Genetic Landscape and Biomarkers of Hepatocellular Carcinoma

Zucman‐Rossi, Jessica; Villanueva, Augusto; Nault, Jean–Charles; Llovet, Josep M.

doi:10.1053/j.gastro.2015.05.061

Cited by 1,061 publications

(1,026 citation statements)

References 161 publications

Supporting

Mentioning

982

Contrasting

Unclassified

Order By: Relevance

“…12 Using these techniques, several critical signaling pathways that promote HCC development and/or progression have been identified, including Wnt/b-catenin, 13 Jak/Stat, 14 Ras/MAPK, 15 PI3K/ AKT/mTOR, 16 c-Met, 17 and EGFR 18 cascades. These pathways can represent potential targets for HCC therapeutics.…”

mentioning

confidence: 99%

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

et al. 2017

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC), the most frequent primary tumor of the liver, is an aggressive cancer type with limited treatment options. Cumulating evidence underlines a crucial role of aberrant lipid biosynthesis (a process known as de novo lipogenesis) along carcinogenesis. Previous studies showed that suppression of fatty acid synthase (FASN), the major enzyme responsible for de novo lipogenesis, is highly detrimental for the in vitro growth of HCC cell lines. To assess whether de novo lipogenesis is required for liver carcinogenesis, we have generated various mouse models of liver cancer by stably overexpressing candidate oncogenes in the mouse liver via hydrodynamic gene delivery. We found that overexpression of FASN in the mouse liver is unable to malignantly transform hepatocytes. However, genetic deletion of FASN totally suppresses hepatocarcinogenesis driven by AKT and AKT/c-Met protooncogenes in mice. On the other hand, liver tumor development is completely unaffected by FASN depletion in mice coexpressing b-catenin and c-Met. Our data indicate that tumors might be either addicted to or independent from de novo lipogenesis for their growth depending on the oncogenes involved. Additional investigation is required to unravel the molecular mechanisms whereby some oncogenes render cancer cells resistant to inhibition of de novo lipogenesis.

show abstract

mentioning

confidence: 99%

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

et al. 2017

View full text Add to dashboard Cite

show abstract

“…21,22 The diminished or absent LFABP expression in all cases of fibrolamellar carcinoma suggests HNF1-α inactivation is an important molecular event in tumorgenesis and should be added to the short list of other distinctive, consistent molecular events, including AGR2 overexpression and protein kinase A activation, which results from DNAJB1-PRKACA fusion or possibly loss of PRKAR1A protein expression.…”

Section: Discussionmentioning

confidence: 99%

Hepatic adenomas with synchronous or metachronous fibrolamellar carcinomas: both are characterized by LFABP loss

et al. 2016

View full text Add to dashboard Cite

Rare hepatic adenomas are associated with synchronous or metachronous fibrolamellar carcinomas. The morphology of these adenomas has not been well described and they have not been subclassifed using the current molecular classification schema. We examined four hepatic adenomas co-occurring with or preceding a diagnosis of fibrolamellar carcinoma in three patients. On histological examination, three of the adenomas showed the typical morphology of HNF1-α inactivated adenomas, whereas one showed a myxoid adenoma morphology. All of the adenomas were negative for PRKACA rearrangements by Fluorescence in situ Hybridization (FISH) analysis. All four of the adenomas showed complete loss or significant reduction of liver fatty acid binding protein (LFABP) expression by immunohistochemistry. Interestingly, the fibrolamellar carcinomas in each case also showed loss of LFABP by immunohistochemistry. One of the fibrolamellar carcinomas was negative for PRKACA rearrangements by FISH, whereas the others were positive. To investigate if LFBAP loss is typical of fibrolamellar carcinomas in general, an additional cohort of tumors was studied (n = 19). All 19 fibrolamellar carcinomas showed the expected PRKACA rearrangements and immunostains showed loss of LFABP in each case, consistent with HNF1-α inactivation. To validate this observation, mass spectrometry-based proteomics was performed on tumor-normal pairs of six fibrolamellar carcinomas and showed an average 10-fold reduction in LFABP protein levels, compared with matched normal liver tissue. In conclusion, hepatic adenomas co-occurring with fibrolamellar carcinomas show LFABP loss and are negative for PRKACA rearrangements, indicating they are genetically distinct lesions. These data also demonstrate that LFABP loss, which characterizes HNF1-α inactivation, is a consistent feature of fibrolamellar carcinoma, indicating HNF1-α inactivation is an important event in fibrolamellar carcinoma pathogenesis.

