二甲双胍在肝细胞癌治疗中的作用及其相关作用机制

Over the last decade, metformin, an anti-diabetic drug, has gained significant attention as an anti-cancer drug because of its association with a dramatically decreased risk of some cancers. The underlying mechanisms of action in hepatocelluar carcinoma(HCC), however, remain largely unknown.Our preliminary study, using a mouse HCC model, found an important and previously unidentified effect of metformin with the inhibition of HCC growth through an indirect path mediated by IL-22. The findings also provide evidence for immune-modulatory effects of metformin in HCC. Based on our in vivo and ex vivo studies which showed that metformin treatment decreased IL-22 expression, we speculate that metformin may suppress HCC growth through a IL-22-dependent way.To prove this theory, we plan to selectively knockout IL-22 in Sprague Dawley（SD） rats，and then subject them to HCC procedures, to show the effect of metformin on HCC in rats with different gene background. Furthermore, we plan to detect the levels of proliferation and apoptosis in different types of liver cancer cells cultured with metformin and analyze these data with tumor volume and weight, to conclude how metformin affects IL-22 signaling in liver cancer. This study may help promote understanding of metformin in the prevention of HCC which may serve as a novel therapeutic strategy

近来研究发现应用二甲双胍可减少糖尿病患者恶性肿瘤发生风险，二甲双胍也因此被视为抗肿瘤药物而受到广泛关注，然而它在肝细胞癌中的作用及机制尚不清楚。我们的前期研究提示二甲双胍能够通过影响IL-22表达从而间接地起到抑制小鼠肝细胞癌生长的作用。此外我们还发现二甲双胍在肝细胞癌的治疗上还具有免疫调节的功效。动物及细胞实验均提示二甲双胍减少IL-22的表达，基于此，我们推测二甲双胍是通过影响IL-22及其相关通路来发挥抑制肝细胞癌生长的效应。我们拟采用IL-22基因敲除的SD大鼠，诱导其发生肝细胞癌，观察二甲双胍干预下各敲除大鼠的肿瘤生长情况；然后检测二甲双胍干预下不同肝癌肿瘤细胞株的增殖及凋亡水平，结合分析肿瘤体积和重量的大小，探索二甲双胍在肝癌中如何影响IL-22及其相关信号通路。本研究将阐明二甲双胍在肝癌治疗过程中的作用及相关分子机制，为肝癌的防治提供新的思路和方案。