Upregulation of nuclear PA28γ expression in cirrhosis and hepatocellular carcinoma

Kondo,Motoi; Moriishi,Kohji; Wada,Hiroshi; Noda,Takehiro; Marubashi,Shigeru; Wakasa,Kenichi; Matsuura,Yoshiharu; Doki,Yuichiro; Mori,Masaki; Nagano,Hiroaki

doi:10.3892/etm.2011.415

Upregulation of nuclear PA28γ expression in cirrhosis and hepatocellular carcinoma

Authors:
- Motoi Kondo
- Kohji Moriishi
- Hiroshi Wada
- Takehiro Noda
- Shigeru Marubashi
- Kenichi Wakasa
- Yoshiharu Matsuura
- Yuichiro Doki
- Masaki Mori
- Hiroaki Nagano
View Affiliations

Affiliations: Evidence Based Medical Research Center, Osaka, Japan, Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan, Department of Diagnostic Pathology, Graduate School of Medicine, Osaka City University, Osaka, Japan
Published online on: December 14, 2011 https://doi.org/10.3892/etm.2011.415
Pages: 379-385

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

We previously reported that proteasome activator 28γ (PA28γ) is an oncogenic protein in hepatitis C virus (HCV) core protein transgenic mice. The aim of this study was to determine the role of PA28γ expression at the protein level in the development and progression of human hepatocarcinogenesis and hepatocellular carcinoma (HCC). Samples from tissues representing a wide spectrum of liver disease were analyzed, including histologically normal livers (n=5), HCV-related chronic hepatitis (CH) (n=15) and cirrhosis (n=31). The level of nuclear PA28γ increased with the progression of liver disease from CH to cirrhosis. The majority of cirrhotic livers (68%; 21/31) displayed high nuclear PA28γ expression. However, in half of the HCCs (50%; 18/36), little or no nuclear PA28γ expression was observed, while the remaining 50% (18/36) of the cases displayed high levels of nuclear PA28γ expression. A clinicopathological survey demonstrated a significant correlation between nuclear PA28γ expression and capsular invasion in HCC (P=0.026); a striking difference was found between nuclear PA28γ expression in non-tumor tissues and shorter disease-free survival (P<0.01). Moreover, nuclear PA28γ expression in non-tumor tissues correlated with the expression of molecules related to the genesis of hepatic steatosis and HCC, such as sterol regulatory element binding protein‑1c mRNA. The findings suggest the involvement of nuclear PA28γ expression in the progression and relapse of HCC, and suggest that nuclear PA28γ is a potentially suitable target for the prevention and/or treatment of HCC.

