Autocrine Sonic hedgehog signaling promotes gastric cancer proliferation through induction of phospholipase Cγ1 and the ERK1/2 pathway

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.

Antitumor Efficacy of Dual Blockade of EGFR Signaling by Osimertinib in Combination With Selumetinib or Cetuximab in Activated EGFR Human NCLC Tumor Models

“…[31][32][33][34][35][36] In pancreatic ductal adenocarcinoma cells and in gastric cancer cells, RAS stimulates Gli transcriptional activity, inducing the expression of hedgehog target genes, using MAPK as a downstream mediator 31,32 and, also, in gastric cancer cells, autocrine sonic hedgehog ligand (SHH) itself produces ERK1/2 activation. 33 In hepatocellular carcinoma, Gli reinforces ERK1/2-dependent invasiveness through MMP9 34 , and in melanoma cells the combination of sonidegib and BRAF-inhibitor vemurafenib synergistically affects proliferation. 35 We speculate that in EGFR-resistant NCLC, the escape to EGFR blockade through downstream MAPK signaling activation is possible through the activation of collateral pathways, including hedgehog, by the final MAPK effectors themselves, as represented schematically in Supplemental Figure 3.…”

Protective potential of miR-146a-5p and its underlying molecular mechanism in diverse cancers: a comprehensive meta-analysis and bioinformatics analysis

“…Prior studies have noted the importance of PLC in modulating proliferation, invasion, and metastasis, suggesting its role in carcinogenesis and tumor progression in various malignancies [62,63]. It has been reported that abnormal expression levels or mutations in PLC-γ (a PLC member) are related to the occurrence of breast cancer, gastric cancer, and oral squamous cell carcinoma [64][65][66][67]. We found potential interactions between EGFR and PLC-γ activities, which have a role in breast cancer, whereby EGFR/ human epidermal growth factor receptor 2/PLC-γ1 signaling results in tumor cell invasion and migration [25,68,69].…”

Human CAFs promote lymphangiogenesis in ovarian cancer via the Hh-VEGF-C signaling axis

“…Previous studies have indicated that tumour cells synthesize and respond to the Hh ligand in an autocrine-juxtacrine manner [ 17 , 18 ]. However, our data suggested a paracrine mode of the canonical Hh signalling pathway in OC.…”