Dynamics of Genomic, Epigenomic, and Transcriptomic Aberrations during Stepwise Hepatocarcinogenesis

Jee, Byul A; Choi, Ji-Hye; Rhee, Hyungjin; Yoon, Sarah; Kwon, So Mee; Nahm, Ji Hae; Yoo, Jeong Eun; Jeon, Youngsic; Choi, Gi Hong; Woo, Hyun Goo; Park, Young Nyun

doi:10.1158/0008-5472.can-19-0991

Cited by 40 publications

(44 citation statements)

References 47 publications

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“…63 Other studies highlighted that transcriptomic dysregulation of signalling pathways, such as TGFb, WNT, and NOTCH, as well as extensive epigenetic modifications occurred after malignant transformation, mainly in progressed HCC, confirming that genomic and epigenomic diversity occurred in the late stages of liver carcinogenesis. [94][95][96] Although recently our understanding of mutations and mutational signatures in human patients at different stages of liver disease has improved greatly, there remain key questions of how a…”

Section: Driver Mutations Involved In Tumour Initiation and Malignantmentioning

confidence: 99%

The landscape of gene mutations in cirrhosis and hepatocellular carcinoma

Müller

Bird

Nault

2020

Journal of Hepatology

129

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Chronic liver disease and primary liver cancer are a massive global problem, with a future increase in incidences predicted. The most prevalent form of primary liver cancer, hepatocellular carcinoma, occurs after years of chronic liver disease. Mutations in the genome are a causative and defining feature of all cancers. Chronic liver disease, mostly at the cirrhotic stage, causes the accumulation of progressive mutations which can drive cancer development. Within the liver, a Darwinian process selects out dominant clones with selected driver mutations but also leaves a trail of passenger mutations which can be used to track the evolution of a tumour. Understanding what causes specific mutations and how they combine with one another to form cancer is a question at the heart of understanding, preventing and tackling liver cancer. Herein, we review the landscape of gene mutations in cirrhosis, especially those paving the way toward hepatocellular carcinoma development, that have been characterised by recent studies capitalising on technological advances in genomic sequencing. With these insights, we are beginning to understand how cancers form in the liver, particularly on the background of chronic liver disease. This knowledge may soon lead to breakthroughs in the way we detect, diagnose and treat this devastating disease.

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Section: Driver Mutations Involved In Tumour Initiation and Malignantmentioning

confidence: 99%

The landscape of gene mutations in cirrhosis and hepatocellular carcinoma

Müller

Bird

Nault

2020

Journal of Hepatology

129

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“…The major risk factors for HCC include chronic infection of hepatitis B and C viruses (HBV and HCV), cirrhosis, alcohol abuse and non-alcoholic fatty liver disease (NAFLD) [2]. Hepatocarcinogenesis is characterized by dysregulated activation and/or expression of relevant genes in/on the hepatocytes, with resultant oncogene upregulation and tumor suppressor downregulation [3]. The last 5 decades has been characterized by discovery several biomarkers for diagnosis of HCC, including the α-fetoprotein (AFP), AFP-L3 (a heteroplast of AFP), des-γ-carboxyprothrombin (DCP), α-L-fucosidase (AFU), golgi protein 73 (GP73), osteopontin (OPN) and carbohydrate antigen 19-9 (CA19-9), which is globally regarded as diagnostic serological biomarkers for diagnosis of HCC patients.…”

Section: Introductionmentioning

confidence: 99%

SUMO-Activating Enzyme Subunit 1 (SAE1) Is a Promising Diagnostic Cancer Metabolism Biomarker of Hepatocellular Carcinoma

