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Non-Coding Rnas in Various Stages of Liver Disease Leading

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Non-Coding Rnas in Various Stages of Liver Disease Leading www.nature.com/scientificreports OPEN Non-coding RNAs in Various Stages of Liver Disease Leading to Hepatocellular Carcinoma: Received: 9 January 2018 Accepted: 10 May 2018 Diferential Expression of miRNAs, Published: xx xx xxxx piRNAs, lncRNAs, circRNAs, and sno/mt-RNAs Srinivas V. Koduru 1, Ashley N. Leberfnger 1, Yuka I. Kawasawa2, Milind Mahajan3, Niraj J. Gusani4, Arun J. Sanyal5 & Dino J. Ravnic 1 Hepatocellular carcinoma (HCC) was the ffth leading cause of cancer death in men and eighth leading cause of death in women in the United States in 2017. In our study, we sought to identify sncRNAs in various stages of development of HCC. We obtained publicly available small RNA-seq data derived from patients with cirrhosis (n = 14), low-grade dysplastic nodules (LGDN, n = 9), high grade dysplastic nodules (HGDN, n = 6), early hepatocellular carcinoma (eHCC, n = 6), and advanced hepatocellular carcinoma (HCC, n = 20), along with healthy liver tissue samples (n = 9). All samples were analyzed for various types of non-coding RNAs using PartekFlow software. We remapped small RNA-seq to miRBase to obtain diferential expressions of miRNAs and found 87 in cirrhosis, 106 in LGDN, 59 in HGDN, 80 in eHCC, and 133 in HCC. Pathway analysis of miRNAs obtained from diseased samples compared to normal samples showed signaling pathways in the microRNA dependent EMT, CD44, and others. Additionally, we analyzed the data sets for piRNAs, lncRNAs, circRNAs, and sno/mt-RNAs. We validated the in silico data using human HCC samples with NanoString miRNA global expression. Our results suggest that publically available data is a valuable resource for sncRNA identifcation in HCC progression (FDR set to <0.05 for all samples) and that a data mining approach is useful for biomarker development. Hepatocellular carcinoma (HCC) was the ffh leading cause of cancer death in men and eighth leading cause of death in women in the United States in 2017. Te incidence of HCC has been increasing every year, with an estimated 40,710 new cases in 20171. In addition, death rates are increasing by 3% every year, with an esti- mated 28,920 deaths in 20171. Tese statistics suggest more research needs to be done towards understanding the biology, diagnosis, and prevention. Primary liver cancer, or HCC can be triggered by ongoing infammation from pathologies such as cirrhosis, dysplastic nodule formation, viral infections (i.e. viral hepatitis), and NASH. Cirrhosis is a condition in which the liver becomes scarred secondary to repeated insults. 1Division of Plastic Surgery, Department of Surgery, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA. 2Department of Pharmacology, Department of Biochemistry & Molecular Biology, and Institute for Personalized Medicine, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA. 3Genomics Facility, Department of Genetics and Genomics Sciences, Icahn School of Medicine, Mount Sinai, 1425 Madison Ave, New York, NY, 10029, USA. 4Program for Liver, Pancreas, & Foregut Tumors, Department of Surgery, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA. 5Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, 1201 E Marshall St, Richmond, VA, 23298, USA. Correspondence and requests for materials should be addressed to S.V.K. (email: [email protected]) or D.J.R. (email: dravnic@ pennstatehealth.psu.edu) SCIENTIFIC REPORTS | (2018) 8:7967 | DOI:10.1038/s41598-018-26360-1 1 www.nature.com/scientificreports/ Figure 1. Diferential expression of miRNAs in liver tissue samples: Diferentially expressed miRNAs were quantifed (FDR < 0.05) and a heatmap was prepared for each disease stage (Cirrhosis, Low-grade dysplastic nodule, High- grade dysplastic nodule, Early stage Hepatocellular carcinoma, and Advanced stage Hepatocellular carcinoma) with healthy control samples (A–E). Enriched miRNAs for all stages of liver disease were summarized by a Venn diagram, which identifed 37 miRNAs commonly expressed in all stages and 29 additional