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An expression signature of phenotypic resistance to hepatocellular carcinoma identified by cross-species gene expression analysis

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Abstract

Background and aims

Hepatocarcinogenesis is under polygenic control. We analyzed gene expression patterns of dysplastic liver nodules (DNs) and hepatocellular carcinomas (HCCs) chemically-induced in F344 and BN rats, respectively susceptible and resistant to hepatocarcinogenesis.

Methods

Expression profiles were performed by microarray and validated by quantitative RT-PCR and Western blot.

Results

Cluster analysis revealed two distinctive gene expression patterns, the first of which included normal liver of both strains and BN nodules, and the second one F344 nodules and HCC of both strains. We identified a signature predicting DN and HCC progression, characterized by highest expression of oncosuppressors Csmd1, Dmbt1, Dusp1, and Gnmt, in DNs, and Bhmt, Dmbt1, Dusp1, Gadd45g, Gnmt, Napsa, Pp2ca, and Ptpn13 in HCCs of resistant rats. Integrated gene expression data revealed highest expression of proliferation-related CTGF, c-MYC, and PCNA, and lowest expression of BHMT, DMBT1, DUSP1, GADD45g, and GNMT, in more aggressive rat and human HCC. BHMT, DUSP1, and GADD45g expression predicted patients’ survival.

Conclusions

Our results disclose, for the first time, a major role of oncosuppressor genes as effectors of genetic resistance to hepatocarcinogenesis. Comparative functional genomic analysis allowed discovering an evolutionarily conserved gene expression signature discriminating HCC with different propensity to progression in rat and human.

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Abbreviations

Anxa5:

Annexin5

Bhmt:

Betaine-homocysteine methyltransferase

BN:

Brown Norway

Bzrp:

Benzodiazepine receptor, peripheral

Cxcl12:

Chemokine, cxc motif, ligand 12

Ctgf:

Connective tissue growth factor

Csmd1:

CUB and SUSHI multiple domain protein 1

Cyp7B1:

Cytochrome P450 7B1

Decr1:

2,4-dienoyl CoA reductase 1

DN:

Dysplastic nodule

Dmbt1:

Deleted in malignant brain tumors 1

Dusp1:

Dual specificity phosphatase 1

Enc1:

Ectodermal-neural cortex 1

ERK:

Extracellular signal-regulated kinase

F344:

Fisher 344

Fath1:

Fat tumor suppressor homologue 1

Fgfr:

Fibroblast growth factor receptor

FoxM1:

Forkhead box M1B

G0s2:

G0-G1 switch gene 2

Gadd45b:

Growth arrest and DNA-damage-inducible-β

Gadd45g:

Gadd45-γ

Gnmt:

Glycine N-methyltransferase

Gng10:

G protein gamma 10

Gpx2:

Glutathione peroxidase 2

Gsta2:

Gutathione-S-transferase, alpha2

HCC:

Hepatocellular carcinoma

HCCA:

HCC with poorer prognosis

HCCB:

HCC with better prognosis

Igfbp:

Insulin-like growth factor binding protein

Klf6:

Kruppel-like suppressor 6

Lcn2:

Lipocalin 2

Mat1A:

Methyl adenosyltransferase 1A

Napsa:

Napsin A

Nqo1:

NAD(P)H dehydrogenase, quinone 1

P2ry2:

Purinergic receptor P2Y

Pcna:

Proliferating cell nuclear antigen

Pckdbp:

Protein kinase δ binding protein

Pdgf-α:

Platelet-derived growth factor-alpha

Pp2A:

Protein phosphatase 2A

Prkci:

Protein kinase C, iota

Ptpn13:

Protein tyrosine phosphatase, non-receptor type 13

qPCR:

Quantitative real-time reverse-transcription polymerase chain reaction; Rin3 Ras and Rab interactor 3

Rapgef2:

Rap guanine nucleotide exchange factor 2

SAM:

S- adenosylmethionine

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Acknowledgements

Supported by grants from Associazione Italiana Ricerche sul Cancro (IG8952), Ministero Università e Ricerca (PRIN 2009), Regione Autonoma Sardegna, Fondazione Banco di Sardegna.

