Proteasome 26S subunit non-ATPase 12 (PSMD12), a critical subunit of the proteasome system, is essential for maintaining protein homeostasis. However, its role in hepatocellular carcinoma (HCC) remains underexplored. Bioinformatics analysis, immunohistochemistry, Western blotting, and qRT-PCR confirmed the upregulation of PSMD12 in HCC tissues compared to normal liver tissues, with this overexpression correlating with poor patient prognosis. Functional assays revealed that PSMD12 knockdown suppressed HCC cell proliferation and migration, inducing G2/M phase cell cycle arrest. In contrast, PSMD12 overexpression promoted these malignant behaviors. Mechanistically, PSMD12 interacts with cyclin-dependent kinase 1 (CDK1), preventing its degradation through deubiquitination, thereby accelerating HCC progression by enhancing cell cycle progression. These findings underscore PSMD12’s role in HCC and highlight its potential as both a prognostic biomarker and therapeutic target, providing new insights into the molecular mechanisms driving HCC progression.

Ubiquitination is an important post-translational modification that can be reversed by a family of enzymes called deubiquitinating enzymes (DUBs). Ubiquitin-specific protease 28 (USP28), a member of the DUBs family, functions as a potential tumour promoter in various cancers. However, the biological function and clinical significance of USP28 in pancreatic cancer (PC) are still unclear. Here, we showed that PC tumours had higher USP28 expression compared with that of normal pancreatic tissues, and high USP28 level was significantly correlated with malignant phenotype and shorter survival in patients with PC. Overexpression of USP28 accelerated PC cell growth, whereas USP28 knockdown impaired PC cell growth both in vitro and in vivo. Further, we found that USP28 promoted PC cell growth by facilitating cell cycle progression and inhibiting apoptosis. Mechanistically, USP28 deubiquitinated and stabilised FOXM1, a critical mediator of Wnt/β-catenin signalling. USP28-mediated stabilisation of FOXM1 significantly promoted nucleus β-catenin trans-activation, which in turn led to the activation of the Wnt/β-catenin pathway. Finally, restoration of FOXM1 expression abolished the anti-tumour effects of USP28-silencing. Thus, USP28 contributes to PC pathogenesis through enhancing the FOXM1-mediated Wnt/β-catenin signalling, and could be a potential diagnostic and therapeutic target for PC cases.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, with high incidence, high malignancy, and low survival rate. Cuproptosis is a novel form of cell death mediated by lipoylated TCA cycle proteins-mediated novel cell death pathway and is highly associated with mitochondrial metabolism. However, the relationship between the expression level of cuproptosis-related genes (CRGs) and the prognosis of HCC is still unclear.Methods: Combining the HCC transcriptomic data from The Cancer Genome Atlas(TCGA) and Gene Expression Omnibus (GEO) databases, we identified the differentially expressed cuproptosis-related genes (DECRGs) and obtained the prognosis-related DECRGs through univariate regression analysis.LASSO and multivariate COX regression analyses of these DECRGs yielded four genes that were used to construct the signature. Next, we use ROC curves to evaluate the performance of signatures. The tumor microenvironment, immune infiltration, tumor mutation load, half-maximum suppression concentration, and immunotherapy effects were also compared between the low-risk and high-risk groups. Finally, we analyzed the expression level, prognosis, and immune infiltration correlation on the four genes that constructed the model.Results: Four DECRGs s were used to construct the signature. The ROC curves indicated that signature can better assess the prognosis of HCC patients. Patients were grouped according to the signature risk score. Patients in the low-risk group had a significantly longer survival time than those in the high-risk group. Furthermore, the tumor mutation burden (TMB) values were associated with the risk score and the higher-risk group had a higher proportion of TP53 mutations than the low-risk group.ESTIMATE analysis showed significant differences in stromal scores between the two groups.N6-methyladenosine (m6A) and multiple immune checkpoints were expressed at higher levels in the high-risk group. Then, we found that signature score correlated with chemotherapeutic drug sensitivity and immunotherapy efficacy in HCC patients. Finally, we further confirmed that the four DECRGs genes were associated with the prognosis of HCC through external validation.Conclusions: We studied from the cuproptosis perspective and developed a new prognostic feature to predict the prognosis of HCC patients. This signature with good performance will help physicians to evaluate the overall prognosis of patients and may provide new ideas for clinical decision-making and treatment strategies.

