Cell Proliferation Pathways Research Articles

Comprehensive genomic and transcriptomic profiling of pulmonary nodules in synchronous multiple primary lung cancer.

Synchronous multiple primary lung cancer (sMPLC) exhibits distinct histopathological characteristics among pulmonary nodules. However, a comprehensive understanding of the somatic mutation landscape and transcriptome heterogeneity is lacking. Therefore, our study aims to meticulously investigate genomic distinctions among multiple pulmonary nodules within individual patients. We performed targeted DNA sequencing on tumor specimens and conducted bulk RNA transcriptome analysis on 53 multiple nodules originating from 26 lung cancer patients. The multiple nodules from the same patient was determined as major nodule and minor nodule. Additionally, the tumor tissues underwent histopathological evaluation through H&E staining, complemented by a comprehensive series of immunohistochemistry (IHC) analyses to detect protein expression. The detected protein markers encompassed PD-L1, Ki67, and others. For the 53 nodule samples from 26 MPLCs patients, EGFR was the mostly mutated genes, and the TP53 mutation frequency was notably different between major and minor nodules. Furthermore, pathway enrichment analysis based on the differentially expressed genes (DEGs) between major and minor nodules revealed the significantly active cell cycle and p53 pathways in the major nodules. Additionally, both major and minor nodules demonstrated mostly similar immune microenvironment and PD-L1 protein expression, and a significantly higher expression of Ki67. A noteworthy suppression was observed in the immune microenvironment in nodules, revealed by the expression of macrophage, neutrophils, and NK cells. Furthermore, minor nodules exhibited a modestly elevated expression of macrophages compared to major nodules. Additionally, among the significantly up-regulated cell cycle-related genes in the major nodules when compared with minor nodules, CCNE1 mRNA expression demonstrated significant correlation with poor prognosis in the lung cancer. Furthermore, the MYC inhibitor demonstrated more sensitivity for the major nodules than minor nodules. This study validated molecular distinctions between samples from major and minor nodules in patients with sMPLC at both genomic and transcriptomic levels. The major nodules exhibited heightened activity in tumor cell proliferation pathways and demonstrated malignancy-related biological characteristics, which correlated with pathological assessment results.

Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients

A substantial portion of patients infected with SARS-CoV-2 experience prolonged complications, known as Long COVID (LC). A subset of these patients exhibits the most debilitating symptoms, similar to those defined in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We performed bulk RNA sequencing (RNAseq) on the whole blood of LC with ME/CFS, at least 12 months post-onset of the acute disease, and compared them with controls. We found that LC patients had a distinct transcriptional profile compared to controls. Key findings include the upregulation of genes involved in immune dysregulation and neuronal development, such as Fezf2, BRINP2, HOXC12, MEIS2, ZFHX3, and RELN. These genes are linked to neuroinflammatory responses, cognitive impairments, and hematopoietic disturbances, suggesting ongoing neurological and immune disturbances in LC patients.RELN, encoding the Reelin protein, was notably elevated in LC patients, potentially serving as a biomarker for LC pathogenesis due to its role in inflammation and neuronal function. Immune cell analysis showed altered profiles in LC patients, with increased activated memory CD4 + T cells and neutrophils, and decreased regulatory T cells and NK cells, reflecting immune dysregulation. Changes in cytokine and chemokine expression further underscore the chronic inflammatory state in LC patients. Notably, a unique upregulation of olfactory receptors (ORs) suggest alternative roles for ORs in non-olfactory tissues.Pathway analysis revealed upregulation in ribosomal RNA processing, amino acid metabolism, protein synthesis, cell proliferation, DNA repair, and mitochondrial pathways, indicating heightened metabolic and immune demands. Conversely, downregulated pathways, such as VEGF signaling and TP53 activity, point to impaired tissue repair and cellular stress responses.Overall, our study underscores the complex interplay between immune and neuronal dysfunction in LC patients, providing insights into potential diagnostic biomarkers and therapeutic targets. Future research is needed to fully understand the roles and interactions of these genes in LC pathophysiology.

CTSL Promotes Autophagy in Laryngeal Cancer Through the IL6-JAK-STAT3 Signalling Pathway.