Ong

Bamodu

Khang

et al. 2021

Cells

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Hepatocellular carcinoma (HCC) is one of the most diagnosed malignancies and a leading cause of cancer-related mortality globally. This is exacerbated by its highly aggressive phenotype, and limitation in early diagnosis and effective therapies. The SUMO-activating enzyme subunit 1 (SAE1) is a component of a heterodimeric small ubiquitin-related modifier that plays a vital role in SUMOylation, a post-translational modification involving in cellular events such as regulation of transcription, cell cycle and apoptosis. Reported overexpression of SAE1 in glioma in a stage-dependent manner suggests it has a probable role in cancer initiation and progression. In this study, hypothesizing that SAE1 is implicated in HCC metastatic phenotype and poor prognosis, we analyzed the expression of SAE1 in several cancer databases and to unravel the underlying molecular mechanism of SAE1-associated hepatocarcinogenesis. Here, we demonstrated that SAE1 is over-expressed in HCC samples compared to normal liver tissue, and this observed SAE1 overexpression is stage and grade-dependent and associated with poor survival. The receiver operating characteristic analysis of SAE1 in TCGA−LIHC patients (n = 421) showed an AUC of 0.925, indicating an excellent diagnostic value of SAE1 in HCC. Our protein-protein interaction analysis for SAE1 showed that SAE1 interacted with and activated oncogenes such as PLK1, CCNB1, CDK4 and CDK1, while simultaneously inhibiting tumor suppressors including PDK4, KLF9, FOXO1 and ALDH2. Immunohistochemical staining and clinicopathological correlate analysis of SAE1 in our TMU-SHH HCC cohort (n = 54) further validated the overexpression of SAE1 in cancerous liver tissues compared with ‘normal’ paracancerous tissue, and high SAE1 expression was strongly correlated with metastasis and disease progression. The oncogenic effect of upregulated SAE1 is associated with dysregulated cancer metabolic signaling. In conclusion, the present study demonstrates that SAE1 is a targetable cancer metabolic biomarker with high potential diagnostic and prognostic implications for patients with HCC.

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“…Hepatocarcinogenesis entails alteration of cellular gene expression with consequent loss of benignity, acquisition of malignant phenotype and enhancement of the aggressiveness of the resultant cancerous liver cells [3]. Previous studies have shown that ubiquitylation and SUMOylation are signi cantly enhanced in HCC [14].…”

Section: Discussionmentioning

confidence: 99%

“…The disease course and progression of HCC is facilitated by altered cellular gene expression with dysregulated metabolism and pathophysiological signaling pathways [3][4][5]. SUMOylation, a posttranslational modi cation that entails addition of small ubiquitin-like modi er (SUMO) groups to target proteins, is involved in numerous cellular events including transcriptional regulation, protein stability, cell cycle and apoptosis [10].…”

Section: Hccmentioning

confidence: 99%

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SUMO-Activating Enzyme Subunit 1 (SAE1) is A Promising Diagnostic Cancer Metabolism Biomarker of Hepatocellular Carcinoma

Ong

Bamodu

Khang

et al. 2020

Preprint

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Background: Hepatocellular carcinoma (HCC) is one of the most diagnosed malignancies and a leading cause of cancer-related mortality globally. This is exacerbated by its highly aggressive phenotype, and limitation in early diagnosis and effective therapies. The SUMO-activating enzyme subunit 1 (SAE1) is a component of a heterodimeric small ubiquitin-related modifier that plays a vital role in SUMOylation, a post-translational modification involving in cellular events such as regulation of transcription, cell cycle and apoptosis. Reported overexpression of SAE1 in glioma in a stage-dependent manner suggests it probable role in cancer initiation and progression. Methods: In this study, hypothesizing that SAE1 is implicated in HCC metastatic phenotype and poor prognosis, we analyzed the expression of SAE1 in several cancer databases. Results: Here, we demonstrated that SAE1 is overexpressed in HCC samples compared to normal liver tissue, and this observed SAE1 overexpression is stage and grade-dependent and associated with poor survival. The receiver operating characteristic analysis of SAE1 in TCGA-LIHC patients (n=421) showed an AUC of 0.925, indicating an excellent diagnostic value of SAE1 in HCC. Our protein-protein interaction analysis for SAE1 showed that SAE1 interacted with and activated oncogenes such as PLK1, CCNB1, CDK4 and CDK1, while simultaneously inhibiting tumor suppressors including PDK4, KLF9, FOXO1 and NEDD4. Immunohistochemical staining and clinicopathological correlate analysis of SAE1 in our TMU-SHH HCC cohort (n =54) further validated the overexpression of SAE1 in cancerous liver tissues compared with ‘normal’ paracancerous tissue, and high SAE1 expression was strongly correlated with metastasis and disease progression. Conclusion: In conclusion, the present study demonstrates that SAE1 is a targetable molecular biomarker with high potential diagnostic and prognostic implications for patients with HCC.

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Dynamics of Genomic, Epigenomic, and Transcriptomic Aberrations during Stepwise Hepatocarcinogenesis

Cited by 40 publications

References 47 publications

The landscape of gene mutations in cirrhosis and hepatocellular carcinoma

The landscape of gene mutations in cirrhosis and hepatocellular carcinoma

SUMO-Activating Enzyme Subunit 1 (SAE1) Is a Promising Diagnostic Cancer Metabolism Biomarker of Hepatocellular Carcinoma

SUMO-Activating Enzyme Subunit 1 (SAE1) is A Promising Diagnostic Cancer Metabolism Biomarker of Hepatocellular Carcinoma

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