[Retracted] Inhibition of neddylation modification by MLN4924 sensitizes hepatocellular carcinoma cells to sorafenib.

Following the publication of the above article, the authors noticed that they had inadvertently included a duplication of the same data in Fig. 3C, portraying colony formation experiments, where the results from differently performed experiments were intended to have been shown, and requested that a corrigendum be published to present the data in this figure accurately. Having investigated this matter in the Editorial Office, however, additional panels of overlapping data were identified, comparing between Figs.

Integrated ubiquitomics characterization of hepatocellular carcinomas.

Background And Aims: Patients with aggressive HCC have limited therapeutic options. Therefore, a better understanding of HCC pathogenesis is needed to improve treatment. Genomic studies of HCC have improved our understanding of cancer biology.

Elevated FBXL6 activates both wild-type KRAS and mutant KRAS and drives HCC tumorigenesis via the ERK/mTOR/PRELID2/ROS axis in mice.

Background: Kirsten rat sarcoma (KRAS) and mutant KRAS have been implicated in human cancers, but it remains unclear whether their activation requires ubiquitination. This study aimed to investigate whether and how F-box and leucine-rich repeat 6 (FBXL6) regulates KRAS and KRAS activity in hepatocellular carcinoma (HCC).

Methods: We constructed transgenic mouse strains LC (LSL-Fbxl6;Alb-Cre, n = 13), KC (LSL-Kras;Alb-Cre, n = 10) and KLC (LSL-Kras;LSL-Fbxl6;Alb-Cre, n = 12) mice, and then monitored HCC for 320 d.

Elevated FBXW10 drives hepatocellular carcinoma tumorigenesis via AR-VRK2 phosphorylation-dependent GAPDH ubiquitination in male transgenic mice.

Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men, but the underlying mechanism remains to be further explored. Here, we report that ubiquitinated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is responsible for HCC tumorigenesis in males. Mechanistically, FBXW10 promotes GAPDH polyubiquitination and activation; VRK2-dependent phosphorylation of GAPDH Ser151 residue is critical for GAPDH ubiquitination and activation.

FBXW10-S6K1 promotes ANXA2 polyubiquitination and KRAS activation to drive hepatocellular carcinoma development in males.

The incidence rate of human hepatocellular carcinoma (HCC) is approximately three times higher in males than in females. A better understanding of the mechanisms underlying HCC development in males could lead to more effective therapies for HCC. Our previous study found that FBXW10 played a critical role in promoting HCC development in male mice and patients, but the mechanism remains unknown.

Silencing of FAM111B inhibited proliferation, migration and invasion of hepatoma cells through activating p53 pathway.

Background: The function of Family with sequence similarity 111 member B (FAM111B) has been reported in multiple malignancies, but its involvement in occurrence and development of hepatocellular carcinoma (HCC) is still unclear.

Purpose: To investigate the role of FAM111B in HCC and explore the potential molecular mechanism.

Methods: We examined the mRNA level of FAM111B via qPCR and protein level via immunohistochemistry in human HCC tissues.

An optimized protocol to detect protein ubiquitination and activation by ubiquitination assay in vivo and CCK-8 assay.

E3 ubiquitin ligases play a role in protein degradation, cellular localization, and activation, and their dysregulation is associated with human diseases. Here, we present a protocol to detect IGF2BP1 ubiquitination and activation by an E3 ubiquitin ligase FBXO45. We describe steps for preparing cells and transfecting plasmids.

FBXO43 increases CCND1 stability to promote hepatocellular carcinoma cell proliferation and migration.

Background And Aims: Abnormal expression of E3 ubiquitin ligase plays an important role in the development and progression of hepatocellular carcinoma (HCC), although the mechanism has remained elusive. This study aimed to investigate the biological function and potential mechanism of FBXO43 in HCC.

Methods: FBXO43 expression in tissues and cells were detected by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemistry (IHC).

In vivo analysis of FBXO45-mediated fibrosis and liver tumorigenesis in a chemically induced mouse model of hepatocellular carcinoma.

FBXO45, an E3 ubiquitin ligase highly expressed in liver tumors, is positively correlated with poor survival of hepatocellular carcinogenesis (HCC) patients, but whether FBXO45 drives HCC tumorigenesis remains largely unclear. Here, we describe a protocol that shortens the observation period for HCC tumorigenesis to assess the effects of FBXO45 in a DEN/CCl-induced HCC mouse model. We describe steps for chemical induction of HCC in FBXO45-overexpressing mice, followed by tissue collection and pathology assessment via quantitative real-time PCR, histology, and immunohistochemistry.