Cathepsin L (CTSL) is an important oncogene. However, its mechanism of action in laryngeal cancer is still unclear. This study aims to explore the role of CTSL in laryngeal cancer and its clinical significance. Conducting bioinformatics analysis utilising the Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. Performing CCK8 analysis, Western blotting, qRT-PCR, wound healing assay and transwell invasion assay. Additionally, conducting immunoprecipitation experiments and immunohistochemical staining to investigate the impact of CTSL on cell proliferation, autophagy and related signalling pathways. We observed a significant upregulation of CTSL in laryngeal cancer tissues, and its elevated levels are indicative of poor prognosis in laryngeal cancer patients. The proliferation of laryngeal cancer cells relies on the expression of CTSL, with overexpression of this gene enhancing the proliferative capacity of these cells. Concurrently, CTSL is closely associated with the autophagic levels in laryngeal cancer cells. During the autophagic process mediated by CTSL, the IL6-JAK-STAT3 signalling pathway is activated, suggesting that CTSL promotes autophagy through the IL6-JAK-STAT3 pathway. Considering the correlation between CTSL and autophagy, we developed and validated a multi-gene signature. The risk score derived from this signature demonstrates significant potential in predicting various aspects. We found that CTSL upregulates autophagy in laryngeal cancer cells by activating the IL6-JAK-STAT3 signalling pathway. By taking into account the autophagy-regulating role of CTSL, the clinical predictive ability of CTSL in HNSC can be enhanced.

DETERMINATION OF THE ANTIPROLIFERATIVE EFFECT OF STERNBERGIA LUTEA (L.) KER GAWL. EX SPRENG. EXTRACTS ON A375 MALIGNANT MELONOMA CELL LINE

Epidemiological evidence confirms that plants are primary sources of drugs used to reduce the incidence of cancer and prevent cancer-related deaths. Sternbergia species are used for therapeutic purposes due to the amaryllidaceae alkaloids, lectins, phenolic acids, pigments, and volatile components they contain. In this study, the anticancer properties of S. lutea extracts were tested on the A375 malignant melonoma cell line. In addition, in the study, the transcriptional expression of BCL-XL and Cas9 genes, which function in cell proliferation and apoptotic pathways, in cells treated with plant extracts were determined by qRT-PCR. According to the cytotoxicity results made by the MTT test, the highest inhibition percentage was determined at the plant's concentration of 500 μg/𝑚L. At this concentration, A375 cells were inhibited by 83.63%, and the IC50 value of the extract was calculated as 194.64 μg/𝑚L. In addition, in qRT-PCR analyses, a statistically significant increase was observed in the mRNA expression levels of Cas9 genes, which are positively correlated with the apoptotic pathway, in the extract and cisplatin-applied groups compared to the control group.

Integrated Computational Analysis Reveals Early Genetic and Epigenetic AML Susceptibility Biomarkers in Benzene-Exposed Workers

Benzene, a well-known carcinogenic airborne pollutant, poses significant health risks, particularly in industries such as petroleum, shoemaking, and painting. Despite strict regulations, chronic occupational exposure persists, contributing to the onset of acute myeloid leukemia (AML) and other malignancies. Benzene’s carcinogenicity stems from its metabolic activation, leading to increased oxidative stress, DNA damage, and cancer transformation. While its toxicity is well-documented, the link between genetic and epigenetic alterations and cancer susceptibility in exposed workers remains underexplored. This study aims to identify early biomarkers of benzene exposure and AML risk by analyzing gene expression and DNA methylation datasets from GEO DataSets, integrated with molecular pathway analyses, as well as miRNA-target and protein-protein network evaluations. This multi-approach led to the identification of nine deregulated genes (CRK, CXCR6, GSPT1, KPNA1, MECP2, MELTF, NFKB1, TBC1D7, ZNF331) in workers exposed to benzene, with NFKB1 showing strong discriminatory potential. Also, dose-dependent DNA methylation changes were observed in CXCR6 and MELTF, while selected miRNAs such as let-7d-5p, miR-126-3p, and miR-361-5p emerged as key post-transcriptional regulators. Furthermore, functional enrichment linked these genes to immune response, inflammation, cell proliferation, and apoptosis pathways. While network analyses highlighted NFKB1, CRK, and CXCR6 as central to benzene-associated leukemogenesis. Altogether, these findings provide novel insights into an early biomarker fingerprint for benzene exposure and AML susceptibility, supporting the future development of biomolecular-based targeted occupational health monitoring and personalized preventive strategies for at-risk workers.

Polychlorinated biphenyls induced toxicities upon cell lines and stem cells: a review.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants emitted during e-waste activities. Upon release into the environment, PCBs can pose harmful effects to the humans and environment. The present review focused on the effects of PCBs on cell proliferation, apoptosis, functional and developmental toxicity and potential possible molecular mechanisms upon cells and stem cells. The review also highlights the effects of low- and high-chlorinated, and dioxin and non-dioxin PCBs. The review suggested that high chlorinated and dioxin like PCBs at higher concentrations posed more toxic effects to cells and stem cells. PCBs at higher levels induced hepatotoxicity, carcinogenicity, reproductive toxicity, neurotoxicity and lung cell toxicity. PCBs triggered reactive oxygen species which actives mitogen activated pathways, nuclear factor and cytochrome pathway for cell proliferation and apoptosis. Further, review highlights PCBs induced toxicity in stem cells with the focus on developmental and functional toxicity. The review could be useful to understand the PCBs toxicities and mechanisms and will guide to policy makers to design policies for e-waste pollutant.

