Risk of HCC: Genetic heterogeneity and complex genetics

Dragani, Tommaso A.

doi:10.1016/j.jhep.2009.11.015

Cited by 208 publications

(154 citation statements)

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“…HCC cells own common characteristics that are often found to be hepatic stem/progenitor cell biomarkers (2,(6)(7)(8)(9)(10), although multiple environmental and genetic risk factors exist. HCC progression and embryonic liver development share many same properties, and a tumor may originate from progenitor/stem cells that receive abnormal proliferation and maturation signals (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit

Liu

Zong

et al. 2015

Mol Med

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On the basis of their characteristics, we presume that developmental stage-specific hepatocytes should have the ability to induce maturation of hepatoma cells. A regulatory circuit formed by hepatocyte nuclear factor (HNF)-4α, HNF-1α, HNF-6 and the upstream stimulatory factor (USF-1) play a key role in the maturation of embryonic hepatocytes; however, it is unclear whether the regulatory circuit mediates the embryonic induction of hepatoma cell maturation. In this study, 12.5-d to 15.5-d mouse embryonic hepatocytes or their medium were used to coculture or treat HepG2 cells, and the induced maturation was evaluated in vitro and in vivo. In the induced HepG2 cells, the components of the regulatory circuit were detected, their cross-regulation was evaluated and HNF-4α RNA interference was performed. We found that 13.5-d to 14.5-d embryonic hepatocytes could induce HepG2 cell maturation, demonstrated by morphological changes, increased maturation markers and decreased c-Myc and α-fetoprotein (AFP) in vitro. The majority of HepG2 tumors were eliminated by 13.5-d embryonic induction in vivo. All components of the regulatory circuit were upregulated and the binding of HNF-4α, HNF-1α, HNF-6 and USF-1 to their target sites was promoted to rebuild the regulatory circuit in the induced HepG2 cells. Moreover, RNA interference targeting HNF-4α, which is the core of the regulatory circuit, attenuated the induced maturation of HepG2 cells with downregulation of the regulatory circuit. These results revealed that developmental stage-specific hepatocytes could induce the maturation of HepG2 cells by rebuilding the regulatory circuit. is believed to be a controller and marker of mature hepatocytes (27,28). As a downstream target of HNF-4α, HNF-1α is also essential for hepatocyte maturation (29,30). USF-1, which competes with the oncogene c-Myc for the E-box regulatory element, is another downstream target of HNF-4α that plays crucial roles in the maturation and formation of functional hepatocytes (31,32). USF-1 can activate HNF-6, which is another important transcription factor for hepatocyte maturation that has been found to regulate 33). Therefore, HNF-4α, HNF-1α, HNF-6 and USF-1 form a positive feedback loop that drives hepatocyte maturation in liver development ( Figure 1A). Because the transcription factor binding sites are generally believed to scatter within 10 kb upstream of the transcriptional start site (34), the 10-kb gene promoters were all analyzed. On the basis of previous reports (25), the predicted binding sites of HNF-4α HNF-1α, HNF-6 and USF-1 were identified, respectively ( Figure 1B). It remains unknown whether developmental stage-specific hepatocytes rebuild the regulatory circuit to induce the maturation of HepG2 cells.In this study, HepG2 cells were cocultured with mouse embryonic hepatocytes at gestation of 12.5-15.5 d, because the mouse hepatocytes differentiated at 12.5 d, and the liver structure became firmly established between 12 and 15 d of gestation (35)(36)(37). The induced maturation of HepG2 cel...

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Section: Introductionmentioning

confidence: 99%

Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit

Liu

Zong

et al. 2015

Mol Med

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“…(11,12) We have observed that most HCC occurs obviously in clusters by geographical distribution or by family aggregation in Guangxi, China. Family aggregation of HCC has received researchers' attention for decades.…”

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confidence: 99%

Comparative proteomic profiles indicating genetic factors may involve in hepatocellular carcinoma familial aggregation

Zhong

Ning

et al. 2012

Cancer Science

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Familial aggregation of hepatocellular carcinoma (HCC), the third leading cause of cancer death worldwide, has shown to be a common phenomenon. We investigated the association between the genetic background and HCC familial aggregation. Serum samples were collected from HCC family members and normal control family members for screening the differentially expressed protein peaks with the approach of surface-enhanced laser desorption ionization time-of-flight mass spectrometry. Potential genetically associated protein peaks were selected and further identified by matrix assisted laser desorption ionization-time of flight mass spectrometry. A panel of six protein peaks (m/z 6432. 94, 8478.35, 9381.91, 17284.67, 17418.34, and 18111.04) were speculated to reflect the genetic susceptibility of HCC familial aggregation. Three of them (m/z 6432.94, 8478.35, and 9381.91) were selected to identify as the candidate proteins. Nine identified proteins, including mostly apolipoprotein family (ApoA1, ApoA2, ApoC3, ApoE) and serum amyloid A protein (SAA), were found overexpressed in the multiple HCC cases family members. The comparative proteomic profiles have suggested that genetic factors ought to be taken into account for familial aggregation of HCC. (Cancer Sci 2012; 103: 1833-1838 H epatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers, and ranks the third cause of cancer related death in the world (9.2% of the total).(1,2) Among different geographical regions, large variation of morbidity and risk factors were observed, with the highest rate in Asian, and lowest rate in the US as well as Europe countries.(3,4) Hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, and chronic exposure to aflatoxin play crucial roles in hepatocarcinogenesis among Asian people, while fatty liver disease and high consumption of alcohol are the dominant causes among low incidence regions.(5,6) The HCC incidence rate is remarkably high in China, accounting for approximately 55% of annual new cases in the world.(7) Particularly in Guangxi province of China, an endemic area of HBV infection, the HCC mortality has risen as the first cause of malignant cancer-relative death. (8) It is well-accepted that HBV infection constitutes the main etiological factor of HCC, while the process of hepatocarcinogenesis integrates multi-stages and multi-factors, including interactions of HBV, chemical carcinogen, and genetic susceptibility.(9) In addiction, the literature conveys that the lifetime risk of developing HCC for HBV infected individuals has been estimated to be 40%, (10) implying that a wide individual discrepancy exists in the HCC susceptibility, and that environmental factors alone are insufficient to fully address the familial aggregation of HCC. (11,12) We have observed that most HCC occurs obviously in clusters by geographical distribution or by family aggregation in Guangxi, China. Family aggregation of HCC has received researchers' attention for decades. Pedigree studies are frequently carried out to val...

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“…This high background of predisposing environmental factors makes identifying less penetrant genetic contributors more difficult. Familial patterns of susceptibility to liver cancer independent of environmental factors have helped identify a few monogenic metabolic syndromes (e.g., hemochromatosis; Dragani, 2010). However, the analysis of liver tumors points to a variety of other genes that affect liver tumor development.…”

Section: Introductionmentioning

confidence: 99%

The Hcs7 Mouse Liver Cancer Modifier Maps to a 3.3 Mb Region Carrying the Strong Candidate Ifi202b

Bilger¹,

Poli²,

Schneider³

et al. 2012

Liver Tumors

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Risk of HCC: Genetic heterogeneity and complex genetics

Cited by 208 publications

References 71 publications

Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit

Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit

Comparative proteomic profiles indicating genetic factors may involve in hepatocellular carcinoma familial aggregation

The Hcs7 Mouse Liver Cancer Modifier Maps to a 3.3 Mb Region Carrying the Strong Candidate Ifi202b

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