Degradation of helicase-like transcription factor (HLTF) by β-TrCP promotes hepatocarcinogenesis via activation of the p62/mTOR axis.

Helicase-like transcription factor (HLTF) has been found to be involved in the maintenance of genome stability and tumour suppression, but whether its downregulation in cancers is associated with posttranslational regulation remains unclear. Here, we observed that HLTF was significantly downregulated in hepatocellular carcinoma (HCC) tissues and positively associated with the survival of HCC patients. Mechanistically, the decreased expression of HLTF in HCC was attributed to elevated β-TrCP-mediated ubiquitination and degradation.

Mutant Kras and mTOR crosstalk drives hepatocellular carcinoma development via PEG3/STAT3/BEX2 signaling.

Abnormal activation of mTOR through loss of tuberous sclerosis complex (Tsc) frequently occurs in hepatocellular carcinoma (HCC). Mutant Kras could induce aggressive HCCs. Here, we aim to identify the predictive or prognostic biomarkers for HCC patients with Kras mutant and mTOR hyperactivation, and to provide potential therapeutic approaches for this subtype of HCCs.

Elevated FBXO45 promotes liver tumorigenesis through enhancing IGF2BP1 ubiquitination and subsequent PLK1 upregulation.

Dysregulation of tumor-relevant proteins may contribute to human hepatocellular carcinoma (HCC) tumorigenesis. FBXO45 is an E3 ubiquitin ligase that is frequently elevated expression in human HCC. However, it remains unknown whether FBXO45 is associated with hepatocarcinogenesis and how to treat HCC patients with high FBXO45 expression.

Reduced IκBα promotes hepatocellular carcinoma cell proliferation and migration via regulation of NF-κB/Erbin axis.

Aberrantly low expression of NF-κB inhibitor α (IκBα) is observed in hepatocellular carcinoma (HCC), yet the underlying mechanism via which IκBα regulates HCC remains largely unknown. Therefore, to determine the potential function of IκBα in hepatocarcinogenesis, the present study used immunohistochemistry (IHC) staining to analyze the associations between IκBα protein expression and clinicopathologic characteristics of 107 patients with HCC. It was found that expression of IκBα was significantly associated with tumor recurrence.

p53 haploinsufficiency and increased mTOR signalling define a subset of aggressive hepatocellular carcinoma.

Background & Aims: p53 mutations occur frequently in human HCC. Activation of the mammalian target of rapamycin (mTOR) pathway is also associated with HCC. However, it is still unknown whether these changes together initiate HCC and can be targeted as a potential therapeutic strategy.

Prognostic and predicted significance of Ubqln2 in patients with hepatocellular carcinoma.

Purpose: Hepatocellular carcinoma (HCC) is a common malignant cancer and the third leading cause of death worldwide. The molecular mechanism of HCC remains unclear. Recent studies have demonstrated that the ubiquitin-proteasome system (UPS) is associated with HCC.

The FBXW2-MSX2-SOX2 axis regulates stem cell property and drug resistance of cancer cells.

SOX2 is a key transcription factor that plays critical roles in maintaining stem cell property and conferring drug resistance. However, the underlying mechanisms by which SOX2 level is precisely regulated remain elusive. Here we report that MLN4924, also known as pevonedistat, a small-molecule inhibitor of neddylation currently in phase II clinical trials, down-regulates SOX2 expression via causing accumulation of MSX2, a known transcription repressor of SOX2 expression.

FBXW10 promotes hepatocarcinogenesis in male patients and mice.

Hepatocellular carcinoma (HCC) is reported to associate with abnormal expression of SCF E3 ubiquitin ligases. FBXW10, an F-box protein of the E3 ubiquitin ligases, was abnormally regulated in HCC patients. However, whether FBXW10 is associated with HCC has not yet been evaluated.

The MTORC1-mediated autophagy is regulated by the FBXW7-SHOC2-RPTOR axis.

MTORC1 is a well-known key regulator of macroautophagy/autophagy. However, the underlying regulatory mechanisms of MTORC1 activity remains elusive. We showed recently that SHOC2, a RAS activator, competes with MTOR for RPTOR (but not RICTOR) binding, leading to MTORC1 inactivation, autophagy induction and cell survival, whereas RPTOR competes with RAS for SHOC2 binding to inactivate RAS-MAPK and suppresses growth.

Targeting autophagy enhances heat stress-induced apoptosis via the ATP-AMPK-mTOR axis for hepatocellular carcinoma.

Purpose: Radiofrequency ablation (RFA) is widely accepted as a curative treatment for small hepatocellular carcinoma (HCC). However, insufficient RFA (IRFA) can lead to rapid local recurrence. The underlying mechanisms remain poorly understood.