Lnc-ZEB2-19 Inhibits the Progression and Lenvatinib Resistance of Hepatocellular Carcinoma by Attenuating the NF-κB Signaling Pathway through the TRA2A/RSPH14 Axis

Mingbo Cao; Yupeng Ren; Yuxuan Li; Junfeng Deng; Xiaorui Su; Yongchang Tang; Feng Yuan; Haixia Deng; Gaoyuan Yang; Zhiwei He; Bo Liu; Zhicheng Yao; Meihai Deng

doi:10.7150/ijbs.85270

Lnc-ZEB2-19 Inhibits the Progression and Lenvatinib Resistance of Hepatocellular Carcinoma by Attenuating the NF-κB Signaling Pathway through the TRA2A/RSPH14 Axis

Int J Biol Sci. 2023 Jul 16;19(12):3678-3693. doi: 10.7150/ijbs.85270. eCollection 2023.

Authors

Mingbo Cao¹, Yupeng Ren¹, Yuxuan Li¹, Junfeng Deng², Xiaorui Su¹, Yongchang Tang³, Feng Yuan⁴, Haixia Deng², Gaoyuan Yang¹, Zhiwei He¹, Bo Liu², Zhicheng Yao², Meihai Deng¹

Affiliations

¹ Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
² Department of Hepatobiliary & Pancreatic Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
³ Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China.
⁴ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China.

Abstract

Long non-coding RNAs have been reported to play a crucial role in tumor progression in hepatocellular carcinoma (HCC). Lnc-ZEB2-19 has been validated to be deficiently expressed in HCC. However, the capabilities and underlying mechanisms of lnc-ZEB2-19 remain uncertain. In this study, we verified that the downregulation of lnc-ZEB2-19 was prevalent in HCC and significantly correlated with the unfavorable prognosis. Further in vitro and in vivo verified that lnc-ZEB2-19 notably inhibited the proliferation, metastasis, stemness, and lenvatinib resistance (LR) of HCC cells. Mechanistically, lnc-ZEB2-19 inhibited HCC progression and LR by specifically binding to transformer 2α (TRA2A) and promoting its degradation, which resulted in the instability of RSPH14 mRNA, leading to the downregulation of Rela(p65) and p-Rela(p-p65). Furthermore, rescue assays showed that silencing RSPH14 partially restrained the effect of knockdown expression of lnc-ZEB2-19 on HCC cell metastatic ability and stemness. The findings describe a novel regulatory axis, lnc-ZEB2-19/TRA2A/RSPH14, downregulating the nuclear factor kappa B to inhibit HCC progression and LR.

Keywords: Hepatocellular Carcinoma; Lenvatinib resistance; Lnc-ZEB2-19; TRA2A; mRNA stability.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / pathology
Cell Line, Tumor
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic / genetics
Humans
Liver Neoplasms* / genetics
Liver Neoplasms* / pathology
NF-kappa B / genetics
RNA, Long Noncoding* / genetics
Signal Transduction / genetics
Zinc Finger E-box Binding Homeobox 2 / genetics

Substances

lenvatinib
NF-kappa B
ZEB2 protein, human
Zinc Finger E-box Binding Homeobox 2
RNA, Long Noncoding
TRA2A protein, human