Role of HSP90, CDC37, and CRM1 as modulators of P16(INK4A) activity in rat liver carcinogenesis and human liver cancer.
Current evidence indicates that neoplastic nodules induced in liver of Brown Norway (BN) rats genetically resistant to hepatocarcinogenesis are not prone to evolve into hepatocellular carcinoma. We show that BN rats subjected to diethylnitrosamine/2-acetylaminofluorene/partial hepatectomy treatment with a "resistant hepatocyte" protocol displayed higher number of glutathione-S-transferase 7-7(+) hepatocytes when compared with susceptible Fisher 344 (F344) rats, both during and at the end of 2-acetylaminofluorene treatment. However, DNA synthesis declined in BN but not F344 rats after completion of reparative growth. Upregulation of p16(INK4A), Hsp90, and Cdc37 genes; an increase in Cdc37-Cdk4 complexes; and a decrease in p16(INK4A)-Cdk4 complexes occurred in preneoplastic liver, nodules, and hepatocellular carcinoma of F344 rats. These parameters did not change significantly in BN rats. E2f4 was equally expressed in the lesions of both strains, but Crm1 expression and levels of E2f4-Crm1 complex were higher in F344 rats. Marked upregulation of P16(INK4A) was associated with moderate overexpression of HSP90, CDC37, E2F4, and CRM1 in human hepatocellular carcinomas with a better prognosis. In contrast, strong induction of HSP90, CDC37, and E2F4 was paralleled by P16(INK4A) downregulation and high levels of HSP90-CDK4 and CDC37-CDK4 complexes in hepatocellular carcinomas with poorer prognosis. CDC37 downregulation by small interfering RNA inhibited in vitro growth of HepG2 cells. In conclusion, our findings underline the role of Hsp90/Cdc37 and E2f4/Crm1 systems in the acquisition of a susceptible or resistant carcinogenic phenotype. The results also suggest that protection by CDC37 and CRM1 against growth restraint by P16(INK4A) influences the prognosis of human hepatocellular carcinoma.
Pascale
Rosa M
RM
Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, Italy.
Simile
Maria M
MM
Calvisi
Diego F
DF
Frau
Maddalena
M
Muroni
Maria R
MR
Seddaiu
Maria A
MA
Daino
Lucia
L
Muntoni
Maria D
MD
De Miglio
Maria R
MR
Thorgeirsson
Snorri S
SS
Feo
Francesco
F
D000328:Adult; D000368:Aged; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D018833:Chaperonins; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D050704:E2F4 Transcription Factor / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000502:physiology*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D013045:Species Specificity; D000097606:Exportin 1 Protein
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D018833:Chaperonins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050704:E2F4 Transcription Factor; D018841:HSP90 Heat-Shock Proteins; D028884:Karyopherins; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C498362:CDC37 protein, human; C103269:Cdc37 protein, rat; C493762:E2F4 protein, human