Cross-talk of Ito(stellate) cell and preneoplastic and cancer cells of hepatocarcinogenesis

我们在研究期间的发现如下：（1）胆碱缺乏L-氨基酸（CDAA）定义的饮食诱导肝细胞死亡和再生，导致星状细胞活化，导致肿瘤前病变周围纤维化。用抗纤维化剂例如脯氨酰4-羟化酶抑制剂治疗导致抑制星状细胞活化，从而预防肿瘤前病变，减少纤维化，而不保护细胞死亡。(2)用胆碱缺乏的L-氨基酸（CDAA）限定的饮食治疗大鼠诱导细胞死亡和再生，引起枯否细胞和星状细胞的活化，其将产生TGF-β 1，导致纤维化的持续。(3)将肝癌细胞培养上清加入星状细胞上可诱导MAP激酶通路的激活，而加入癌细胞上清对癌细胞的细胞周期无影响。星状细胞与癌细胞共培养表明星状细胞向癌细胞移动。这一结果可能表明星状细胞可以阻止癌细胞的侵袭。然而，还需要进一步的研究。(4)腺病毒介导的MAP激酶通路的激活揭示了MMP-9的表达主要受ERK通路的调控，而MMP-13的表达受P38通路的独立调控，这一结果将为肝纤维化的治疗和肿瘤转移机制的研究提供新的思路。

Our finding during investigation terms are as follows ;(1) Choline deficient L-amino acid (CDAA) defined diet induced hepatocyte cell death and regeneration resulting in stellate cell activation leading to preneoplastic lesions surrounded with fibrosis. Treatment with anti-fibrotic agent e.g. prolyl 4-hydrohylase inhibitor lead to the inhibition of stellate cell activation resulting in the prevention of preneoplastic lesions with reduced fibrosis without the protection of cell death.(2) Treatment rats with Choline deficient L-amino acid (CDAA) defined diet induced the cell death and regeneration causing the activation of Kupffer and stellate cells which will produce TGF-beta 1 resulting in the perpetuation of fibrosis.(3) Addition of the supernatant of cultured hepatic cancer cells on stellate cells induced activation of MAP kinase pathway but addition of the supernatant of stellate cells on cancer cells did not change the cell cycle of cancer cell. Co-culture of stellate cells and cancer cells indicated that the movement of stellate cells to cancer cells. This result may suggest the prevention of cancer cell invasion by stellate cells. However further studies are necessary.(4) The activation of MAP kinase pathway by using adenovirus system revealed that the expression of MMP-9 is regulated mainly by ERK pathway and MMP-13 is regulated by P38 pathway independently.These results will give the new insight for the therapy of liver fibrosis as well as the mechanism of cancer metastasis.