View Figures

View References

1.	G MontaltoM CervelloL GiannitrapaniF DantonaA TerranovaLA CastagnettaEpidemiology, risk factors, and natural history of hepatocellular carcinomaAnn NY Acad Sci9631320200210.1111/j.1749-6632.2002.tb04090.x12095924
2.	K OkudaHepatocellular carcinoma: Recent progressHepatology15948963199210.1002/hep.1840150532
3.	MC KewH PopperRelationship between hepatocellular carcinoma and cirrhosisSemin Liver Dis4136146198410.1055/s-2008-10406536087459
4.	K IkedaS SaitohI KoidaY AraseA TsubotaK ChayamaH KumadaM KawanishiA multivariate analysis of risk factors for hepatocellular carcinogenesis: A prospective observation of 795 patients with viral and alcoholic cirrhosisHepatology184753199310.1002/hep.18401801097686879
5.	Y ShiratoriS ShiinaM ImamuraCharacteristic difference of hepatocellular carcinoma between hepatitis B- and C- viral infection in JapanHepatology2210271033199510.1002/hep.18402204037557847
6.	N NagasueM UchidaY MakinoIncidence and factors associated with intrahepatic recurrence following resection of hepatocellular carcinomaGastroenterology10548849419938392955
7.	K IkedaS SaitohA TsubotaY AraseK ChayamaH KumadaG WatanabeM TsurumaruRisk factors for tumor recurrence and prognosis after curative resection of hepatocellular carcinomaCancer711925199310.1002/1097-0142(19930101)71:1%3C19::AID-CNCR2820710105%3E3.0.CO;2-I8380116
8.	M ShimadaK TakenakaT GionPrognosis of recurrent hepatocellular carcinoma: a 10-year surgical experience in JapanGastroenterology11172072619968780578
9.	T KumadaS NakanoI TakedaPatterns of recurrence after initial treatment in patients with small hepatocellular carcinomaHepatology258792199710.1002/hep.5102501168985270
10.	K MoriishiR MochizukiK MoriyaCritical role of PA28gamma in hepatitis C virus-associated steatogenesis and hepatocarcinogenesisProc Natl Acad Sci USA10416611666200710.1073/pnas.060731210417234812
11.	J MyersP MehtaAW HunterSA BernsteinPA EricksonAutomated double-label immunohistochemistryJ Surg Pathol11051131995
12.	S ChretienA DubartD BeaupainAlternative transcription and splicing of the human porphobilinogen deaminase gene result either in tissue-specific or in housekeeping expressionProc Natl Acad Sci USA85610198810.1073/pnas.85.1.6
13.	S NagelM SchmidtC ThiedeD HuhnA NeubauerQuantification of Bcr-Abl transcripts in chronic myelogenous leukemia (CML) using standardized, internally controlled, competitive differential PCR (CD-PCR)Nucleic Acids Res2441024103199610.1093/nar/24.20.4102
14.	KH KimSP HongK KimMJ ParkKJ KimJ CheongHCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPARgammaBiochem Biophys Res Commun355883888200710.1016/j.bbrc.2007.02.04417331464
15.	J FinkeR FritzenP TernesW LangeG DolkenAn improved strategy and a useful housekeeping gene for RNA analysis from formalin-fixed, paraffin-embedded tissues by PCRBiotechniques1444845319937681300
16.	Y SasakiS ImaokaM FujitaRegional therapy in the management of intrahepatic recurrence after surgery for hepatomaAnn Surg.2064047200710.1097/00000658-198707000-000063038040
17.	S KoY NakajimaH KanehiroSignificant influence of accompanying chronic hepatitis status on recurrence of hepatocellular carcinoma after hepatectomyResult of multivariate analysis. Ann Surg22459159519968916872
18.	Y SasakiS ImaokaS MasutaniI OhashiO IshikawaH KoyamaT IwanagaInfluence of coexisting cirrhosis on long-term prognosis after surgery in patients with hepatocellular carcinomaSurgery1125152119921325673
19.	T OkamuraS TaniguchiT OhkuraAbnormally high expression of proteasome activator-gamma in thyroid neoplasmJ Clin Endocrinol Metab8813741383200310.1210/jc.2002-02141312629132
20.	ON El-AssalA YamanoiY SodaClinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver: possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liverHepatology2715541562199810.1002/hep.510270613
21.	J RaedleG OremekM TruschnowitschM LorenzWK RothWF CasparyS ZeuzemClinical evaluation of autoantibodies to p53 protein in patients with chronic liver disease and hepatocellular carcinomaEur J Cancer3411981203199810.1016/S0959-8049(98)00056-29849479
22.	Y KishimotoG ShiotaY KamisakiLoss of the tumor suppressor p53 gene at the liver cirrhosis stage in Japanese patients with hepatocellular carcinomaOncology54304310199710.1159/0002277089216855
23.	K TaraoS TakemiyaS TamaiRelationship between the recurrence of hepatocellular carcinoma (HCC) and serum alanine aminotransferase levels in hepatectomized patients with hepatitis C virus-associated cirrhosis and HCCCancer79688694199710.1002/(SICI)1097-0142(19970215)79:4%3C688::AID-CNCR5%3E3.0.CO;2-A
24.	S KoY NakajimaH KanehiroInfluence of associated viral hepatitis status on recurrence of hepatocellular carcinoma after hepatectomyWorld J Surg2110821086199610.1007/s0026899001648798368