Nuclear factor erythroid 2-related factor 2 (NRF2) hyperactivation has been established as an oncogenic driver in a variety of human cancers, including non-small cell lung cancer (NSCLC). However, despite massive efforts, no specific therapy is currently available to target NRF2 hyperactivation. Here, we identify peptidylprolyl isomerase A (PPIA) is required for NRF2 protein stability. Ablation of PPIA promotes NRF2 protein degradation and blocks NRF2-driven growth in NSCLC cells. Mechanistically, PPIA physically binds to NRF2 and blocks the access of ubiquitin/Kelch Like ECH Associated Protein 1 (KEAP1) to NRF2, thus preventing ubiquitin-mediated degradation. Our X-ray co-crystal structure reveals that PPIA directly interacts with a NRF2 interdomain linker via a trans -proline 174-harboring hydrophobic sequence. We further demonstrate that an FDA-approved drug, cyclosporin A (CsA), impairs the interaction of NRF2 with PPIA, inducing NRF2 ubiquitination and degradation. Interestingly, CsA interrupts glutamine metabolism mediated by the NRF2/KLF5/SLC1A5 pathway, consequently suppressing the growth of NRF2-hyperactivated NSCLC cells. CsA and a glutaminase inhibitor combination therapy significantly retard tumor progression in NSCLC patient-derived xenograft (PDX) models with NRF2 hyperactivation. Our study demonstrates that targeting NRF2 protein stability is an actionable therapeutic approach to treat NRF2-hyperactivated NSCLC.

The prognosis of hepatocellular carcinoma (HCC) is universally poor. Early diagnosis plays a pivotal role in determining the outcome of HCC. We employed a comparative proteomics approach to identify potential biomarkers and validated the application of retinol-binding protein 4 (RBP4) as a biomarker for HCC. RBP4 protein expression was examined in liver tissues from 80 HCC patients through immunohistochemical analysis. Serum RBP4 concentrations were measured by ELISA in a cohort comprising 290 HCC patients, matched 202 chronic hepatitis B patients and 269 healthy controls. Survival data were collected from HCC patients. The diagnostic and prognostic values of RBP4 were evaluated using receiver operating curve (ROC) analysis. The validation results demonstrated a significant reduction in RBP4 levels in both liver tissues and serum samples from HCC patients. ROC analysis of the diagnostic value of RBP4 revealed an AUC of 0.879 (95 % CI: 0.854∼0.903) for HCC. When combined with AFP, the AUC increased to 0.919, with a sensitivity of 87.9 % and specificity of 80 %. Survival analysis revealed significantly reduced overall survival time in individuals with low-expression of RBP4 compared to those with high-expression. The joint prognostic model exhibited an AUC of 0.926 (95 % CI: 0.888∼0.964), which was significantly higher than that of AFP alone (AUC=0.809; P <0.0001). RBP4 shows a great potential as a biomarker with appreciable diagnostic value, complementing the AFP in HCC diagnosis. Additionally, it holds promise as a prognostic biomarker that, when integrated into a combined prognostic model, could greatly improve HCC prognosis efficiency.

Oncolytic vaccinia viruses armed with interleukins represent a promising frontier in tumor therapy. Oncolytic vaccinia viruses express IL-2, IL-10, IL-12, IL-15, IL-21, IL-23, IL-24, and IL-36γ remodel the tumor microenvironment,enhance immune cell infiltration, suppress immunosuppressive elements and promot systemic antitumor immunity. Combinatorial strategies with chemotherapy, radiotherapy, metabolic modulators, immune checkpoint inhibitors, or natural compounds amplify therapeutic efficacy for tumors. In addition, we review the existing solutions to the problems of the immune clearance of virus, such as the use of inhibitors to prevent neutralizing antibodies from binding to the virus and the use of polymer encapsulation or mesenchymal stem cell loading. We also discussed Current directions include optimizing delivery systems, leveraging Artificial Intelligence for personalized designs of Oncolytic vaccinia virus inserted interleukins to guide the research in the future.

