Mechanism Of XCT On Regulating Metastasis Of Hepatocelluar Carcinoma

Objective:Hepatocellular carcinoma is one of the most ten popular cancers in the world, and it has the highest mortality rate besides pancreatic carcinoma. The symptoms in the early stage are not obvious, and some of the more common symptoms in the advanced stage show up including fatigue, jaundice, ascites and so on. Conventional treatments are surgery, radiotherapy and chemotherapy, but advanced patients have low recovery rate due to metastatic cancer cells. xCT, a functional subunit of the cystine/glutamate transporter Xc-system, plays a critical role in the maintenance of intracellular glutathione and redox balance. In recent years, some studies focused on the role of xCT in metastatic cancer. However, whether xCT is involved in hepatocellular carcinoma metastasis remains unclearly. This research focus on the regulatory mechanism of xCT on metastasis in Hepatocellular carcinoma.Methods:In order to analyze the influence of xCT expression on metastasis, RT-PCR was used to identify the expression level of xCT in hepatocellular carcinomas with different metastatic ability. Western Blot and RT-PCR were used to detect the expression levels of autophagy and EMT related genes after treated with sulfasalazine (SASP), an inhibitor of xCT activity. Wound healing assay and transwell assay were performed to evaluate the disruption effect of xCT on cell motility. Cells were treated with3-MA or β-ME combined with SASP separately to further analyzes whether xCT is involved in EMT and metastasis of hepatocellular carcinoma. Results:Part Ⅰ:1. The expression level of xCT in hepatocellular carcinoma and melanoma are higher than normal hepatocytes and melanocytes.2. The expression level of xCT in hepatocellular carcinoma and melanoma with high metastatic ability are higher than hepatocellular carcinoma and melanoma with low metastatic ability.Part Ⅱ: 1. Metastasic ability of hepatocellular carcinoma97H was inhibited after treated with SASP.2. Autophagy was induced in high metastatic hepatocellular carcinoma97H after treated with SASP.3. Autophagy can degrade the expression of transcription factor Snail and attenuate EMT process in Hepatocellular carcinoma.4. Inhibition of autophagy can rescue the degradation of Snail and suppression of EMT in Hepatocellular carcinoma.Conclusion:1. xCT was up-regulated in several kinds of cancer, especially in high metastatic cancer.2. Autophagy, which can degrade the expression of transcription factor Snail, was induced by inhibition of xCT activity. EMT was attenuated and migration was suppressed by xCT-dependent autophagy in Hepatocellular carcinoma.