Abstract
HER2 becomes the standard of care for guiding adjuvant treatment of gastric cancer with trastuzumab in recent years. However, the usage of this target agent is still limited because of the resistance to trastuzumab or the negative expression of HER2 in tumor tissues. The Gli1 and HER2 both play an important role in the pathogenesis of gastric cancer. However, the correlation of them is still unclear. Here we found Gli1 and HER2 are highly expressed in gastric cancer tissues, and they are positively related. Next, we found Gli1 positive patients live a shorter survival time no matter HER2 positive or negative. Furthermore, univariate and multivariate analysis revealed that venous invasion, HER2 expression, Gli1 expression were independent prognostic factors for the survival time in gastric cancer. In addition, suppressing the expression level of Gli1 can decrease the cell viability and migration ability in cells and subcutaneous tumors. Finally, we found that HER2 may regulate Gli1 by Akt–mTOR–p70S6K pathway. Inhibit of HER2 and SMO have synergistic effect on reduction of cell viability. In conclusion, Gli1 is a favorable prognostic indicator in gastric cancer. As a novel target, Gli1 worth further study, especially in Her2-targeted therapy-resistant cancers.
Highlights
human epidermal growth factor receptor 2 (HER2) becomes the standard of care for guiding adjuvant treatment of gastric cancer with trastuzumab in recent years
The result showed the expression levels of Gli[1] and HER2 were significantly higher in gastric cancer than in para-cancer tissues (P < 0.001 and P < 0.001, Fig. 1B)
We concluded that Gli[1] and HER2 were overexpressed in gastric cancer tissues
Summary
HER2 becomes the standard of care for guiding adjuvant treatment of gastric cancer with trastuzumab in recent years. The usage of this target agent is still limited because of the resistance to trastuzumab or the negative expression of HER2 in tumor tissues. The Hedgehog (HH) pathway plays a crucial role in cell proliferation and metastasis in human tumors[7,8,9,10]. Because the HER2 positive gastric cancer patients receive significant benefit from trastuzumab, testing the expression of HER2 before targeted therapy is necessary[19]. That is to say, inhibiting Hedgehog pathway, especially targets Gli[1], may become one of the effective treatments of this lethal disease. We validated the anti-tumor effects of down-regulation of Gli[1] in gastric cancer cells and in heterologous subcutaneous caner mice, trying to identify a novel target for therapeutic intervention, especially in HER2-targeted therapy-resistant gastric cancer
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