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

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.