Mechanism Of Regulating Liver Derived Cells Proliferation By KIAA0157 And Hepassocin

Regulation of cell proliferation play critical roles in cell survival and development. Study on mechanism of cells proliferation and regulation may help to find drug targets and provides theoretical support during drugs development. This study mainly is focused on the mechanism of cell proliferation by KIAA0157 and Hepassocin both of which are related with cells growth.KIAA0157 (ABRO1) is a newly found member from KIAA gene family with unknown function. Our previous studies found that expression of KIAA0157 was frequently downregulated in many kinds of tumor tissues comparing to normal tissues, and introduction of KIAA0157 into HCC inhibited its colony formation. This thesis found that introduction of KIAA0157 stabilized p53 and enhanced activity of p53, and degradation of p53 was enhanced while knocking down of KIAA0157 by RNA interference; Meanwhile, KIAA0157 also inhibited cells colony formation and induced G0/G1 arrest in a p53 dependent manner. Furthermore, KIAA0157 was shown interacted with MDM2 by immunoprecipitation assay, and KIAA0157 might inhibit p53 degradation and reduced MDM2-mediated p53 ubquitination. These findings indicated that KIAA0157 might regulate p53 through interaction with MDM2, and it might be a new target for cancer therapy.Hepassocin (HPS), is a liver-specific expressed protein, and plays an important role in repair of liver damage. Previous studies indicates that HPS specifically stimulate proliferation of normal liver cells, introduction of HPS can inhibit growth in HCC, with unknown mechanism. Our studies found that: 1) Hepatic cell line L02 cells produced and secreted HPS by analyzing with Immunoblot and ELISA; 2) HPS secretion was depended on its N-terminal 22 amino acids; 3) FITC labeled HPS protein binding assay confirmed the existence of HPS specific receptor in L02 cells; 4) HPS neutralizing antibody could block proliferation activity of L02 condition medium and inhibit L02 cells proliferation. These studies suggested that HPS regulated L02 cells proliferation via an autocrine mechanism. To reveal the effects of HPS in HCC cells, wild type and N-terminal 22 amino acids deletion HPS (non-secretory) was constructed. The results showed that introduction of HPS and non-secretory HPS could inhibit colony formation in HepG2 cells, and both of them could induce G0/G1 arrest, furtherly, non-secretory HPS had stronger inhibition than wild type HPS. In addition, ectogenous HPS did not significantly affect growth in HCC, although HPS could be produced and secreted. These results suggested that HPS regulated cells growth via an intracrine mechanism in HCC. The mechanism of proliferation regulation by HPS in hepatic cells and hepatoma carcinoma cells laid a theoretical foundation for HPS as liver injury drugs.