Meta-Analysis
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Sep 15, 2022; 14(9): 1856-1873
Published online Sep 15, 2022. doi: 10.4251/wjgo.v14.i9.1856
Dissecting novel mechanisms of hepatitis B virus related hepatocellular carcinoma using meta-analysis of public data
Jihad Aljabban, Michael Rohr, Saad Syed, Eli Cohen, Naima Hashi, Sharjeel Syed, Kamal Khorfan, Hisham Aljabban, Vincent Borkowski, Michael Segal, Mohamed Mukhtar, Mohammed Mohammed, Emmanuel Boateng, Mary Nemer, Maryam Panahiazar, Dexter Hadley, Sajid Jalil, Khalid Mumtaz
Jihad Aljabban, Vincent Borkowski, Michael Segal, Mary Nemer, Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
Michael Rohr, Department of Medicine, University of Central Florida College of Medicine, Orlando, FL 32827, United States
Saad Syed, Department of Medicine, Northwestern Memorial Hospital, Chicago, IL 60611, United States
Eli Cohen, Emmanuel Boateng, Department of Medicine, Vanderbilt Medical Center, Nashville, TN 37232, United States
Naima Hashi, Department of Medicine, Mayo Clinic, Rochester, MN 55905, United States
Sharjeel Syed, Department of Medicine, University of Chicago Hospitals, Chicago, IL 60637, United States
Kamal Khorfan, Department of Gastroenterology and Hepatology, University of California San Francisco-Fresno, Fresno, CA 93701, United States
Hisham Aljabban, Department of Medicine, Barry University, Miami, FL 33161, United States
Mohamed Mukhtar, Department of Medicine, Michigan State University College of Human Medicine, Lansing, MI 49503, United States
Mohammed Mohammed, Department of Medicine, Windsor University School of Medicine, Frankfort, IL 60423, United States
Maryam Panahiazar, Department of Surgery, University of California San Francisco, San Francisco, CA 94143, United States
Dexter Hadley, Department of Pathology, University of Central Florida College of Medicine, Orlando, FL 32827, United States
Sajid Jalil, Khalid Mumtaz, Department of Gastroenterology and Hepatology, Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
Author contributions: Aljabban J and Rohr M contributed to the conception or design of the work; Aljabban J, Rohr M, and Hadley D involved in the data collection; Aljabban J, Rohr M, Syed S, Cohen E, Hashi N, Syed S, Khorfan K, Aljabban H, and Mumtaz K drafted manuscript; Aljabban J, Rohr M, Syed S, Cohen E, Hashi N, Syed S, Khorfan K, Aljabban H, Boateng E, Nemer M, Panahiazar M, Hadley D, Jalil S, and Mumtaz K involved in the critical revision of manuscript; Aljabban J, Rohr M, Syed S, Cohen E, Hashi N, Syed S, Khorfan K, Aljabban H, Boateng E, Nemer M, Panahiazar M, Hadley D, Jalil S, and Mumtaz K contributed to the final edits and approval.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jihad Aljabban, MD, MSc, Academic Research, Doctor, Department of Medicine, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792, United States. jaljabban@uwhealth.org
Received: January 20, 2022
Peer-review started: January 20, 2022
First decision: April 17, 2022
Revised: April 26, 2022
Accepted: August 7, 2022
Article in press: August 7, 2022
Published online: September 15, 2022
Processing time: 232 Days and 10.9 Hours
Abstract
BACKGROUND

Hepatitis B virus (HBV) is a cause of hepatocellular carcinoma (HCC). Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways were affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation and has implications in early diagnosis and treatment.

AIM

To elucidate HBV oncogenesis in HCC and identify potential therapeutic targets.

METHODS

We employed our Search, Tag, Analyze, Resource platform to conduct a meta-analysis of public data from National Center for Biotechnology Information’s Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent non-tumor samples and analyzed results with ingenuity pathway analysis.

RESULTS

Our analysis revealed liver X receptors/retinoid X receptor (RXR) activation and farnesoid X receptor/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene rab-like protein 6 (RABL6). The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. We conducted survival analysis that demonstrated increased mortality with higher RABL6 expression. Additionally, homeobox A10 (HOXA10) was a top upstream regulator and was strongly upregulated in our analysis. HOXA10 has recently been demonstrated to contribute to HCC pathogenesis in vitro. Our causal analysis suggests an in vivo role through downregulation of tumor suppressors and other mechanisms.

CONCLUSION

This meta-analysis describes possible roles of RABL6 and HOXA10 in the pathogenesis of HBV-related HCC. RABL6 and HOXA10 represent potential therapeutic targets and warrant further investigation.

Keywords: Hepatitis B virus; Hepatocellular carcinoma; Genomics; Meta-analysis

Core Tip: Hepatitis B virus (HBV) is a cause of hepatocellular carcinoma (HCC). Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways were affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation, and has implications in early diagnosis and treatment. Our manuscript leverages big data to offer key insights to oncogenesis of HBV infection in HCC. We were able to dissect key genetic drivers to disease and namely demonstrate a newfound role for rab-like protein 6 and homeobox A10.