Interferon‐induced transmembrane protein 3 (IFITM3) has been shown to be overexpressed in multiple cancers. However, the role of IFITM3 in metastasis of hepatocellular carcinoma (HCC) is still poorly understood. In this study, we showed that IFITM3 was frequently overexpressed in HCC tissues compared with adjacent nontumor tissues. Overexpression of IFITM3 was significantly correlated with tumor metastasis and poor prognosis in HCC. Knockdown of IFITM3 dramatically decreased MMP9 expression and inhibited the invasion and metastasis of HCC in vitro and in vivo. Moreover, the upregulation of MMP9 rescued the decreased migration and invasion induced by the knockdown of IFITM3, whereas the knockdown of MMP9 decreased IFITM3‐enhanced HCC migration and invasion. Mechanistically, we found that IFITM3 regulates MMP9 expression through the p38/MAPK pathway. Taken together, we identified a novel IFITM3–p38/MAPK–MMP9 regulatory circuitry, the dysfunction of which drives invasive and metastatic character in HCC.

Background: Ubiquitination is a critical post-translational modification which can be reversed with an enzyme family known as deubiquitinating enzymes (DUBs). It has been reported that dysregulation of deubiquitination leads to carcinogenesis. As a member of the DUBs family, proteasome 26 S subunit non-ATPase 7 (PSMD7) serves as an underlying tumour-promoting factor in multiple cancers. However, the clinical significance and biological functions of PSMD7 in pancreatic cancer (PC) remain unclear. Results: In this study, we first reported frequent overexpression of PSMD7 in PC tissues, and high levels of PSMD7 were markedly linked to shorter survival and a malignant phenotype in PC patients. An array of in vitro and in vivo gain/loss-of-function tests revealed that PSMD7 facilitates the progression of PC cells. Additionally, we found that PSMD7 promotes PC cell progression by activating the Notch homolog 1 (Notch1) signalling. Interestingly, in PC cells, the inhibitory effect of PSMD7 knockdown on cellular processes was comparable to that observed upon Notch1 knockdown. Mechanistically, PSMD7 deubiquitinated and stabilised sex determining region Y (SRY)-box 2 (SOX2), a key mediator of Notch1 signalling. The stabilisation of SOX2, mediated by PSMD7, dramatically increased SOX2 protein levels, subsequently activating the Notch1 pathway. Finally, restoration of SOX2 expression abrogated the PSMD7-silenced antitumour effect. Conclusions: Taken together, our work identifies and validates PSMD7 as a promoter of PC progression through augmentation of the Notch1 signalling pathway mediated by SOX2. This finding suggests that PSMD7 holds promise as a potential therapeutic target for the management of this refractory disease.

Background: Previous studies have demonstrated that PANoptosis is strongly correlated with cancer immunity and progression. This study aimed to develop a PANoptosis-related signature (PANRS) to explore its potential value in predicting the prognosis and immunotherapy response of hepatocellular carcinoma (HCC).Methods: Based on the expression of PANoptosis-related genes, three molecular subtypes were identified. To construct a signature, the differentially expressed genes between different molecular subtypes were subjected to multivariate least absolute shrinkage and selection operator Cox regression analyses. The risk scores of patients in the training set were calculated using the signature. The patients were classified into high-risk and low-risk groups based on the median risk scores. The predictive performance of the signature was evaluated using Kaplan-Meier plotter, receiving operating characteristic curves, nomogram, and calibration curve. The results were validated using external datasets. Additionally, the correlation of the signature with the immune landscape and drug sensitivity was examined. Furthermore, the effect of LPCAT1 knockdown on HCC cell behavior was verified using in vitro experiments.Results: This study developed a PANRS. The risk score obtained by using the PANRS was an independent risk factor for the prognosis of patients with HCC and exhibited good prognostic predictive performance. The nomogram constructed based on the risk score and clinical information can accurately predicted the survival probability of patients with HCC. Patients with HCC in the high-risk groups have high immune scores and tend to generate an immunosuppressive microenvironment. They also exhibited a favorable response to immunotherapy, as evidenced by high tumor mutational burden, high immune checkpoint gene expression, high human leukocyte antigen gene expression, low tumor immune dysfunction and low exclusion scores. Additionally, the PANRS enabled the identification of 15 chemotherapeutic agents, including sorafenib, for patients with HCC with different risk levels, guiding clinical treatment. The signature gene LPCAT1 was upregulated in HCC cell lines. LPCAT1 knockdown markedly decreased HCC cell proliferation and migration.Conclusion: PANRS can accurately predict the prognosis and immunotherapy response of patients with HCC and consequently guide individualized treatment.