Platinum resistance of ovarian cancer is one of the primary factors of poor prognosis and inter‑α‑trypsin inhibitor heavy chain 3 (ITIH3) is a potential DDP resistance‑associated gene. The present study assessed protein expression levels of ITIH3 in human ovarian cancer and evaluated the relationship between its expression and platinum‑resistance in patients. Furthermore, the effect of ITIH3 on cisplatin (DDP)‑resistant ovarian cancer cells and the underlying molecular mechanism were evaluated. Tissue microarrays of ovarian cancer samples were used to assess the association between ITIH3 protein expression levels and drug resistance and the prognosis of ovarian cancer. ITIH3 RNA interference (RNAi) ovarian cancer cell lines were constructed and expression levels of anti‑ and pro‑apoptotic proteins of the Bcl‑2 associated pathway, including Bcl‑2, Bcl‑xL, Mcl‑1, Bak, Bim, Bax, caspase 3 and poly ADP‑ribose polymerase (PARP), were assessed following DDP treatment. The Bcl‑2 inhibitor ABT‑737 was used to rescue DDP‑resistance induced by loss of ITIH3 in vitro. Finally, a subcutaneous xenograft tumor model was used to evaluate the effect of multiple DDP injections on expression levels of apoptosis‑related proteins like Bcl‑2, Bcl‑xL, Bak, caspase 3 and PARP. The results of tissue microarray immunohistochemistry revealed that decreased ITIH3 protein expression levels were associated with a shorter overall survival for patients with ovarian cancer. The results of Cell Counting Kit‑8 assay showed that the half‑maximal inhibitory concentration and resistance index of DDP in SKOV3‑ITIH3 and OVCAR3‑ITIH3 RNAi cells were significantly higher than in control groups. Following DDP treatment, the results of western blotting revealed that expression levels of anti‑apoptotic proteins of the Bcl‑2 family significantly increased in SKOV3‑ITIH3 and OVCAR3‑ITIH3 RNAi cells. Pro‑apoptotic protein expression was not significantly changed following DDP treatment, whereas cleaved caspase 3, caspase 3 and cleaved (C‑PARP) were markedly downregulated. The Bcl‑2 inhibitor ABT‑737 was demonstrated to reverse increased DDP resistance induced by ITIH3 expression in flow cytometric and western blotting analysis. In the subcutaneous murine xenograft model, an increased number of DDP injections yielded a decrease in phosphorylated Bcl‑2, cleaved caspase 3, caspase 3 and C‑PARP protein expression levels in the SKOV3‑ITIH3 RNAi group tested by western blotting. To the best of our knowledge, this is the first study to demonstrate that ITIH3 could be a vital molecule involved in chemosensitivity via regulation of the Bcl‑2 family‑mediated apoptotic pathway. Lower protein expression levels of ITIH3 were significantly associated with platinum resistance and poor prognosis in ovarian cancer. ITIH3 may predict cisplatin‑resistance in ovarian cancer.

Background: Combined biomarkers can improve the sensitivity and specificity of ovarian cancer (OC) diagnosis and effectively predict patient prognosis. This study explored the diagnostic and prognostic values of serum CCL18 and CXCL1 antigens combined with C1D, FXR1, ZNF573, and TM4SF1 autoantibodies in OC.Methods: CCL18 and CXCL1 monoclonal antibodies and C1D, FXR1, ZNF573, and TM4SF1 antigens were coated with microspheres. Logistic regression was used to construct a serum antigen‐antibody combined detection model; receiver‐operating characteristic curve (ROC) was used to evaluate the diagnostic efficacy of the model; and the Kaplan‐Meier method and Cox regression models were used for survival analysis to evaluate the prognosis of OC. Data from The Cancer Genome Atlas (TCGA) and Genotype‐Tissue Expression (GTEx) projects and online survival analysis tools were used to evaluate prognostic genes for OC. The CIBERSORT immune score was used to explore the factors influencing prognosis and their relationship with tumor‐infiltrating immune cells.Results: The levels of each index in the blood samples of patients with OC were higher than those of the other groups. The combined detection model has higher specificity and sensitivity in the diagnosis of OC, and its diagnostic efficiency is better than that of CA125 alone and diagnosing other malignant tumors. CCL18 and TM4SF1 may be factors affecting the prognosis of OC, and CCL18 may be related to immune‐infiltrating cells.Conclusions: The serum antigen‐antibody combined detection model established in this study has high sensitivity and specificity for the diagnosis of OC.

Clinical decisions based on the test results for prostate-specific antigen often result in overdiagnosis and overtreatment. Multiparametric magnetic resonance imaging (mpMRI) can be used to identify high-grade prostate cancer (HGPCa; Gleason score ≥3 + 4); however, certain limitations remain such as inter-reader variability and false negatives. The combination of mpMRI and prostate cancer (PCa) biomarkers (prostate-specific antigen density, Proclarix, TMPRSS2:ERG gene fusion, Michigan prostate score, ExoDX prostate intelliscore, four kallikrein score, select molecular diagnosis, prostate health index, and prostate health index density) demonstrates high accuracy in the diagnosis of HGPCa, ensuring that patients avoid unnecessary prostate biopsies with a low leakage rate. This manuscript describes the characteristics and diagnostic performance of each biomarker alone and in combination with mpMRI, with the intension to provide a basis for decision-making in the diagnosis and treatment of HGPCa. Additionally, we explored the applicability of the combination protocol to the Asian population.