OBJECTIVE:Parabens, esters of p-hydroxybenzoic acid, are widely utilized as antimicrobial preservatives in consumer products. While increasing evidence implicates parabens in tumor progression across cancers, their role and mechanisms in bladder cancer (BLCA) remain uncharacterized. METHODS:Methylparaben (MP) and propylparaben (PP) effects on invasion, migration, and proliferation were assessed in BLCA T24 and SW780 cells. The above effects have also been verified through in vivo experiments. Genes linked to MP, PP, and BLCA were curated from public databases. Hub genes were identified through protein-protein interaction (PPI) networks and an optimized prognostic model using 101 machine learning algorithms. Molecular docking (MD) and molecular dynamics simulations (MDS) evaluated hub gene-paraben interactions, followed by functional validation via transfection assays. RESULTS:MP and PP significantly enhanced BLCA cell invasion (all P < 0.05) without affecting proliferation or migration. It can also promote tumor growth in nude mice (all P < 0.05). Network toxicology and prognostic modeling identified MMP2 and PPARG as key targets for MP and PP, respectively. MD/MDS confirmed stable binding between parabens and their targets. MP upregulated MMP2 expression, while PP downregulated PPARG (all P < 0.05). MMP2 knockdown and PPARG overexpression partly reversed paraben-induced invasion (all P < 0.05). CONCLUSION:This study reveals that MP and PP promote BLCA invasion via MMP2 and PPARG modulation, providing mechanistic insights into paraben-associated tumorigenesis and underscoring potential public health implications of paraben exposure. These findings have raised concerns about the risk of BLCA caused by low level environmental exposure to parabens, especially among people with impaired detoxification pathways.

Membrane exposure of phosphatidylserine (PS) on platelets is critical for the binding of coagulation factors leading to coagulation activation, however, the mechanism controlling PS exposure remains largely unknown. Using genetically modified mouse models, we previously reported that a transmembrane disulfide isomerase TMX1 inhibited integrin αIIbβ3 outside-in signaling which is important for PS exposure on platelets. In this study, we investigated the role of TMX1 in PS exposure and coagulation. We found that the deficiency of TMX1 in platelets enhanced fibrin formation and PS exposure at the site of injury. In vitro, TMX1 inhibited thrombin generation mediated by activated platelets, and attenuated PS exposure on platelets, the effect of which was prevented when integrin αIIbβ3 outside-in signaling was blocked, suggesting that TMX1 inhibition of integrin αIIbβ3 outside-in signaling suppresses PS exposure. Moreover, TMX1 deficiency increased the free thiols of TMEM16 F in platelets including Cys338, Cys349 and Cys352. In HEK293 T cells overexpressing C338S-, C349S-mutated TMEM16 F, the PS exposure was increased, suggesting that TMX1 oxidizes these disulfide bonds of TMEM16 F, decreasing its activity to externalize PS on the membrane. Together, our observations for the first time demonstrate that TMX1 inhibits PS exposure in platelets downregulating the procoagulant activity, by which TMX1 plays a critical role in maintaining vascular quiescence.

The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) is a recognized resistance mechanism and a hindrance to therapies using epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The paucity of pretranslational/posttranslational clinical samples limits the deeper understanding of resistance mechanisms and the exploration of effective therapeutic strategies. Here, we developed preclinical neuroendocrine (NE) transformation models. Next, we identified a transcriptional reprogramming mechanism that drives resistance to erlotinib in NE transformation cell lines and cell-derived xenograft mice. We observed the enhanced expression of genes involved in the EHMT2 and WNT/β-catenin pathways. In addition, we demonstrated that EHMT2 increases methylation of the SFRP1 promoter region to reduce SFRP1 expression, followed by activation of the WNT/β-catenin pathway and TKI-mediated NE transformation. Notably, the similar expression alterations of EHMT2 and SFRP1 were observed in transformed SCLC samples obtained from clinical patients. Importantly, suppression of EHMT2 with selective inhibitors restored the sensitivity of NE transformation cell lines to erlotinib and delayed resistance in cell-derived xenograft mice. We identify a transcriptional reprogramming process in NE transformation and provide a potential therapeutic target for overcoming resistance to erlotinib.

