桑葉萃取物抑制肥胖因子誘導肝癌細胞增生之作用機制

流行病學研究表明，肥胖增加罹患癌症的風險。許多研究指出肥胖促進肝癌的發展主要是透過發炎因子的產生，如tumor necrosis factor-α (TNF-α)及interleukin-6 (IL-6)等，和活化的致癌基因轉錄因子。從脂肪細胞釋出發炎因子而活化TNF-α及IL-6下游蛋白（IκB、STAT3），進而導致肝細胞發炎及增生。先前的研究中指出桑葉萃取物內含之天然化合物中具有抗炎、抗氧化劑及保護肝臟活性之生物活性功能，因此，它在脂肪細胞所誘導之肝癌細胞增生上，其功效仍有待確認，故本項研究主要探討桑葉萃取物是否可以抑制由脂肪細胞所誘導的肝癌細胞增生之作用機制。研究結果顯示，3T3脂肪細胞分泌之培養液(conditioned medium，CM)與肝癌細胞(HepG2)共同培養後，脂肪細胞分泌之培養液內含細胞發炎物質；如TNF-α、IL-6 及 MCP-1等，其物質會誘導肝癌細胞HepG2增生。進一步將桑葉萃取物加入共同培養的模式內，桑葉萃取物(MLE)對TNF-α及IL-6活化途徑皆具有抑制作用，並且對TNF-α、IL-6之共同活化途徑PI3K/Akt/mTOR也具有相同的調控作用，這顯示桑葉萃取物(MLE)是透過阻斷TNF-α及IL-6的活化，使得脂肪細胞培養液誘導之HepG2 細胞的增生也被抑制。因此桑葉萃取物對改善及預防肝臟脂肪堆積所引發的發炎現象及肝癌細胞的增生應具有良好之潛力，並且針對其作用機轉仍需進行更深入研究。

Epidemiological studies have shown that overweight and obesity are associated with increase in risk of cancer. In addition, it well known that obesity-promoted hepatocellular carcinoma (HCC) development was dependent on enhanced production of the proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α)、interleukin-6 (IL-6) and activation of oncogenic transcription factor, such as IκB、STAT3 from adipocytes, which can led to hepatic inflammation and increase growth or abnormal liver cells.Researchers have pinpointed a number of biologically active compounds in mulberry leaf extract that are effective in anti-inflammatory, antioxidant, and hepatoprotective activities, however, by which it exerts its effects on adipocyte induced in liver cancer cell proliferation are not known. Therefore, in this study, we assayed the ability of mulberry leaf extract on the proliferation of HepG2 liver cancer cells in co-culture with adipocytes system. Our results demonstrated, for the first, that mulberry leaf extract can inhibit the HepG2 cell proliferation in the co-culture system and impedes the cytokine production in the culture medium. Consequently, blockage of PI3K / Akt / mTOR signaling might explain the inhibitory effects of mulberry leaf extract onHepG2 proliferation. Over all, these results may bear important implications of mulberry leaf extract for the manipulation of the inflammatory properties of adipocytes, in potential therapeutic applications against liver cancer.