DNA Methylation-Based Diagnosis and Treatment of Breast Cancer.

DNA methylation is a key epigenetic modifier involved in tumor formation, invasion, and metastasis. The development of breast cancer is a complex process, and many studies have now confirmed the involvement of DNA methylation in breast cancer. Moreover, the number of genes identified as aberrantly methylated in breast cancer is rapidly increasing, and the accumulation of epigenetic alterations becomes a chronic factor in the development of breast cancer. The combined effects of external environmental factors and the internal tumor microenvironment promote epigenetic alterations that drive tumorigenesis. This article focuses on the relevance of DNA methylation to breast cancer, describing the role of detecting DNA methylation in the early diagnosis, prediction, progression, metastasis, treatment, and prognosis of breast cancer, as well as recent advances. The reversibility of DNA methylation is utilized to target specific methylation aberrant promoters as well as related enzymes, from early prevention to late targeted therapy, to understand the journey of DNA methylation in breast cancer with a more comprehensive perspective. Meanwhile, methylation inhibitors in combination with other therapies have a wide range of prospects, providing hope to drug-resistant breast cancer patients.

Occult urothelial carcinoma with mediastinal metastasis: A case report.

Occult urothelial carcinoma (UC), particularly with mediastinal metastases, is an uncommon clinical occurrence. The present study describes the unusual case of a 70-year-old male patient who developed mediastinal metastases from an occult UC. Histological evaluations and immunohistochemical features of the mediastinal tumor were indicative of UC; however, extensive imaging failed to identify the primary urological lesion. The findings suggest that mediastinal metastases from UCs, despite their rarity, should be considered in cases where patients with mediastinal tumors exhibit chest-related symptoms. Prompt pathological examinations are crucial for ascertaining the nature and origin of the tumor. Moreover, individualized treatment should be performed in strict accordance with the established oncology guidelines.

Disulfidptosis-related signature predicts prognosis and characterizes the immune microenvironment in hepatocellular carcinoma.

BACKGROUND: Disulfidptosis is a type of programmed cell death caused by excessive cysteine-induced disulfide bond denaturation leading to actin collapse. Liver cancer has a poor prognosis and requires more effective intervention strategies. Currently, the prognostic and therapeutic value of disulfidptosis in liver cancer is not clear. METHODS: We investigated the features of 16 disulfidptosis-related genes (DRGs) of HCC patients in the TCGA and classified the patients into two disulfidptosis pattern clusters by consensus clustering analysis. Then, we constructed a prognostic model using LASSO Cox regression. Next, the microenvironment and drug sensitivity were evaluated. Finally, we used qPCR and functional analysis to verify the reliability of hub DRGs. RESULTS: Most of the DRGs showed significantly higher expression in cancer tissues than in adjacent tissues. Our prognostic model, the DRG score, can well predict the survival of HCC patients. There were significant differences in survival, features of the microenvironment, effects of immunotherapy, and drug sensitivity between the high- and low-DRG score groups. Ultimately, we demonstrated that a few hub DRGs have differential mRNA expression between liver cancer cells and normal cells and that the protective gene LCAT can inhibit liver cancer metastasis in vitro. CONCLUSION: We established a novel risk model based on DRG scores to predict HCC patient prognosis, drug sensitivity and immunotherapy efficacy, which provides new insight into the relationship between disulfidptosis and HCC and provides valuable assistance for the personalized treatment of HCC.

BRCC36 Deubiquitinates HMGCR to Regulate the Interplay Between Ferroptosis and Pyroptosis.

Various forms of programmed cell death (PCD) exhibit distinct characteristics depending on their specific molecular mechanisms, and there are interactions among these different forms. Ferroptosis, which is related to autophagy and apoptosis, has an unknown potential interaction with pyroptosis. This study revealed a mutually antagonistic relationship between ferroptosis and pyroptosis, with 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) playing a key role in their interaction. It is found that HMGCR predominantly localized to mitochondria during ferroptosis but shifted to the endoplasmic reticulum following treatment with a pyroptosis inducer. Furthermore, this study demonstrated that BRCC36 (BRCA1/BRCA2-containing complex subunit 36) deubiquitinated HMGCR in a manner dependent on deubiquitinating enzyme (DUB) activity, and inhibited ferroptosis and promoted pyroptosis. Moreover, as an oncogene in hepatocellular carcinoma (HCC), BRCC36 promoted cancer cell proliferation, migration, invasion, and tumor growth. Thiolutin, an inhibitor of BRCC36, effectively suppressed the interaction between BRCC36 and HMGCR, leading to the inhibition of HCC growth. Therefore, targeting BRCC36 can offer a novel and promising therapeutic strategy for HCC treatment. In conclusion, these findings provide new theoretical evidence for further characterizing tumor heterogeneity and offer new molecular targets for the diagnosis and treatment of HCC.

Tumor Microenvironment Heterogeneity, Potential Therapeutic Avenues, and Emerging Therapies.

