MicroRNA-494 within an oncogenic microRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of mutated in colorectal cancer
Copyright policy )MicroRNA-494 within an oncogenic microRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of mutated in colorectal cancer
Hepatocellular carcinoma (HCC) is associated with poor survival for patients and few effective treatment options, raising the need for novel therapeutic strategies. MicroRNAs (miRNAs) play important roles in tumor development and show deregulated patterns of expression in HCC. Because of the liver's unique affinity for small nucleic acids, miRNA-based therapy has been proposed in the treatment of liver disease. Thus, there is an urgent need to identify and characterize aberrantly expressed miRNAs in HCC. In our study, we profiled miRNA expression changes in de novo liver tumors driven by MYC and/or RAS, two canonical oncogenes activated in a majority of human HCCs. We identified an up-regulated miRNA megacluster comprised of 53 miRNAs on mouse chromosome 12qF1 (human homolog 14q32). This miRNA megacluster is up-regulated in all three transgenic liver models and in a subset of human HCCs. An unbiased functional analysis of all miRNAs within this cluster was performed. We found that miR-494 is overexpressed in human HCC and aids in transformation by regulating the G1/S cell cycle transition through targeting of the Mutated in Colorectal Cancer tumor suppressor. miR-494 inhibition in human HCC cell lines decreases cellular transformation, and anti-miR-494 treatment of primary MYC-driven liver tumor formation significantly diminishes tumor size. Conclusion : Our findings identify a new therapeutic target (miR-494) for the treatment of HCC.
- University of Iowa United States
- University of Hong Kong (香港大學) China (People's Republic of)
- Hannover Medical School Germany
- University of Hong Kong China (People's Republic of)
- Mirna Therapeutics (United States) United States
Male, Medical Biochemistry and Metabolomics, Cell Transformation, Transgenic, Mice, Liver Neoplasms, Experimental, 1103 Clinical Sciences (for), Hepatocellular (mesh), 2.1 Biological and endogenous factors, Animals (mesh), Cell Proliferation (mesh), 32 Biomedical and Clinical Sciences (for-2020), Liver Disease (rcdc), Male (mesh), Cancer, Colo-Rectal Cancer (rcdc), G1 Phase Cell Cycle Checkpoints (mesh), Cancer (rcdc), Humans (mesh), Liver Disease, Liver Neoplasms, Mice (mesh), Experimental (mesh), ras Proteins (mesh), Colo-Rectal Cancer, Up-Regulation, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, Female, Biotechnology, Digestive Diseases (rcdc), Tumor Suppressor Proteins (mesh), Liver Cancer, Carcinoma, Hepatocellular, Oncology and Carcinogenesis, Chronic Liver Disease and Cirrhosis, Clinical Sciences, Immunology, Transgenic (mesh), 610, 1107 Immunology (for), Mice, Transgenic, Biotechnology (rcdc), Chronic Liver Disease and Cirrhosis (rcdc), Rare Diseases (rcdc), MicroRNAs (mesh), Proto-Oncogene Proteins c-myc, Experimental, Rare Diseases, Genetics, Hepatobiliary Malignancies, Animals, Humans, 3204 Immunology (for-2020), Up-Regulation (mesh), Cell Proliferation, Neoplastic, Neoplastic (mesh), Biomedical and Clinical Sciences, Gastroenterology & Hepatology, Genetics (rcdc), Tumor Suppressor Proteins, Carcinoma, Hepatocellular, 1101 Medical Biochemistry and Metabolomics (for), 2.1 Biological and endogenous factors (hrcs-rac), Cancer (hrcs-hc), 3202 Clinical sciences (for-2020), Proto-Oncogene Proteins c-myc (mesh), G1 Phase Cell Cycle Checkpoints, MicroRNAs, Orphan Drug, 3211 Oncology and Carcinogenesis (for-2020), Gene Expression Regulation, Liver Cancer (rcdc), Female (mesh), Orphan Drug (rcdc), ras Proteins, Gastroenterology & Hepatology (science-metrix), Digestive Diseases
Male, Medical Biochemistry and Metabolomics, Cell Transformation, Transgenic, Mice, Liver Neoplasms, Experimental, 1103 Clinical Sciences (for), Hepatocellular (mesh), 2.1 Biological and endogenous factors, Animals (mesh), Cell Proliferation (mesh), 32 Biomedical and Clinical Sciences (for-2020), Liver Disease (rcdc), Male (mesh), Cancer, Colo-Rectal Cancer (rcdc), G1 Phase Cell Cycle Checkpoints (mesh), Cancer (rcdc), Humans (mesh), Liver Disease, Liver Neoplasms, Mice (mesh), Experimental (mesh), ras Proteins (mesh), Colo-Rectal Cancer, Up-Regulation, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, Female, Biotechnology, Digestive Diseases (rcdc), Tumor Suppressor Proteins (mesh), Liver Cancer, Carcinoma, Hepatocellular, Oncology and Carcinogenesis, Chronic Liver Disease and Cirrhosis, Clinical Sciences, Immunology, Transgenic (mesh), 610, 1107 Immunology (for), Mice, Transgenic, Biotechnology (rcdc), Chronic Liver Disease and Cirrhosis (rcdc), Rare Diseases (rcdc), MicroRNAs (mesh), Proto-Oncogene Proteins c-myc, Experimental, Rare Diseases, Genetics, Hepatobiliary Malignancies, Animals, Humans, 3204 Immunology (for-2020), Up-Regulation (mesh), Cell Proliferation, Neoplastic, Neoplastic (mesh), Biomedical and Clinical Sciences, Gastroenterology & Hepatology, Genetics (rcdc), Tumor Suppressor Proteins, Carcinoma, Hepatocellular, 1101 Medical Biochemistry and Metabolomics (for), 2.1 Biological and endogenous factors (hrcs-rac), Cancer (hrcs-hc), 3202 Clinical sciences (for-2020), Proto-Oncogene Proteins c-myc (mesh), G1 Phase Cell Cycle Checkpoints, MicroRNAs, Orphan Drug, 3211 Oncology and Carcinogenesis (for-2020), Gene Expression Regulation, Liver Cancer (rcdc), Female (mesh), Orphan Drug (rcdc), ras Proteins, Gastroenterology & Hepatology (science-metrix), Digestive Diseases
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