Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 28, 2019; 25(36): 5483-5493
Published online Sep 28, 2019. doi: 10.3748/wjg.v25.i36.5483
CARMA3/NF-κB signaling contributes to tumorigenesis of hepatocellular carcinoma and is inhibited by sodium aescinate
Hui Hou, Wei-Xiang Li, Xiao Cui, Da-Chen Zhou, Bin Zhang, Xiao-Ping Geng
Hui Hou, Wei-Xiang Li, Xiao Cui, Da-Chen Zhou, Bin Zhang, Xiao-Ping Geng, Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
Xiao Cui, Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, United States
Xiao-Ping Geng, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, Anhui Province, China
Author contributions: Hou H wrote the paper and performed the operations and pathological test; Li WX and Zhou DC performed molecular experiments; Cui X and Zhang B analyzed the data; Geng XP designed the experiments and reviewed the manuscript; Hui H, Li WX, and Cui X contributed equally to this work.
Supported by the Nature Science Foundation of High Education Institution of Anhui Province, No. KJ2017A825; Anhui Provincial Natural Science Foundation, No. 1808085MH270; Foundation of the Higher Education Institution of Henan Province, No. 16A320007; “ Huohua Jihua” Foundation of the Second Hospital of Anhui Medical University Science, No. 2015hhjh05; and Anhui Medical University Science Foundation, No. 2017xkj033.
Institutional review board statement: This study was approved by the Ethics Committee of The Second Affiliated Hospital.
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: No additional unpublished data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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:
Corresponding author: Xiao-Ping Geng, MD, Director, Professor, Department of Hepato-Pancreato-Biliary Surgery, Department of Surgery, The second hospital of Anhui Medical University, Furong Road, 678#, Hefei 230601, Anhui Province, China.
Telephone: +86-551-63869594 Fax: +86-551-63869594
Received: June 17, 2019
Peer-review started: June 18, 2019
First decision: August 3, 2019
Revised: August 13, 2019
Accepted: August 24, 2019
Article in press: August 24, 2019
Published online: September 28, 2019
Research background

Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors in the world. The incidence rate of HCC continuously rises over the last decades. The therapeutic effects are still unsatisfied.

Research motivation

As an oncogenic factor, CARMA3 has been explored in various types of tumors. The role of CARMA3 in the tumorigenesis of HCC and its potential therapeutic application have not been fully identified.

Research objectives

To investigate the biological function of CARMA3 in the progression of HCC, and the potential therapeutic effects of sodium aescinate (SA) in HCC.

Research methods

TMA slides with paraffin-embedded HCC samples from 100 patients were employed in this study. Expression of CARMA3 in HCC tissues was detected by immunohistochemistry (IHC). The biological function of CARMA3 in HCC was investigated by increasing or decreasing endogenous CARMA3 expression in HepG2 and Hep3B cells using plasmid transfection in vitro. The proliferation and colony formation assays and apoptosis detection kits were used to investigate the role of CARMA3 and SA in HCC cells. Western blot and immunofluorescence assays were used to detect the expression of targeted proteins.

Research results

IHC analysis showed that CARMA3 was increased in HCC tissues compared with adjacent non-cancerous liver tissues. High CARMA3 expression in HCC predicted less overall survival time and disease-free survival time in HCC patients. Knockdown of CARMA3 expression inhibited proliferation and colony formation, and induced early apoptosis in HCC cells. Increasing endogenous CARMA3 expression in HCC cells promoted cell growth and suppressed apoptosis. SA inhibited the growth of HCC cells and decreased the expression of CARMA3 and its targeted protein nuclear factor kappa-B (NF-κB). No anti-proliferation or pro-apoptosis effect was observed in human hepatocytes treated with SA.

Research conclusions

Expression of CARMA3 increases in HCC tissues and correlates with a poor prognosis in HCC patients. CARMA3 acts pro-tumorigenic effects by enhancing HCC growth and inhibiting apoptosis partly through activation of CARMA3/NF-κB. SA inhibits HCC growth by targeting CARMA3/NF-κB.

Research perspectives

Our work gave an insight of the mechanism of CARMA3 in the pathogenesis of HCC and explored its potential therapeutic application for HCC, which provide a promising target for HCC treatment.