Regulation Of CD44v6 Expression In Gastric Carcinoma By The IL-6/STAT3 Signaling Pathway And Its Clinical Significance

Backgroud and Object:As a cancer stem cell marker,CD44 variant 6(CD44v6)has been implicated in carcinogenesis,tumor progression,and metastasis in a variety of human carcinomas.However,little is known about the expression of CD44v6 in Gastric Carcinoma(GC).Therefore we investigated CD44v6 expression in clinical specimen and further explore the underlying molecular mechanisms.Methods:In this study,we systemically investigated CD44v6 expression by immunohistochemistry in chronic gastritis(normal),premalignant gastric mucosa(Low-grade and high-grade intraepithelial neoplasia),and advanced GC at various stages.The correlation of CD44v6 expression with clinicopathological characteristics,and prognosis in GC was also analyzed.Western Blot was used to detect the expression of CD44v6 and p-STAT3 in gastric carcinoma tissues and adjacent tissues.Then,the protein and mRNA expression of CD44v6 in normal gastric cells GES-1 and gastric cancer cell lines MKN-45,N87,AGS,HGC-27 were detected by Western Blot and fluorescence quantitative PCR respectively.Next,the CD44v6 small interfering RNA was used to perform CCK-8 experiments,colony formation experiments,invasion and metastasis experiments to study the function of CD44v6 in gastric cancer cells.Finally,HGC-27 and AGS cells were treated with STAT3 small interfering RNA,AG490 and IL-6 to further study the related mechanism.Results:The expression of CD44v6 and p-STAT3 in advanced gastric carcinoma were higher than those in early cancer,precancerous and normal tissues(p<0.05).Enhanced expression of CD44v6 was closely associated with tumor differentiation,lymph node metastasis,TNM stage and poor prognosis in GC patients.(p<0.05).CD44v6 involves in GC cell proliferation,migration and invasion.Next,report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3(IL-6/STAT3)signaling up-regulates protein expression of CD44v6.RNA small interference silencing of STAT3 resulted in decrease of CD44v6 levels.We also found that STAT3 inhibitor AG490 down-regulate expression of CD44v6 by blocking activation of STAT3,even in the presence of IL-6.Conclusions:The expression of CD44v6 was increased by different stages of gastric cancer.Patients with CD44v6-high expression showed significantly poorer prognosis than those with CD44v6-low expression.In gastric cancer cell line HGC-27,CD44v6 involved in cell invasion and metastisis.IL-6/STAT3 signaling induces expression of CD44v6.Targeting STAT3-mediated CD44v6 up-regulation may represent a novel,effective treatment by eradicating the stomach tumor microenvironment.