show abstract

“…11668027; Invitrogen; Thermo Fisher Scientific, Inc.), according to the manufacturer's protocols. Transfected pcDNA3.0-GTSF1-transfected cells were incubated at 37˚C for 1-2 days and these cells (2x10 6 ) were suspended in 100 µl PBS prior to being injected subcutaneously into either side of the posterior flank of each 5-6-week-old male BALB/c athymic nude mouse. A total of 12 mice were divided into two groups (Shanghai Chinese Academy of Sciences, Shanghai, China).…”

Section: Vector Construction and Tumorigenicity Assays In Nude Micementioning

confidence: 99%

“…There is an urgent requirement to develop novel molecular tools for assisting early HCC diagnosis, prognosis and treatment stratification. Molecular profiling of gene expression has improved the understanding of the mechanisms of HCC development, allowing the identification of biomarkers for HCC diagnosis and the stratification of patients with HCC for prognosis and therapy (6). Takuji Yoshimura et al (7) previously identified that the gametocyte specific factor 1 (GTSF1) gene, a member of the evolutionarily conserved UPF0224 family, is expressed predominantly in male germ cells.…”

Section: Introductionmentioning

confidence: 99%

GTSF1 gene may serve as a novel potential diagnostic biomarker for liver cancer

et al. 2017

View full text Add to dashboard Cite

Abstract. The gametocyte-specific factor 1 (GTSF1) gene participates in DNA methylation and retrotransposon activation in germ cells, particularly during cell proliferation. The present study aimed to assess the level of GTSF1 gene expression in liver cancer tumor tissues, and its role in human hepatoma cell lines in vitro and in a nude mouse model in vivo. GTSF1 gene expression was detected in liver cancer tumor tissues, compared with in healthy controls, via reverse transcription quantitative polymerase chain reaction. An adeno-associated virus vector was used to study tumor stem cell proliferation in vivo. A plasmid expressing GTSF1 was constructed and transfected into various human hepatoma cell lines, in order to analyze the cellular proliferation and apoptosis of liver cancer cells using small interfering (si)RNAs in vitro. In the present study, GTSF1 gene expression was detected in 18/24 (75.0%) liver cancer tumor tissues from patients with hepatocellular carcinoma (HCC), and elevated GTSF1 expression was identified in the tissue of one of 32 healthy control samples (3.13%; P<0.05). Notably, the GTSF1 gene was expressed at a higher frequency in AFP-positive HCC samples (14/16, 87.50%) compared with in AFP-negative HCC samples (4/8, 50.0%; P=0.129). In addition, there was no statistical significance between GTSF1 expression in non-HBV-infected (71.42%) and HBV-infected HCC specimens (76.47%), as determined by a χ 2 test (P=0.921). It was demonstrated that GTSF1 significantly increased the tumorigenicity of Ad-shNC-transfected (GTSF1-positive) HepG2 cells in the nude mouse xenograft model, whereas the sizes and weights of the tumors in the GTSF1-negative group were dercreased in comparison with the GTSF1-positive group (P<0.05). Reduced levels of GTSF1 mRNA, along with fewer and smaller colonies, were identified in two groups of human liver cancer cells treated with with GTSF1-targeting siRNA, when compared with cells without GTSF1 mRNA interference (P<0.05). In summary, the present study elucidated the GTSF1 mRNA expression pattern in liver cancer, and investigated the potential role of GTSF1 in tumorigenesis. The data suggest an important role for the GTSF1 gene in the molecular etiology of hepatocarcinogenesis, and indicate a potential application of GTSF1 mRNA expression in liver cancer diagnosis and therapy.

show abstract

Genetic Landscape and Biomarkers of Hepatocellular Carcinoma

Cited by 1,061 publications

References 161 publications

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

Hepatic adenomas with synchronous or metachronous fibrolamellar carcinomas: both are characterized by LFABP loss

GTSF1 gene may serve as a novel potential diagnostic biomarker for liver cancer

Contact Info

Product

Resources

About