OBJECTIVE: This review describes the comprehensive portrait of tumor microenvironment (TME). Additionally, we provided a panoramic perspective on the transformation and functions of the diverse constituents in TME, and the underlying mechanisms of drug resistance, beginning with the immune cells and metabolic dynamics within TME. Lastly, we summarized the most auspicious potential therapeutic strategies. RESULTS: TME is a unique realm crafted by malignant cells to withstand the onslaught of endogenous and exogenous therapies. Recent research has revealed many small-molecule immunotherapies exhibiting auspicious outcomes in preclinical investigations. Furthermore, some pro-immune mechanisms have emerged as a potential avenue. With the advent of nanosystems and precision targeting, targeted therapy has now transcended the "comfort zone" erected by cancer cells within TME. CONCLUSION: The ceaseless metamorphosis of TME fosters the intransigent resilience and proliferation of tumors. However, existing therapies have yet to surmount the formidable obstacles posed by TME. Therefore, scientists should investigate potential avenues for therapeutic intervention and design innovative pharmacological and clinical technologies.

Frailty and prognosis in lung cancer: systematic review and meta-analysis.

Lung cancer is one of the most common malignant tumours. Patients are frequently at risk of frailty as lung cancer progresses. The meta-analysis aims to explore the impact of frailty on the long-term prognosis and the incidence of short-term chemotherapy toxicity in patients with lung cancer. This study was designed adhered to the criteria of Cochrane Handbook for Systematic Reviews. Systematic searches were performed on PubMed, Embase, Web of Science and Cochrane Library databases for relevant studies until December 2022. The outcome measures were overall survival, progression-free survival, chemotherapy toxicity and all-cause mortality. We then performed sensitivity analyses, subgroup analyses and evidence quality. This meta-analysis was performed using Review Manager V.5.4 software. Of the included studies, six were retrospective and five were prospective. There was a statistically significant difference between the frail and non-frail groups in overall survival (HR 2.27, 95% CI 1.24 to 4.15, p=0.008), all-cause mortality (HR 1.63, 95% CI 1.00 to 2.65, p=0.05) and chemotherapy toxicity (OR 3.73, 95% CI 1.99 to 7.00, p<0.0001). We conducted a sensitivity analysis, and the result was stable. The study revealed frail group had shorter survival and experienced more severe adverse effects than the non-frail group. Frailty affects the long-term prognosis and the incidence of short-term chemotherapy toxicity of patients with lung cancer. Consequently, medical professionals should focus on frailty screening in patients with lung cancer and implement active intervention measures. PROSPERO registration number is CRD42023398606.

Lung carcinoma with small intestinal metastases and gastrointestinal bleeding: A rare case report.

The occurrence of small intestinal metastases from primary lung cancer is rare. This report documents the case of a 57-year-old male patient initially diagnosed with non-metastatic lung adenocarcinoma, who presented with abdominal pain 6 months later. Postoperative pathological analysis confirmed the final diagnosis to be small intestinal metastasis from primary lung cancer. Thoracoscopic surgery and systemic chemotherapy were the preferred treatment options. However, the lung tumor spread to the small intestine, causing intestinal obstruction. As the patient could not tolerate anti-tumor therapy, only symptomatic treatment was provided. The patient experienced massive gastrointestinal bleeding and died the next day. Although small intestinal metastasis from lung cancer is rare and difficult to diagnose accurately, it should be considered when encountering a patient with lung cancer exhibiting abdominal symptoms and associated imaging findings. At this point, a pathological diagnosis should be performed immediately to determine the nature and source of the tumor. Furthermore, individualized treatment should be conducted in strict accordance with oncology guidelines. Of note, early detection and treatment are critical to ensure favorable outcomes.

AhR Promotes the Development of Non-small cell lung cancer by Inducing SLC7A11-dependent Antioxidant Function.

Objective: Aryl hydrocarbon receptor (AhR) is a transcription factor. It is reported that AhR is associated with non-small cell lung cancer (NSCLC), but the mechanisms underlying this relationship remain unclear. Therefore, we investigated the role of AhR in NSCLC to elucidate the underlying mechanisms. Methods: We collected clinical lung cancer samples and constructed AhR overexpression and knockdown cell lines to investigate the tumorigenicity of AhR in vivo and in vitro. Furthermore, we performed a ferroptosis induction experiment and chromatin immunoprecipitation experiment. Results: AhR was highly expressed in NSCLC tissue. AhR knockdown cells showed ferroptosis related phenomenon. Furthermore, Chromatin immunoprecipitation confirmed the correlation between AhR and solute carrier family 7 member 11 (SLC7A11) and ferroptosis induction experiment confirmed that AhR affects ferroptosis via SLC7A11. Specifically, AhR regulates ferroptosis-related SLC7A11, which affects ferroptosis and promotes NSCLC progression. Conclusions: AhR promoted NSCLC development and positively correlated with SLC7A11, affecting its actions. AhR bound to the promoter region of SLC7A11 promotes NSCLC by activating SLC7A11 expression, improving the oxidative sensitivity of cells, and inhibiting ferroptosis. Thus, AhR affects ferroptosis in NSCLC by regulating SLC7A11, providing foundational evidence for novel ferroptosis-related treatments.