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Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, 07100, Sassari, Italy

    Maddalena Frau, Maria M. Simile, Maria L. Tomasi, Maria I. Demartis, Lucia Daino, Maria A. Seddaiu, Giuliana Solinas, Francesco Feo & Rosa M. Pascale

  2. Department of Surgery “Pietro Valdoni”, University of Rome “La Sapienza”, Rome, Italy

    Stefania Brozzetti

  3. Department of Clinical and Experimental Medicine, Division of Surgery, University of Sassari, Sassari, Italy

    Claudio F. Feo

  4. Department of Clinical and Experimental Medicine and Oncology. Division of Morbid Anatomy, University of Sassari, Sassari, Italy

    Giovanni Massarelli

  5. MD Anderson Cancer Center, University of Texas, Huston, TX, USA

    Ju-Seog Lee

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  1. Maddalena Frau
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  2. Maria M. Simile
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Corresponding author

Correspondence to Rosa M. Pascale.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 49 kb)

Supplementary Table S1

Clinicopathological Features of HCC Patients (DOC 36 kb)

Supplementary Table S2

Gene expression profile of dysplastic nodule and hepatocellular carcinoma of F344 rats. (DOC 475 kb)

Supplementary Table S3

Gene expression profile of dysplastic nodule and hepatocellular carcinoma of BN rats (DOC 529 kb)

Supplementary Table S4

Gene features significantly different between BN and F344 dysplastic nodules (DOC 182 kb)

Supplementary Table S5

Gene features significantly different between BN and F344 HCCs (DOC 144 kb)

Figure S1

Hematoxylin-eosin (H&E) and reticulin straining, and glutamine synthase (GS) immunostaining of DN and HCC from F344 and BN rats. DNs were collected from both strains 32 weeks after initiation, and HCC were collected from F344 and BN rats at 50 and 65 weeks, respectively. Note the presence of partially preserved reticulin fibers array in DNs and cytoplasmic GS-positivity in HCC. Abbreviaitons: HGDN, high-grade dysplastic nodule; LGDN, low-.grade dysplastic nodule; MDHCC, moderately differentiated hepatocellular carcinoma; WDHCC, well differentiated hepatocellular casrcinoma. Original magnification: x400. (TIFF 28690 kb)

Figure S2

Expression patterns of differentially expressed genes between BN and F344 nodules, out of 22,575 gene features, 91 differently expressed gene features were selected for cluster analysis (p < 0.001, t-test between BN vs F344 DNs). The two groups compared in t-test are indicated by the blue segments. The data were presented in a matrix format in which columns represent each tissue and rows represent individual genes. (TIFF 16077 kb)

Figure S3

Expression patterns of differentially expressed genes between BN and F344 tumors. Out of 22,575 gene features, 55 differentially expressed gene features were selected for cluster analysis (p < 0.001, t-test between BN tumor vs F344 tumor). The two groups compared in t-test are shown by blue segments. The data are presented in a matrix format in which columns represent each tissue and rows represent individual genes. (TIFF 13592 kb)

Figure S4

Schematic representation of the effects of some oncosuppressor genes upregulated in DN and/or HCC of BN rats. The effects of the oncosuppressors Dusp1, Pp2ca, Ptpten13, Bhmt, Gnmt, Gadd45g, are shown by red arrows. Blunt arrows indicated inhibition. DM—glycine, dimethyl-glycine. (TIFF 4614 kb)

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Frau, M., Simile, M.M., Tomasi, M.L. et al. An expression signature of phenotypic resistance to hepatocellular carcinoma identified by cross-species gene expression analysis. Cell Oncol. 35, 163–173 (2012). https://doi.org/10.1007/s13402-011-0067-z

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