SENP2 Reduces Hepatocellular Carcinoma Stemness and Improves Sorafenib Sensitivity Through Inactivating the AKT/GSK3β/CTNNB1 Pathway

Abstract

BackgroundSmall ubiquitin-like modifier specific peptidase 2 (SENP2) suppresses the progression and chemoresistance of several cancers, while few studies report its role in hepatocellular carcinoma (HCC). This study aimed to evaluate the effect of SENP2 on stemness, sorafenib sensitivity, and downstream pathway in HCC, with validation of its molecular mechanisms by compensation experiment.MethodsSENP2 was regulated by plasmid transfection; meanwhile, in a compensation experiment, protein kinase B (AKT) was activated by SC79 treatment and β-catenin (CTNNB1) was overexpressed by plasmid transfection. After modification, sorafenib sensitivity was detected by cell counting kit-8 assay; stemness was evaluated by CD133+ cell proportion and sphere formation assay.ResultsSENP2 was decreased in HCC cell lines (including Hep3B, Li7, and Huh7) compared with normal human liver epithelial cell lines, which was further reduced in HCC stem cells than in normal HCC cells. Subsequently, SENP2 overexpression inhibited CD133+ cell proportion, decreased sphere formation ability, promoted sorafenib sensitivity, suppressed AKT and glycogen synthase kinase-3β (GSK3β) phosphorylation, and reduced CTNNB1 expression in Huh7 and Hep3B cells, while SENP2 knockdown showed the reverse effects. The following compensation experiment revealed that activating AKT or overexpressing CTNNB1 promoted CD133+ cell proportion and sphere formation ability but suppressed sorafenib sensitivity in Huh7 and Hep3B cells. Moreover, activating AKT or overexpressing CTNNB1 attenuated the effect of SENP2 overexpression on stemness and sorafenib sensitivity in Huh7 and Hep3B cells.ConclusionSENP2 suppresses HCC stemness and increases sorafenib sensitivity through inactivating the AKT/GSK3β/CTNNB1 signaling pathway.

RETRACTED: Exosomes From Cancer-Associated Mesenchymal Stem Cells Transmit TMBIM6 to Promote the Malignant Behavior of Hepatocellular Carcinoma via Activating PI3K/AKT Pathway

“…Finally, all cells were incubated with DMEM/F12 medium (Gibco, USA) supplemented with 20 ng/ml of EGF (Gibco, USA), 10 ng/ml of bFGF, and 10 μl/ml of B27 (Gibco, USA) for 10 days. The number of spheres (diameter > 50 µm) was counted under a microscope ( 30 ).…”

A Pan-Cancer Analysis of UBE2S in Tumorigenesis, Prognosis, Pathway, Immune Infiltration and Evasion, and Therapy Response from an Immune-Oncology Perspective

“…Hence, it is essential to discover additional robust indicators for efficacy prediction and therapeutic target potential therapeutic targets. An increasing number of studies have addressed the importance of cancerous stemness and DNA methylation for drug sensitivity and resistance [ 22 , 30 , 31 ]. Beyond this, genome instability markers, including TMB, HRD, MSI, and MMR deficiency, were also reported to yield a profound impact on the immunotherapeutic response profiles [ 18 – 21 ].…”

Cancer-Associated Dysregulation of Sumo Regulators: Proteases and Ligases

“…It is commonly acknowledged that stemness is important for cancer metastasis and recurrence, contributing as well to drug resistance, resulting in poor patient prognosis. Overexpression of SENP2 has been shown to diminish HCC stemness and to sensitize cells to sorafenib [ 109 ]. HCC cell lines have lower SENP2 levels than normal human liver epithelial cell lines, while HCC stem cells had much lower levels than regular HCC cells.…”

“…HCC cell lines have lower SENP2 levels than normal human liver epithelial cell lines, while HCC stem cells had much lower levels than regular HCC cells. Mechanistically, SENP2 overexpression results in inhibition of the AKT/GSK3β/CTNNB1 pathway, which is linked to stemness suppression and drug sensitivity increase of HCC cells [ 109 ]. Meanwhile, a study with bladder cancer cells revealed that overexpression of SENP2 suppresses the TGFβ pathway and the ensuing EMT, preventing cell invasion.…”