NIK‐mediated reactivation of SIX2 enhanced the CSC‐like traits of hepatocellular carcinoma cells through suppressing ubiquitin–proteasome system

Abstract

The critical roles of NF‐κB Inducing Kinase (NIK) in tumor progression have been elucidated in various tumors; however, its effects on hepatocellular carcinoma (HCC) progression are still confusing. Here, we found that NIK level was upregulated in HCC tissues compared to that of normal tissues, and positively correlated with the levels of cancer stem cell (CSC) markers. Then we established HCC cells with NIK‐stable knockdown and found that NIK knockdown suppressed the CSC—like traits of HCC cells through in vivo and in vitro experiments. Mechanistically, we revealed that SIX2 protein level, but not its mRNA level, was significantly reduced in HCC cells with NIK knockdown, which was rescued by MG132 treatment. Furthermore, NIK knockdown promoted the ubiquitination level of SIX2 and decreased its protein stability. Moreover, Six2 overexpression partially reversed the inhibition of NIK knockdown on the CSC‐like traits of HCC cells. This study identified a novel NIK/SIX2 axis conferring HCC stemness.

Potential Role of MAP3K14 in Hepatocellular Carcinoma: A Study Based on Comprehensive Bioinformatical Analysis and Validation

“…Additionally, research has revealed upregulation of NIK expression in HCC tissues and cells. Knockdown of NIK reduces the cancer stem cell-like characteristics of HCC cells 36 . These findings offer important clues for further understanding the role of NIK in disease progression and developing relevant therapeutic approaches.…”