment of GC patients
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