The EGFR-TK pathway is pivotal in non-small-cell lung cancer (NSCLC) treatment, drugs targeting both EGFR wild-type and mutant tumor cells are still urgently needed. The focus of our study is on ATP-competitive inhibitors crucial for NSCLC therapy, specifically targeting the epidermal growth factor receptor (EGFR). A series of derivatives of Erlotinib and Icotinib were developed by incorporating a macrocyclic polyamine into a quinazoline scaffold to enhance their inhibitory activity against drug-resistant cells. The compounds exhibit modest activity against EGFR triple mutants (EGFR(del)(19)(/T790M/C797S)). Compound b demonstrated slightly improved inhibition activity against PC-9(d)(el19/T790M/C797S) (IC50 = 496.3 nM). This could provide some insights for optimizing EGFR inhibitors, particularly in the context of EGFR triple mutants.

Prolyl 4-hydroxylase subunit beta (P4HB) can catalyze the formation, breakage and rearrangement of disulfide bonds through two thioredoxin domains, which is important for the maintenance of oxidizing environment in endoplasmic reticulum. Recently, P4HB has been demonstrated its oncogenic role of tumorigenesis and development in cancers. Therefore, we comprehensively deciphered P4HB in human cancer from various aspects, including pan-cancer analysis and narrative summary. We also provided some possible interacted molecules and the top 10 predicted drugs targeting P4HB to contribute to future research. We proposed that P4HB was a potential target and brought new therapeutic opportunities for cancer patients.

Immature overall survival (OS) data is a key challenge in assessing the cost-effectiveness of new oncology drugs. Leveraging external data to inform OS extrapolation has become an area of research. This review surveyed data sources and methods used to incorporate external data in OS extrapolations in National Institute for Health and Care Excellence (NICE) oncology technology appraisals.

Direct dehydroxytrifluoromethylthiolation of alcohols is an attractive strategy for accessing CF3S-containing compounds. Herein, we report a method for dehydroxytrifluoromethylthiolation of alcohols by using the combination of hypervalent iodine(III) reagent TFTI and N-heterocyclic carbenes. This method shows excellent stereospecificity and chemoselectivity to give a product with clean inversion of the configuration of hydroxyl groups as well as can be used for late-stage modification of structurally complex alcohols. The reaction mechanism is proposed with experimental and computational evidence.

Interactions between oncogenic proteins contribute to the phenotype and drug resistance. Here, EZH2 (enhancer of zest homolog 2) is identified as a crucial factor that mediates HIF-1 (hypoxia-inducible factor) inhibitor resistance. Mechanistically, targeting HIF-1 enhanced the activity of EZH2 through transcription activation of SUZ12 (suppressor of zest 12 protein homolog). Conversely, inhibiting EZH2 increased HIF-1α transcription, but not the transcription of other HIF family members. Additionally, the negative feedback regulation between EZH2 and HIF-1α is confirmed in lung cancer patient tissues and a database of cell lines. Moreover, molecular prediction showed that a newly screened dual-target compound, DYB-03, forms multiple hydrogen bonds with HIF-1α and EZH2 to effectively inhibit the activity of both targets. Subsequent studies revealed that DYB-03 could better inhibit migration, invasion, and angiogenesis of lung cancer cells and HUVECs in vitro and in vivo compared to single agent. DYB-03 showed promising antitumor activity in a xenograft tumor model by promoting apoptosis and inhibiting angiogenesis, which could be almost abolished by the deletion of HIF-1α and EZH2. Notably, DYB-03 could reverse 2-ME2 and GSK126-resistance in lung cancer. These findings clarified the molecular mechanism of cross-regulation of HIF-1α and EZH2, and the potential of DYB-03 for clinical combination target therapy.

In the INSIGHT trial primary analysis (NCT01982955; median follow-up: 21.8 months), tepotinib (a highly selective, once daily [QD] MET inhibitor) + gefitinib improved efficacy versus chemotherapy in patients with EGFR-mutant NSCLC, and resistance to anti-EGFR therapy due to METamp. Here, we report final analyses from INSIGHT (data cut-off: September 3, 2021; median follow-up: 57.5 months). Previously presented at AACR 2022.

