Mechanistic roles of microRNAs in hepatocarcinogenesis: A study of thioacetamide with multiple doses and time-points of rats

Dweep, Harsh; Morikawa, Yuji; Gong, Binsheng; Yan, Jian; Liu, Zhichao; Chen, Tao; Bisgin, Halil; Zou, Wen; Hong, Huixiao; Shi, Tieliu; Gong, Ping; Castro, Christina; Uehara, Takeki; Wang, Yuping; Tong, Weida

doi:10.1038/s41598-017-02798-7

Mechanistic roles of microRNAs in hepatocarcinogenesis: A study of thioacetamide with multiple doses and time-points of rats

Journal Article · Thu Jun 08 00:00:00 EDT 2017 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-017-02798-7· OSTI ID:1624294

Dweep, Harsh ^[1]; Morikawa, Yuji ^[2]; Gong, Binsheng ^[3]; Yan, Jian ^[3]; Liu, Zhichao ^[3]; Chen, Tao ^[4]; Bisgin, Halil ^[5]; Zou, Wen ^[3]; Hong, Huixiao ^[3]; Shi, Tieliu ^[6]; Gong, Ping ^[7]; Castro, Christina ^[8]; Uehara, Takeki ^[9]; Wang, Yuping ^[3]; Tong, Weida ^[3]

U.S. Food and Drug Administration (FDA), Jefferson, AR (United States). Div. of Bioinformatics and Biostatistics, National Center for Toxicological Research; DOE/OSTI
Shionogi & Co. Ltd., Osaka (Japan). Informatics & Structure-based Drug Discovery, Discovery Research Laboratories for Innovative Frontier Medicines
U.S. Food and Drug Administration (FDA), Jefferson, AR (United States). Div. of Bioinformatics and Biostatistics, National Center for Toxicological Research
U.S. Food and Drug Administration (FDA), Jefferson, AR (United States). Division of Genetic and Molecular Toxicology, National Center for Toxicological Research
Univ. of Michigan, Flint, MI (United States). Dept. of Computer Science, Engineering, and Physics
East China Normal Univ. (ECNU), Shanghai (China). Center for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, College of Life Science
U.S. Army Engineer Research and Development Center, Vicksburg, MS (United States). Environmental Lab.
Univ. of North Carolina, Charlotte, NC (United States)
Shionogi & Co., Ltd., Osaka (Japan). Global Project Management Dept.

Environmental chemicals exposure is one of the primary factors for liver toxicity and hepatocarcinoma. Thioacetamide (TAA) is a well-known hepatotoxicant and could be a liver carcinogen in humans. The discovery of early and sensitive microRNA (miRNA) biomarkers in liver injury and tumor progression could improve cancer diagnosis, prognosis, and management. To study this, we performed next generation sequencing of the livers of Sprague-Dawley rats treated with TAA at three doses (4.5, 15 and 45 mg/kg) and four time points (3-, 7-, 14- and 28-days). Overall, 330 unique differentially expressed miRNAs (DEMs) were identified in the entire TAA-treatment course. Of these, 129 DEMs were found significantly enriched for the “liver cancer” annotation. These results were further complemented by pathway analysis (Molecular Mechanisms of Cancer, p53-, TGF-β-, MAPK- and Wnt-signaling). Two miRNAs (rno-miR-34a-5p and rno-miR-455-3p) out of 48 overlapping DEMs were identified to be early and sensitive biomarkers for TAA-induced hepatocarcinogenicity. We have shown significant regulatory associations between DEMs and TAA-induced liver carcinogenesis at an earlier stage than histopathological features. Most importantly, miR-34a-5p is the most suitable early and sensitive biomarker for TAA-induced hepatocarcinogenesis due to its consistent elevation during the entire treatment course.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: US Food and Drug Administration; USDOE

Grant/Contract Number:: SC0014664

OSTI ID:: 1624294

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 7; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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