Investigation of long noncoding RNAs expression profile as potential serum biomarkers in patients with hepatocellular carcinomaby Marwa M. Kamel, Marwa Matboli, Maha Sallam, Iman F. Montasser, Amr S. Saad, Ahmed H.F. El-Tawdi

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Investigation of long non coding RNAs expression profile as potential serum biomarkers in patients with hepatocellular carcinoma

Marwa M. Kamel, Marwa Matboli, Maha Sallam, Iman F. Montasser, Amr S. Saad,

Ahmed H.F. El-Tawdi

PII: S1931-5244(15)00335-7

DOI: 10.1016/j.trsl.2015.10.002

Reference: TRSL 970

To appear in: Translational Research

Received Date: 2 September 2015

Revised Date: 26 September 2015

Accepted Date: 6 October 2015

Please cite this article as: Kamel MM, Matboli M, Sallam M, Montasser IF, Saad AS, El-Tawdi AHF,

Investigation of long non coding RNAs expression profile as potential serum biomarkers in patients with hepatocellular carcinoma, Translational Research (2015), doi: 10.1016/j.trsl.2015.10.002.

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Kamel et al., 2015 · 1

Investigation of long non coding RNAs expression profile as potential serum biomarkers in patients with hepatocellular carcinoma

Running title: Role of Long non coding RNAs in hepatocellular carcinoma

Marwa M. Kamel 1, Marwa Matboli1, Maha Sallam1, Iman F Montasser, Amr S.

Saad3, Ahmed H.F.El-Tawdi4 1Oncology Diagnostic Unit, Medical Biochemistry and Molecular biology

Department, Faculty of Medicine, Ain Shams University, Abbassia, Cairo, Egypt,

P.O. box 11381. 2 Gastroenterology, Hepatology & Infectious Diseases; Tropical Medicine

Department, Faculty of Medicine, Ain Shams University 3Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Ain

Shams University 4

General and Plastic Surgery Department, Military Medical Academy Department. #corresponding author:

Marwa Matboli1, 1Oncology Diagnostic Unit, Medical Biochemistry and Molecular biology Department, Faculty of Medicine, Ain Shams University, Abbassia, Cairo,

Egypt, P.O. box 11381. habiba20062001@yahoo.com.

DrMarwa__Matboly@med.asu.edu.eg

Conflict of interest statement

The authors declare that they have no competing interests.

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Kamel et al., 2015 · 2

Abstract

There is an increasing interest in using long non coding RNAs (lncRNAs) as biomarkers in cancer. Predictive biomarkers in hepatocellular carcinoma (HCC) have great benefit in the choice of therapeutic modality for HCC. To assess Long non-coding RNA- Urothelial Carcinoma Associated-1(lncRNA–UCA1) and WD repeat containing, antisense to TP53 (WRAP53) expression as novel non-invasive biomarkers for diagnosis of HCC in sera of HCC patients compared with chronic

HCV patients and healthy volunteers and to analyze their relationship with respect to the clinicopathological features. We retrieved HCC characteristic lncRNA; lncRNAUCA1 and lncRNA-WRAP53 based on the microarray signature profiling (released by LncRNA Disease database). Quantitative reverse-transcriptase polymerase chain reaction assay (Qpcr) was then employed to evaluate the expression of selected lncRNAs in the serum of 160 participants. Furthermore, in twenty of 82 HCC cases involved in the study; we examined the expression of lncRNA-UCA1 and lncRNAWRAP53 in 20 HCC tissues and adjacent non-tumor tissues and analyzed its correlation with the serum level of these lncRNAs. The prognostic significance of the investigated parameters in HCC patients was explored. We found that lncRNA–

UCA1 and lncRNA-WRAP53 were significantly higher in sera of HCC than those with chronic HCV infection (CHC) or healthy volunteers. Our data suggested that the increased expression of UCA1 and WRAP53 was associated with advanced clinical parameters in HCC. Of note, tissue levels of the chosen lncRNAs strongly correlate with their sera level. The combination of both lncRNAs with serum alpha fetoprotein (AFP) resulted in improved sensitivity to 100%. The median follow up period was 21.5 months. LncRNA-WRAP53 was significant independent prognostic markers in Relapse-Free Survival (RFS). LncRNA–UCA1 and lncRNA-WRAP53 upregulation may serve as novel serum biomarkers for HCC diagnosis and prognosis.

Keywords: lncRNA-UCA1; lncRNA-WRAP53; lncRNA; hepatocellular carcinoma,

Bioinformatic; Biomarkers.

Abbreviation: ALT: Alanine transaminase, ALT: Aspartate transaminase, AFP:

Alpha fetoprotein, CHC: Chronic HCV infection, CHC: Chronic HCV Infection,

HCC: Hepatocellular Carcinoma, lncRNA–UCA1: Long non-coding RNAUrothelial Carcinoma Associated-1, WRAP53: WD repeat containing, antisense to

TP53, qPCR: Quantitative reverse-transcriptase polymerase chain reaction assay . 1. Introduction

Hepatocellular carcinoma (HCC) ranks as the fifth most common cancer worldwide and the second most frequent cause of cancer-related death globally [1]. The majority of HCC cases can be attributed to either hepatic cirrhosis or viral hepatitis infection (hepatitis B or C) [2].

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Kamel et al., 2015 · 3

Egypt has the highest prevalence of hepatitis C virus (HCV) in the world, ranging from 6% to 28%[3]. Primary Liver cancer is the fourth most common cancer and is the leading cause of cancer mortality in Egypt [3]. Moreover, there is some epidemiologic evidence that Schistosoma infection may modify hepatitis C course and may lead to an accelerated liver fibrosis and thus quicker progression to HCC [4]. The most widely used screening tools for HCC come under one of two categories; either imaging tools or serum tumor biomarkers in the form of alpha-fetoprotein (AFP) which lack an adequate diagnostic performance particularly for the detection of early-stage HCC [5].

A considerable effort has been directed to unravel the molecular mechanisms of HCC hence identifying new targets for therapies as well as diagnostic and prognostic markers to improve the clinical outcome of HCC patients. Along with an extensive characterization of the protein-coding genome of liver tumors, there has been a great interest in the study of non-coding RNAs (ncRNA) [6].