Breast cancer is a leading type of malignant tumor in women; however, the immunotherapy in breast cancer is still underappreciated. In this study, we demonstrated that tumor necrosis factor receptor 2 (TNFR2) is highly expressed in both breast tumor tissue and tumor-infiltrating immunosuppressive CD4(+)Foxp3(+) regulatory T cells (Tregs). We found that TNFR2 antagonistic antibody reduced Foxp3 expression and the proliferation of Tregs and impaired the inhibitory effect of Tregs on CD4(+)CD25(-) effector T (Teff) cells in a dose-dependent manner. The treatment of anti-TNFR2 antibody not only inhibited the proliferation of breast tumor cells in vitro but also suppressed the tumorigenesis of murine mammary carcinoma 4T1 cells in vivo. Mice recovered from tumor growth also developed 4T1-specific immunity. Furthermore, we demonstrated that anti-TNFR2 antibody in combination with anti-PD-L1 exhibited augmented antitumor effects than monotherapy. Anti-TNFR2 treatment also tended to increase the expression of proinflammatory cytokines in tumor tissues. In conclusion, our study suggests that TNFR2 antagonist could potentially offer a clinical benefit as a single agent or in combination with immune checkpoint blockade treatment for breast cancer immunotherapy.

Cancer has always been one of the main threats to human health. Looking for its potential pathogenic mechanism is a major challenge facing humanity. Epigenetic mechanisms are essential to maintain specific gene expression patterns and the normal development of life individuals. They mainly regulate gene function and expression levels through DNA methylation, histone modification, and RNA regulation. When the epigenetic regulation is abnormal, it interferes with the expression and function of normal genes to a certain extent, which may lead to the occurrence of tumors. Therefore, epigenetic modification is closely related to tumorigenesis. In order to understand the nature of cancer and open up novel treatment methods, it is particularly important to figure out the mechanism of epigenetics in cancer. This article outlines the research content of epigenetics, focusing on its relationship with tumorigenesis. At the same time, the application of epigenetics in cancer therapy is prospected.

A number of novel anticancer drugs have been developed in recent years. However, the mortality of cancer patients remains high because of the emergence of drug resistance. It was reported that drug resistance might involved in changes in gene expression without changing genotypes, which is similar to epigenetic modification. Some studies indicated that targeting histone methyltransferase can reverse drug resistance. Hence, the use of histone methyltransferase inhibitors or histone demethylase inhibitors opens new therapeutic approaches for cancer treatment. While the relationship between histone methyltransferase and tumor resistance has been determined, there is a lack of updated review on the association between them. In this review, we summarized the mechanisms of histone methyltransferases in cancer drug resistance and the therapeutic strategies of targeting histone methyltransferase to reverse drug resistance.

As a common type of malignant tumor diseases, hematological malignancies mainly include various types of leukemia, multiple myeloma and malignant lymphoma. With the rapid development of modem society, the incidence rate of hematological malignancies is increasing year by year, and the age of disease onset gradually tend to a younger age. The pathogenesis of hematological malignancies is inseparable from environmental factors and genetic factors. Recent studies have found that epigenetic modification plays an important role in the development of hematological tumors and some epigenetic related genes have made important progress in clinical application as therapeutic targets for hematological tumors. In view of the advances progress of the research that focus on the role of epigenetic modification in the pathogenesis of hematological malignancies, this paper will systematically review the research progress of DNA methylation, histone modification, non-coding RNA and RNA modification in the pathogenesis of hematological tumors.

DNA methyltransferases are an essential class of modifiers in epigenetics. In mammals, DNMT1, DNMT3A and DNMT3B participate in DNA methylation to regulate normal biological functions, such as embryo development, cell differentiation and gene transcription. Aberrant functions of DNMTs are frequently associated with tumorigenesis. DNMT aberrations usually affect tumor-related factors, such as hypermethylated suppressor genes and genomic instability, which increase the malignancy of tumors, worsen the prognosis for patients, and greatly increase the difficulty of cancer therapy. However, the impact of DNMTs on tumors is still controversial, and therapeutic approaches targeting DNMTs are still under exploration. Here, we summarize the biological functions and paradoxes associated with DNMTs and we discuss some emerging strategies for targeting DNMTs in tumors, which may provide novel ideas for cancer therapy.