Loss of Cyclin E1 attenuates hepatitis and hepatocarcinogenesis in a mouse model of chronic liver injury

Ehedego, Haksier; Mohs, Antje; Jansen, Bettina; Hiththetiya, K; Siciński, Piotr; Liedtke, Christian

doi:10.1038/s41388-018-0181-8

Cited by 17 publications

(17 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our present study, ablation of CcnE1 largely prevented the development of HCC in two independent tumor models, and previous analysis indicated that inhibition of CcnE1 may also attenuate hepatocarcinogenesis in an inflammatory environment (6). In sharp contrast, CcnE2 was fully dispensable for HCC formation.…”

Section: Discussionsupporting

confidence: 75%

See 1 more Smart Citation

Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma

Sonntag

Giebeler

Nevzorova

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

E-type cyclins E1 (CcnE1) and E2 (CcnE2) are regulatory subunits of cyclin-dependent kinase 2 (Cdk2) and thought to control the transition of quiescent cells into the cell cycle. Initial findings indicated that CcnE1 and CcnE2 have largely overlapping functions for cancer development in several tumor entities including hepatocellular carcinoma (HCC). In the present study, we dissected the differential contributions of CcnE1, CcnE2, and Cdk2 for initiation and progression of HCC in mice and patients. To this end, we tested the HCC susceptibility in mice with constitutive deficiency for CcnE1 or CcnE2 as well as in mice lacking Cdk2 in hepatocytes. Genetic inactivation of CcnE1 largely prevented development of liver cancer in mice in two established HCC models, while ablation of CcnE2 had no effect on hepatocarcinogenesis. Importantly, CcnE1-driven HCC initiation was dependent on Cdk2. However, isolated primary hepatoma cells typically acquired independence on CcnE1 and Cdk2 with increasing progression in vitro, which was associated with a gene signature involving secondary induction of CcnE2 and up-regulation of cell cycle and DNA repair pathways. Importantly, a similar expression profile was also found in HCC patients with elevated CcnE2 expression and poor survival. In general, overall survival in HCC patients was synergistically affected by expression of CcnE1 and CcnE2, but not through Cdk2. Our study suggests that HCC initiation specifically depends on CcnE1 and Cdk2, while HCC progression requires expression of any E-cyclin, but no Cdk2.

show abstract

Section: Discussionsupporting

confidence: 75%

“…These signatures are useful for predicting patient prognosis and for developing novel cyclin E-based HCC therapies. chronic hepatitis (6). Here, we aimed to genetically dissect the precise contribution of CcnE1, CcnE2, or Cdk2 for HCC initiation and/or progression.…”

Section: Significancementioning

confidence: 99%

Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma

Sonntag

Giebeler

Nevzorova

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Overexpression of the CCNE1 gene, which is correlated with poorer prognosis, is observed in around 70% of HCC patients. High levels of CCNE1 have recently been associated with a hepatic inflammatory response, liver disease progression and hepatocarcinogenesis (Ehedego et al, 2018). HBV mainly integrates into the promoter or introns of the CCNA2 gene and may lead to the expression of a chimeric HBV-human protein which was reported to deregulate cell cycle in liver cells (Chiu et al, 2016).…”

Section: Fusion Sites Within Hbv and The Human Genomementioning

confidence: 99%

Comprehensive review of Hepatitis B Virus‐associated hepatocellular carcinoma research through text mining and big data analytics