diferentially expressed miRNAs were enriched in advanced hepatocellular carcinoma alone (F). (G) A Circos plot was prepared incorporating all diferential expressions of miRNAs in cirrhosis, low-grade dysplastic nodule, high-grade dysplastic nodule, early hepatocellular carcinoma, and hepatocellular carcinoma tissue samples compared with healthy samples (FDR < 0.05). Chromosomes and bands were listed in the chromosomal positions of miRNAs afected expression in liver disease vs healthy samples. Te innermost ring is for cirrhosis, followed by low-grade dysplastic nodule, high-grade dysplastic nodule, early hepatocellular carcinoma, and hepatocellular carcinoma. Darker and lighter background colors represent upregulated and downregulated genes respectively. We validated the miRNA sequence data using NanoString global miRNA expression assay. Data was exported using nSolver sofware. (H) A Venn diagram showing miRNA overlap between HCC miRNA-seq data and HCC-NanoString validation data. (I) A heat map illustrating the top 20 up- and down- regulated miRNAs in the HCC-NanoString validation data. SCIENTIFIC REPORTS | (2018) 8:7967 | DOI:10.1038/s41598-018-26360-1 2 www.nature.com/scientificreports/ microRNA ID Chromosome Fold change FDR hsa-miR-122-5p 18 −312.73 1.58E-08 hsa-let-7g-5p 3 −204.40 2.12E-04 hsa-mir-103a-2 20 −83.22 3.85E-04 hsa-miR-532-5p X −79.93 2.96E-04 hsa-miR-451a 17 −62.96 3.56E-04 hsa-miR-378c 10 −59.31 2.52E-04 hsa-mir-27b 9 −44.44 5.86E-04 hsa-miR-152-3p 17 −44.35 6.26E-04 hsa-mir-194-2 11 −44.16 3.85E-04 hsa-miR-185-5p 22 −39.71 1.44E-03 hsa-miR-128-3p 2 −31.89 2.15E-03 hsa-miR-24-3p 19 −27.07 1.38E-03 hsa-let-7a-5p 11 −25.41 1.22E-04 hsa-let-7b-5p 22 −23.18 6.26E-04 hsa-miR-148b-3p 12 −21.63 9.32E-04 hsa-miR-210-3p 11 −19.22 1.11E-04 hsa-mir-23a 19 −14.26 5.34E-03 hsa-miR-139-5p 11 −14.07 4.82E-03 hsa-mir-101-2 9 −13.98 2.96E-04 hsa-mir-17 13 −13.52 6.00E-03 hsa-miR-99a-5p 21 −12.34 1.77E-04 hsa-miR-93-5p 7 −12.26 6.12E-03 hsa-mir-199a-2 1 −12.07 3.85E-04 hsa-miR-125b-5p 11 −12.00 4.74E-03 hsa-mir-3591 18 −11.52 2.12E-04 hsa-miR-148a-3p 7 −10.94 2.52E-04 hsa-mir-224 X −10.83 7.73E-03 hsa-mir-23b 9 −10.81 7.29E-03 hsa-mir-3607 5 −9.29 3.71E-04 hsa-miR-450a-5p X −7.90 1.22E-02 hsa-miR-200a-3p 1 −7.80 1.08E-02 hsa-mir-140 16 −7.77 1.38E-03 hsa-miR-92a-3p 13 −7.70 1.08E-02 hsa-mir-103a-1 5 −7.57 1.03E-03 hsa-mir-152 17 −7.05 1.49E-02 hsa-mir-378a 5 −6.78 2.78E-02 hsa-miR-126-3p 9 −6.45 1.72E-03 hsa-miR-574-3p 4 −6.41 9.98E-03 hsa-mir-126 9 −6.26 1.55E-02 hsa-mir-128-1 2 −5.62 2.27E-02 hsa-mir-144 17 −5.51 9.16E-03 hsa-miR-29a-3p 7 −5.21 5.08E-03 hsa-mir-21 17 −4.99 3.56E-03 hsa-mir-101-1 1 −4.51 3.95E-03 hsa-let-7e-5p 19 −4.45 2.27E-02 hsa-miR-340-5p 5 −4.04 9.41E-03 hsa-miR-27a-3p 19 −3.92 6.00E-03 hsa-miR-100-5p 11 −3.89 7.36E-03 hsa-miR-26a-5p 12 −3.79 5.34E-03 hsa-mir-199a-1 19 −3.20 8.12E-03 hsa-miR-215-5p 1 −3.07 4.17E-02 hsa-miR-423-3p 17 −3.07 1.60E-02 hsa-miR-21-5p 17 −3.01 1.03E-02 hsa-miR-30b-5p 8 −3.00 2.58E-02 hsa-mir-106b 7 −3.00 1.92E-02 hsa-mir-125b-2 21 −2.96 1.95E-02 hsa-mir-455 9 −2.92 3.76E-02 Continued SCIENTIFIC REPORTS | (2018) 8:7967 | DOI:10.1038/s41598-018-26360-1 3 www.nature.com/scientificreports/ microRNA ID Chromosome Fold change FDR hsa-mir-195 17 −2.80 3.58E-02 hsa-mir-26b 2 −2.69 1.28E-02 hsa-miR-107 10 −2.62 1.55E-02 hsa-mir-3653 22 −2.58 4.32E-02 hsa-miR-103a-3p 20 −2.40 1.84E-02 hsa-miR-103b 20 −2.40 1.84E-02 hsa-mir-660 X −2.34 3.88E-02 hsa-let-7a-1 9 −2.21 3.76E-02 hsa-mir-505 X −2.21 4.32E-02 hsa-mir-192 11 −2.03 2.27E-02 hsa-miR-194-5p 1 −1.86 2.04E-02 hsa-miR-25-3p 7 −1.84 3.23E-02 hsa-let-7i 12 −1.65 4.73E-02 hsa-let-7i-5p 12 −1.58 4.77E-02 hsa-mir-148a 7 −1.48 2.51E-02 hsa-mir-409 14 7.84 4.00E-02 hsa-miR-769-5p 19 8.13 6.63E-03 hsa-miR-320b 1 14.14 2.89E-04 hsa-mir-136 14 15.82 1.80E-02 hsa-miR-127-3p 14 17.15 3.85E-04 hsa-miR-320a 8 17.51 9.02E-06 hsa-mir-186 1 19.52 3.85E-04 hsa-mir-181c 19 24.73 4.46E-02 hsa-miR-1307-5p 10 26.74 6.00E-03 hsa-mir-10b 2 28.57 3.03E-02 hsa-miR-192-5p 11 31.98 1.83E-02 hsa-mir-486-2 8 75.42 9.02E-06 hsa-miR-101-3p 1 113.21 2.51E-02 hsa-mir-22 17 142.96 1.05E-07 hsa-miR-7704 2 403.15 1.11E-04 Table 1.
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