MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations
Open accessAbstract
Molecular classifications defining new tumor subtypes have been recently refined with genetic and transcriptomic analyses of benign and malignant hepatocellular tumors. Here, we performed microRNA (miRNA) profiling in two series of fully annotated liver tumors to uncover associations between oncogene/tumor suppressor mutations and clinical and pathological features. Expression levels of 250 miRNAs in 46 benign and malignant hepatocellular tumors were compared to those of 4 normal liver samples with quantitative reverse-transcriptase polymerase chain reaction. miRNAs associated with genetic and clinical characteristics were validated in a second series of 43 liver tumor samples and 16 nontumor samples. miRNA profiling unsupervised analysis classified samples in unique clusters characterized by histological features (tumor/nontumor, P < 0.001; benign/malignant tumors, P < 0.01; inflammatory adenoma and focal nodular hyperplasia, P < 0.01), clinical characteristics [hepatitis B virus (HBV) infection, P < 0.001; alcohol consumption, P < 0.05], and oncogene/tumor suppressor gene mutations [β-catenin, P < 0.01; hepatocyte nuclear factor 1α (HNF1α), P < 0.01]. Our study identified and validated miR-224 overexpression in all tumors and miR-200c, miR-200, miR-21, miR-224, miR-10b, and miR-222 specific deregulation in benign or malignant tumors. Moreover, miR-96 was overexpressed in HBV tumors, and miR-126* was down-regulated in alcohol-related hepatocellular carcinoma. Down-regulations of miR-107 and miR-375 were specifically associated with HNF1α and β-catenin gene mutations, respectively. miR-375 expression was highly correlated to that of β-catenin–targeted genes as miR-107 expression was correlated to that of HNF1α in a small interfering RNA cell line model. Thus, this strongly suggests that β-catenin and HNF1α could regulate miR-375 and miR-107 expression levels, respectively. Conclusion: Hepatocellular tumors may have a distinct miRNA expression fingerprint according to malignancy, risk factors, and oncogene/tumor suppressor gene alterations. Dissecting these relationships provides a new hypothesis to understand the functional impact of miRNA deregulation in liver tumorigenesis and the promising use of miRNAs as diagnostic markers.
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No Wnt-class-specific miRNA expression profiles or Wnt-related miRNA-signatures have been described so far.
“Although several studies have implicated these Wnt-related miRNAs in Wnt-signaling, including the association of miR-375 expression to CTNNB1-mutation (32), no Wnt-class-specific miRNA expression profiles or Wnt-related miRNA-signatures have been described so far.”
From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [32]
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The crosstalk between microRNAs and the Wnt/β-catenin signaling pathway in cancer
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- Authors
- Ladeiro, Y., Couchy, G., Balabaud, C., Bioulac-Sage, P., Pelletier, L., Rebouissou, S., & Zucman-Rossi, J.
- Affiliations
- Inserm (FR)
- Venue
- Hepatology
- Published
- 2008-06
- Volume
- 47
- Issue
- 6
- Pages
- 1955-1963
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2030607381
- Cited by
- 684
- References
- 1
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 15 · 2023: 18 · 2022: 12 · 2021: 16 · 2020: 19 · 2019: 28 · 2018: 38 · 2017: 33 · 2016: 33 · 2015: 60 · 2014: 69 · 2013: 68 · 2012: 72
- FWCI
- 22.25
- Type
- journal article
- Language
- en
- Open access
- green
- inserm.hal.science
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- miRNA expression profiling, hepatocellular tumors, hepatocellular carcinoma, benign liver tumors, focal nodular hyperplasia, miR-224, miR-375, miR-107, miR-200 family, miR-21, miR-126, miR-96, CTNNB1 mutation, hepatitis B virus, alcohol-related liver cancer
- MeSH terms
- Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Mutation, Phenotype, Risk Factors, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Gene Expression Profiling, MicroRNAs, beta Catenin, Hepatocyte Nuclear Factor 1-alpha
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