HOXC11 drives lung adenocarcinoma progression through transcriptional regulation of SPHK1.

Lung adenocarcinoma (LUAD) is a fatal threat to human health, while the mechanism remains unclear, and the therapy brings limited therapeutic effects. Transcription factor Homeobox C11 (HOXC11) was previously proved to be related to hind limbs and metanephric development during the embryonic phase, and its role in tumors has been gradually recognized. Our study found that HOXC11 overexpressed in LUAD and was associated with worse overall survival. Moreover, its expression in lung cancer was regulated by IκB kinase α (IKKα), a pivotal kinase in NF-κB signaling, which was related to the ubiquitination of HOXC11. We further proved that HOXC11 could enhance the ability of proliferation, migration, invasion, colony formation, and the progression of the cell cycle in LUAD cells. Meanwhile, it also accelerated the formation of subcutaneous and lung metastases tumors. In contrast, loss of HOXC11 in LUAD cells significantly inhibited these malignant phenotypes. At the same time, HOXC11 regulated the expression of sphingosine kinase 1 (SPHK1) by directly binding to its promoter region. Therefore, we conclude that HOXC11 impacts the development of LUAD and facilitates lung cancer progression by promoting the expression of SPHK1.

Systematic analysis of the oncogenic role of FAM83D across cancers based on data mining.

Family with sequence similarity of 83D (FAM83D) is overexpressed in various cancers. However, no pan-cancer analysis is presently available. In the present study, we used a bioinformatics analysis to explore the diagnostic and prognostic value of FAM83D expression levels in human cancers. The GEPIA 2, TIMER 2.0, ENCORI, and DriverDBV3 databases were used to evaluate FAM83D expression levels. The potential prognostic value of FAM83D expression was analyzed using the GEPIA 2, UALCAN, and TISIB databases. The driver gene and promoter methylation levels regarding FAM83D were evaluated using the TIMER 2.0 and UALCAN databases. To further analyze interactive networks for FAM83D, FAM83D-binding proteins and related genes were determined using STRING and Gene MANIA analytic tools. Highly expressed FAM83D could be associated with mutated TP53 and promoter DNA methylation. Relative network analysis suggested that FAM83D was mainly involved in the progesterone-mediated oocyte maturation pathway, cell cycle regulation, and several other signaling pathways. Therefore, the differential expression of FAM83D could serve as a diagnostic and prognostic biomarker for various cancers. Our study revealed useful information about the differential expression of FAM83D, prognostic values, and potential functional networks in a variety of cancers, providing valuable substantive and methodological information to explore the underlying mechanisms.Abbreviations: BP: Biological processes; CC: Cellular components; DAVID: Database for Annotation, Visualization, and Integrated Discovery; DFS: Disease-free survival; ENCORI: Encyclopedia of RNA Interactomes; FAM83: Family with sequence similarity 83; FAM83D: Family with sequence similarity of 83D; GEO: Gene Expression Omnibus; GEPIAx2: Gene Expression Profiling Interactive Analysis 2; GO: Gene Ontology; GTEx: Genotype-Tissue Expression; KEGG: Kyoto Encyclopedia of Genes and Genomes; KIRC: Kidney renal clear cell carcinoma; LIHC: Liver hepatocellular carcinoma; LUAD: Lung adenocarcinoma; MF: Molecular functions miRNA: microRNA; OS: Overall survival; PAAD: Pancreatic adenocarcinoma; PPI: Protein - protein interaction; RNA-seq: RNA-sequencing; TCGA: The Cancer Genome Atlas; TIMER 2.0: Tumor Immune Estimation Resource 2.0; UALCAN: University of Alabama at Birmingham Cancer; UCEC: Uterine corpus endometrial carcinoma.

Nasopharyngeal Carcinoma: The Role of the EGFR in Epstein-Barr Virus Infection.

Epstein-Barr virus (EBV), a type 4 γ herpes virus, is recognized as a causative agent in nasopharyngeal carcinoma (NPC). Incidence of EBV-positive NPC have grown in recent decades along with worse outcomes compared with their EBV-negative counterparts. Latent membrane protein 1 (LMP1), encoded by EBV, induces NPC progression. The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases (RTK), is a driver of tumorigenesis, including for NPC. Little data exist on the relationship between EGFR and EBV-induced NPC. In our initial review, we found that LMP1 promoted the expression of EGFR in NPC in two main ways: the NF-κB pathway and STAT3 activation. On the other hand, EGFR also enhances EBV infection in NPC cells. Moreover, activation of EGFR signalling affects NPC cell proliferation, cell cycle progression, angiogenesis, invasion, and metastasis. Since EGFR promotes tumorigenesis and progression by downstream signalling pathways, causing poor outcomes in NPC patients, EGFR-targeted drugs could be considered a newly developed anti-tumor drug. Here, we summarize the major studies on EBV, EGFR, and LMP1-regulatory EGFR expression and nucleus location in NPC and discuss the clinical efficacy of EGFR-targeted agents in locally advanced NPC (LA NPC) and recurrent or metastatic NPC (R/M NPC) patients.