et al. 2018

View full text Add to dashboard Cite

PubMed was text mined to glean insights into the role of Hepatitis B virus (HBV) in hepatocellular carcinoma (HCC) from the massive number of publications (9249) available to date. Reports from ∼70 countries identified >1300 human genes associated with either the Core, Surface or X gene in HBV-associated HCC. One hundred and forty-three of these host genes, which can potentially yield 1180 biomolecular interactions, each were reported in at least three different publications to be associated with the same HBV. These 143 genes function in 137 pathways, involved mainly in the cell cycle, apoptosis, inflammation and signalling. Fourteen of these molecules, primarily transcriptional regulators or kinases, play roles in several pathways pertinent to the hallmarks of cancers. 'Chronic' was the most frequent word used across the 9249 abstracts. A key event in chronic HBV infection is the integration of HBV into the host genome. The advent of cost-effective, next-generation sequencing technology facilitated the employment of big-data analytics comprehensively to characterize HBV-host integration within HCC patients. A total of 5331 integration events were reported across seven publications, with most of these integrations observed between the Core/X gene and the introns of genes. Nearly one-quarter of the intergenic integrations are within repeats, especially long interspersed nuclear elements (LINE) repeats. Integrations within 13 genes were each reported by at least three different studies. The human gene with the most HBV integrations observed is the TERT gene where a total of 224 integrations, primarily at its promoter and within the tumour tissue, were reported by six of seven publications. This unique review, which employs state-of-the-art text-mining and data-analytics tools, represents the most complete, systematic and comprehensive review of nearly all the publications associated with HBV-associated HCC research. It provides important resources to either focus future research or develop therapeutic strategies to target key molecules reported to play important roles in key pathways of HCC, through the systematic analyses of the commonly reported molecules associated with the various HBV genes in HCC, including information about the interactions amongst these commonly reported molecules, the pathways in which they reside as well as detailed information regarding the viral and host genes associated with HBV integration in HCC patients. Hence this review, which highlights pathways and key human genes associated with HBV in HCC, may facilitate the deeper elucidation of the role of HBV in hepato-carcinogenesis, potentially leading to timely intervention against this deadly disease.

show abstract

“…19,20 CCNE1, a kind of cyclins, is required for cell cycle G1/S transition. 22 In spite of a study demonstrated that the down expression of CCNE1 reduced the liver tumorigenesis significantly in a mouse model, 23 the function of CCNE1 in human HCC is poorly understood. 22 In spite of a study demonstrated that the down expression of CCNE1 reduced the liver tumorigenesis significantly in a mouse model, 23 the function of CCNE1 in human HCC is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

“…21 The abnormal expression of CCNE1 was reported in ovarian cancer. 22 In spite of a study demonstrated that the down expression of CCNE1 reduced the liver tumorigenesis significantly in a mouse model, 23 the function of CCNE1 in human HCC is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Upregulated LncRNA‐CCAT1 promotes hepatocellular carcinoma progression by functioning as miR‐30c‐2‐3p sponge

Zhang

Cai

Jiang

et al. 2019

Cell Biochemistry & Function

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death over the world. It is well studied that long noncoding RNA colon cancer-associated transcript-1 (CCAT1) played important roles in variety of cancers promoting cell proliferation and metastasis by acting as a competing endogenous RNA (ceRNA) of microRNAs. However, whether CCAT1 could regulate HCC by serving as a ceRNA of microRNA remains to be revealed. In this study, we demonstrated that CCAT1 was highly expressed in HCC tissues and remarkably associated with metastasis. With a bioinformatics prediction and functional assay validation, we found a binding site of miR-30c-2-3p on CCAT1, which was important for CCAT1 to promote cell proliferation. Interestingly, we further revealed a novel recognition site for miR-30c-2-3p on the 3′UTR of CCNE1 by mutative method, luciferase assay, and cell viability confirmation. In general, CCAT1 regulate the expression of CCNE1 by acting as a ceRNA to sponge miR-30c-2-3p in regulating the cell proliferation of HCC. These results suggest that CCAT1 may be a new therapy target for HCC in the future.Significance of the study: Our findings may broaden the understanding of the role of CCAT1 in tumorigenesis and may provide a new therapy target for HCC.

show abstract

Loss of Cyclin E1 attenuates hepatitis and hepatocarcinogenesis in a mouse model of chronic liver injury

Cited by 17 publications

References 22 publications

Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma

Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma

Comprehensive review of Hepatitis B Virus‐associated hepatocellular carcinoma research through text mining and big data analytics

Upregulated LncRNA‐CCAT1 promotes hepatocellular carcinoma progression by functioning as miR‐30c‐2‐3p sponge

Contact Info

Product

Resources

About