Profiling the circulating mRNA transcriptome in human liver disease
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Aejaz Sayeed1, Brielle E. Dalvano1, David E. Kaplan2,3, Usha Viswanathan1, John Kulp1, Alhaji H. Janneh1,4, Lu-Yu Hwang5, Adam Ertel6, Cataldo Doria7 and Timothy Block1
1 Baruch S. Blumberg Institute, Doylestown, PA, USA
2 University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
3 The Corporal Michael J. Crescenz Veterans Administration Hospital, Philadelphia, PA, USA
4 Current address: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
5 Department of Epidemiology, Human Genetics and Environment Science Center for Infectious Diseases School of Public Health, the University of Texas HSC, Houston, TX, USA
6 Department of Cancer Biology, Sidney Kimmel Cancer Center, Cancer Genomics Core Facility, Thomas Jefferson University, Philadelphia, PA, USA
7 Capital Health Cancer Center, One Capital Way, Pennington, NJ, USA
Keywords: hepatocellular carcinoma; circulating transcripts; biomarkers; liver cirrhosis; extracellular vesicles
Received: February 28, 2020 Accepted: May 16, 2020 Published: June 09, 2020
The human circulation contains cell-free DNA and non-coding microRNA (miRNA). Less is known about the presence of messenger RNA (mRNA). This report profiles the human circulating mRNA transcriptome in people with liver cirrhosis (LC) and hepatocellular carcinoma (HCC) to determine whether mRNA analytes can be used as biomarkers of liver disease. Using RNAseq and RT-qPCR, we investigate circulating mRNA in plasma from HCC and LC patients and demonstrate detection of transcripts representing more than 19,000 different protein coding genes. Remarkably, the circulating mRNA expression levels were similar from person to person over the 21 individuals whose samples were analyzed by RNAseq. Liver derived circulating transcripts such as albumin (ALB), apolipoprotein (APO) A1, A2 & H, serpin A1 & E1, ferritin light chain (FTL) and fibrinogen like 1 (FGL1) were significantly upregulated in HCC patient samples. Higher levels of some of these liver-specific transcripts in the plasma of HCC patients were confirmed by RT-qPCR in another cohort of 20 individuals. Several less abundant circulating transcripts associated with cancer were detected in most HCC samples, but not in healthy subjects. Liver specificity of circulating transcripts was confirmed by investigating their expression in HCC tumor and liver cancer cell lines. Liver specific mRNA sequences in the plasma were predominantly present outside circulating extracellular vesicles.
Conclusions: The circulating “mRNA” transcriptome is remarkably consistent in diversity and expression from person to person. Detection of transcripts corresponding to disease selective polypeptides suggests the possibility that circulating mRNA can work as a biomarker analyte for cancer detection.
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