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目的 分析Shp2分子在肝癌干细胞(LCSC)中的表达和对肝癌(HCC)干性调控的意义,进而阐明Shp2调控LCSC的分子机制,探讨其作为HCC治疗靶点及HCC个体化治疗标志物的可行性.方法 采用real-time PCR检测化学治疗抵抗HCC皮下荷瘤中Shp2的表达,进而利用多种分选技术在HCC细胞系富集的干性样本中,通过real-time PCR技术检测Shp2的表达.采用干扰Shp2细胞系,通过Western blot方法明确Shp2对LCSC可能的调控机制.结果 裸鼠体内实验发现,Shp2在化学治疗抵抗HCC细胞皮下荷瘤中表达升高.细胞体外实验中Shp2在富集HCC干性细胞系中表达特异性升高.而在建立的HCC干扰Shp2细胞系中Shp2的表达与β-catenin密切相关,提示Shp2可能通过Wnt/β-catenin通路促进HCC干性形成能力.结论 本研究发现Shp2在HCC细胞中通过激活Wnt/β-catenin信号通路,促进LCSC的扩增.提示Shp2可能作为LCSC的标志物,为临床探索LCSC的靶向治疗提供新的分子靶点和临床转化依据.

Objective To study the expression of Shp2 in liver cancer stem cells and the significance of liver stem cells regulation,and then clarify the molecular mechanism of Shp2 in regulating the liver cancer stem cells,explore its feasibility as a therapeutic target for liver cancer and liver cancer biomarkers for individualized treatment.Methods Real-time PCR was used to detect the expression of Shp2 in chemotherapy resistant in HCC cells xenografts.In addition,the expression of Shp2 was detected by real-time PCR technique in stem cell enriched HCC cells using a variety of sorting techniques.The interfering Shp2 cell line was used to define the possible regulation mechanism of Shp2 on liver cancer stem cells by Western blot method.Results In vivo experiments showed that Shp2 expression increased in chemotherapy resistant liver cancer xenografts.What′s more,in vitro experiments,the expression of Shp2 was elevated in the liver cancer stem cells.The expression of Shp2 is closely related to the b-catenin in the interfering Shp2 HCC cell lines,suggesting that Shp2 may promote the formation of liver cancer stem cells through the Wnt/b-catenin pathway.Conclusion In this study,we found that the activation of Wnt/b-catenin signaling pathway by Shp2 in HCC cells promotes cancer stem cell expansion,which suggesting that Shp2 maybe as a biomarker of liver cancer stem cells,and provide a new molecular target and clinical basis for clinical transformation study.