| Gastric cancer is one of the malignant tumors with the highest morbidity and mortality in the world,and more than 35% of gastric cancer cases occur in China.As a common gastrointestinal cancer,the incidence and mortality of gastric cancer in China are all in the forefront of the world.At present,the efficacy of conventional treatment strategies of gastric cancer,such as surgery,chemotherapy,radiotherapy and molecular targeted therapy is limited.Immunotherapy has become a new breakthrough in the development of cancer therapeutics.Immunomodulation within the tumor microenvironment plays an important role in tumorigenesis and progression.The combined effect of multiple factors form a special mode of tumor local immunity.Cytokines,a class of small molecule proteins with a wide range of biological activities synthesized and secreted by immune cells(e.g.monocytes,macrophages,T cells,B cells and NK,etc.)and non-immune cells(e.g.endothelial cells,epidermal cells,fibroblasts,etc.),can regulate cell growth,differentiation,effects and immune responses by binding to their receptors.Interleukin-33(IL-33),a member of the interleukin-1 family,is expressed on a variety of immune and tissue cells and is an important cytokine that initiates and regulates immune responses.This study consists of three parts.Part I investigated the expression characteristics of IL-33 in gastric cancer.Part II assessed the role of soluble IL-33 in chemotherapy effect evaluation and prognosis of gastric cancer patients.Part III explored the regulatory mechanism of IL-33/ST2 signaling pathway on gastric cancer metastasis.Part I the expression characteristics of IL-33 in gastric cancer and its relationship with prognosis ObjectiveTo investigate the expression of interleukin-33 in gastric cancer patients and its relationship with clinicopathological parameters.MethodsThe expression of IL-33 in tumor and adjacent normal tissues of 180 gastric cancer patients from large sample of high-density tumor tissue microarray was detected by immunohistochemistry,and its correlation with the clinicopathological features and prognosis was analyzed.ResultsThe expression level of IL-33 in gastric cancer tissues was significantly lower than that in adjacent normal tissues,and was related to age,invasion depth and tumor morphology.IL-33 expression was higher in the elderly and well-differentiated groups.The correlation between IL-33 expression and invasion depth and tumor morphology suggest that IL-33 is involved in the inflammatory reaction during the development of gastric cancer.The expression of IL-33 in gastric cancer was significantly lower than paracancerous tissues,suggesting that the suppression of IL-33 may be an important reason for anti-tumor immune dysfunction.However,there was no significant correlation between the expression of IL-33 and the survival of patients.Therefore,IL-33 expression in tissues can not be used as a biological factor to predict the prognosis of gastric cancer patients.Part II the role of soluble IL-33 in chemotherapy effect evaluation and prognosis of gastric cancer patients ObjectiveTo investigate the expression of soluble IL-33 in gastric cancer and its value in chemotherapy effect evaluation and prognosis.MethodsSoluble IL-33 expression in 62 patients with gastric cancer was detected by ELISA,and the correlation between soluble IL-33 and PFS after chemotherapy was evaluated.ResultsThe level of soluble IL-33 in gastric cancer patients before chemotherapy was significantly higher than that in patients after chemotherapy and healthy controls.However,there was no significant difference of soluble IL-33 between patients after chemotherapy and healthy controls.Soluble IL-33 can be used as a sensitive indicator of chemotherapy response.In addition,the decrease of soluble IL-33 expression after chemotherapy is related to PFS.The decrease of IL-33 more than 30.1% after chemotherapy suggested a better PFS.Part III soluble ST2 inhibits malignant growth of gastric cancer cells via regulating tumor microenvironment ObjectiveTo explore the mechanism of soluble ST2(s ST2)inhibiting the malignant growth of gastric cancer cells via regulating tumor microenvironment.MethodThe expression levels of soluble ST2 and IL-33 protein and m RNA in four kind of cell lines were analyzed by Western blotting,Real-time PCR and ELISA.s ST2 knockdown cell line GC9811-P and its empty vector control were constructed to investigate the effect of downregulation of s ST2 on invasion and migration of tumor cells in vitro.Mouse implanted tumor model was constructed using GC9811-P cells with s ST2 down-regulated by lentivirus-encoding sh RNA transfection to observe the effect of downregulation s ST2 on tumor growth in vivo.s ST2 knock-down mice were treated by tail vein injection with s ST2-Fc expressing cells to observe whether s ST2-Fc could inhibit the growth of metastatic gastric cancer in s ST2-knockdown mice.ResultsThe downregulation of s ST2 expression is beneficial to the growth and metastasis of gastric cancer.The inhibitory effect of s ST2 on tumor growth depends on its synergy with other immune cells in tumor microenvironment.Recombinant s ST2-FC protein treatment can inhibit the growth and metastasis of gastric cancer.s ST2 may become a potential new target for gastric cancer therapy. |
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