A Set Of Protein Degradation-related Molecules Play A Role In Hepatocarcinogenesis

Hepatocellular carcinoma is a kind of malignant tumor which happened in liver cell orintrahepatic bile ducts cells with high malignant degree, fast progress and poor prognosis.Its incidence ranks sixth in malignant tumors and the death rate in third. Unfortunately,about half of HCC patients concentrated in China, seriously endangers our people’s health.In recent years, through technologies such as high throughput protein microarray andproteomics, new markers of metastasis and recurrence of HCC studies has considerableprogress. Establishment of more molecular prediction of liver cancer metastasis model, alarge number of clinical specimens for further verification, especially prospective scalevalidation and accelerated clinical application will be the main trend and research prioritiesin the future, which has a very important clinical significance to improve prognosis.Eukaryotic cells has two main protein degradation pathways: the ubiquitin-proteasomepathway and the lysosome pathway. Among them, the ubiquitin-proteasome pathway hasthe ability of highly selective degradation of those proteins cells produce under stress ornon-stress conditions, which is of great significance for the maintenance of normal cellphysiological function.Recent studies found that changes in polyubiquitinated anddeubiquitinated are closely related to occurrence of multiple tumors and malignant tumoroften couple with abnormal expression of oncogene and tumor-suppressor gene product.Based on the above research background, we speculated that key elements in proteindegradation system may play an important role in the development of liver cancer throughdirectly affect certain oncogene expression-related protein, thus has a value as HCCprognosis and treatment targets. Our previous reseach detected70cases of patients withHCC and adjacent tissue samples using gene chip and filtered out a set ofprotein-degradation related genes, PSMD4,UBD and CSTB, which expressed abnormallyin HCC and we planned to further explore their biological function in HCC.PSMD4gene coded protein is one of the26S proteasome non-ATPase regulatory subunit4, the molecular contains two segments of the ubiquitin-proteasome15amino acid sequence interaction model (ubiquitin interacting motif, UIM), can selectively bind proteinto mediate protein degradation. Existing research report, PSMD4abnormal expression hasa relationship with inflammatory bowel disease, ulcerative colitis and so on. But theexpression level and the biological function of PSMD4in liver cancer have not beenclearly elucidated. Foreign research institutions and our laboratory previous studies havefound that Gankyrin, also known as PSMD10which also belong to26S proteasomenon-ATPase regulatory subunit, play a vital role in hepatocarcinogenesis. Whether PSMD4like P28GANK play an important role in liver cancer or there exist some similaritybetween them is worth deep research.Ubiquitin D, that is UBD, belongs to the ubiquitin-like modifer (UBL) family and it cancovalently bind to target protein and mediate its degradation by ubiquitin-proteasomesystem. UBD can regulate TNF-α or LPS induced internal immunization activation bydegradating IκBα and it may be involved in the muturation process of DC cell, thereforeancient study were confined to its role in immune system. But its specific function in HCCprocess and its relationship with HCC patients prognosis haven’t been reported.Cystatin B, short for CSTB, is a member of the superfamily of cysteine proteinaseinhibitors. M.J. Lee et al. carried on the microarray and statistical analyses, whichidentified248genes expressed differently between HCC and nontumor liver tissues. CSTBwas expressed preferentially in the HCCs compared with the nontumor tissues,36of45specimens (80%) by Northern blot and semiquantitative reverse transcription-PCRanalyses. More importantly, the serum CSTB level was much higher in HCC patients thanin those with nonmalignant chronic liver disease. These results showed that CSTB jointAFP may be a more sensitive molecular diagnostic biomarkers of HCC. However, CSTBexpression level and its biological funtion in HCC as well as its relationship with prognosisin patients with HCC need further research.This project aims to validate the expression levels of the three molecules related toprotein degradation (PSMD4/UBD/CSTB) in HCC and study on their malignant biologicalbehaviour in hepatocarcinogenesis. Finding out a key molecule, analyze its value as HCCprognosis and therapy target to lay the foundation for the subsequent translational medicalresearch.