Role And Mechanism Of Autophagy In Invasion And Metastasis Of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is characteristic of very poor prognosis and high recurrence. China is a high incidence area of HCC, and HCC mortality is2nd of cancer cause of death. Although the diagnosis and therapy of HCC have improved dramatically in the past30years, it couldn’t change the situation of high mortality fundamentally. And the primary cause is the characteristic of high metastasis and recurrence of HCC.There is very close relationship between tumor microenviroment and metastasis of tumor. Tumor microenviroment is characteristic of inflammation, ischemia and starvation of nutrient. These factors are identified as in statical condition in the past study. But as a matter of fact, they are in a cyclic fashion of dynamic change through the progression of tumor.Tumor microenviroment can induce Epithelial-mesenchymal-transition (EMT) of tumor cells and cause invasion and metastasis of tumor cells. It has been proven that inflammatory factors and dynamic hypoxia condition can induce EMT and maintain the mesenchymal trait of tumor cells. It also point out that the dynamic change of starvation is possible to induce EMT and maintain the mesenchymal trait of tumor cells. And this also can induce and maintain autophagy of tumor cells. It suggests that the dynamic change of starvation play a key role of maintain the situation of autophagy and mesenchymal traits.For simulating the dynamic change of starvation in our study, we treat the HCC cell line in starvation and then recover to normal nutrient (S-R). And this study proceeded from the following three aspects, for exploring the relationship between the situation of autophagy and mesenchymal traits.Part1The role of starvation treatment in invasion and migration of different cell lines.For simulating the dynamic change of starvation in tumor microenviroment, we treat the normal human liver cell line and HCC cell line in starvation and then recover to normal nutrient (S-R). We can observe that the invasion and migration of MHCC-97L and SMMC-7721have enhanced significantly. And the enhanced invasion and migration of MHCC-97L and SMMC-7721are due to EMT. It has also been proved in the in vivo experiment.Part2The role of inhibition of autophagy in mesenchymal traits of hepatocellular carcinoma cells.In this part of our study, we found that SMMC-7721maintained a situation of ongoing activated autophagy after S-R treatment. And starvation is not the key factor of maintaining this situation.3-MA and CQ are the inhibitors of autophagy. Inhibition of autophagy can attenuate the enhanced invasion and migration of SMMC-7721. It suggest that the enhanced invasion and migration of SMMC-7721are due to the situation of ongoing activated autophagy. It has also been proved in the in vivo experiment.Part3The mechanism of autophagy in enhanced invasion and migration of hepatocellular carcinoma cells.We found that SMMC-7721maintained upregulated autocrine level of TGF-β1after S-R treatment. And this played a key role in maintaining the situation of ongoing activated autophagy and the mesenchymal traits. Inhibition of TGF-β1can attenuate the situation of ongoing activated autophagy and the mesenchymal traits in SMMC-7721. Moreover, the autocrine level of TGF-β1in SMMC-7721is controlled by the situation of ongoing activated autophagy.To sum up, we conclude as follows:1. HCC cells can maintain the situation of ongoing activated autophagy after S-R treatment.2. The ongoing activated autophagy can upregulate the autocrine of TGF-β1. And the autocrine of TGF-β1can also maitian the situation of ongoing activated autophagy as positive feedback.3. The autocrine of TGF-β1induce EMT and maintain the mesenchymal traits, which generates the HCC with enhanced invasion and metastasis potential.