Menopausal Hormone Therapy: Its Role in the Prevention of Cardiovascular Diseases and the Risk of Breast Cancer in Women

Objective: This review was conducted to explain how menopausal hormone therapy (MHT) benefits cardiovascular diseases (CVDs) and how to control the risk of breast cancer. Mechanism: Estrogen deficiency, altered energy homeostasis, adipocyte changes, inflammation, and insulin resistance are responsible for the development of metabolic syndrome and CVDs. Estrogen influences hypothalamic function and maintains the energy balance, protecting menopausal women from these cardiovascular risk factors. However, estrogen metabolism plays a crucial role in the genotoxic pathway that leads to breast cancer. Moreover, MHT is associated with cell proliferation and mutation signaling pathways in breast cancer, as well as the process of growing the breast cancer stem cell. Findings in Brief: While MHT may have favorable effects when started early, introducing it later in the course of atherosclerosis may pose major dangers, underlining the importance of timing in hormone therapy. Estrogen-only therapy has a greater favorable effect on CVDs than the estrogen-progesterone combination. Although the connection between MHT and breast cancer is well-documented, significant knowledge gaps remain, especially regarding the long-term effects of newer MHT formulations. Current studies support using the lowest effective dose for the shortest possible duration, with a focus on tailoring therapy to individual risk factors, such as obesity, smoking, and alcohol consumption. Thus, MHT should be customized due to the intricacy of individual risk factors and differences in responses to therapy. Conclusions: Although MHT is effective for controlling CVDs in women entering menopause, it must be used with caution, especially in women at high risk of breast cancer.

Benzo[a]pyrene exposure and incident risks of digestive system cancers: Insights from nested case-control studies and adverse outcome pathway network analysis.

Benzo[a]pyrene (B[a]P) is a recognized carcinogen for lung cancer, but its associations with digestive system cancers (DSCs) remain unclear and the common carcinogenic mechanisms are not fully understood. We conducted five nested case-control studies within the Dongfeng-Tongji cohort, including esophageal (EC, n = 58), gastric (GC, n = 103), colorectal (CRC, n = 220), hepatic (HC, n = 117), and pancreatic cancers (PC, n = 45). For each case, two sex and age ( ± 5 years) matched healthy controls were selected. We observed significant J-shaped associations between plasma concentrations of benzo[a]pyrene diol epoxide-albumin (BPDE-Alb) adducts and five DSCs (all P for non-linear <0.05). The subjects with high BPDE-Alb exposure exhibited a separate 2.19, 2.14, 1.67, 2.40, and 1.78-fold incident risks of EC, GC, CRC, HC, and PC (95%CI: 1.00-4.83, 1.24-3.67, 1.15-2.43, 1.48-3.90, and 0.71-4.47, respectively) than those with low exposure. Furthermore, the adverse outcome pathway (AOP) network indicated five molecular initiation events and 18 subsequent key events, particularly, the alterations in receptors of AhR, EGFR accompanied by regulations of cell proliferation and apoptosis pathways (e.g., PI3K-Akt, TNF signaling) may facilitate common carcinogenic processes. Our findings revealed the positive associations of B[a]P exposure with five DSCs, and the dysregulation of proliferation and apoptosis may initiate B[a]P-induced cancer development.

Association between dietary fructose and human colon DNA methylation: implication for racial disparities in colorectal cancer risk using a cross-sectional study.

An increasing body of evidence has linked fructose intake to colorectal cancer (CRC). African American (AA) adults consume greater quantities of fructose and are more likely to develop right-side colon cancer than European American (EA) adults. We examined the hypothesis that fructose consumption leads to epigenomic and transcriptomic differences associated with CRC tumor biology. Deoxyribonucleic acid (DNA) methylation data from this cross-sectional study was obtained using the Illumina Infinium MethylationEPIC kit (GSE151732). Right and left colon differentially methylated regions (DMRs) were identified using DMRcate through analysis of food frequency questionnaire data on fructose consumption in normal colon biopsies (n=79) of AA adults undergoing screening colonoscopy. Secondary analysis of CRC tumors was carried out using data derived from TCGA-COAD, GSE101764 and GSE193535. Right colon organoids derived from AA (n=5) and EA (n=5) adults were exposed to 4.4mM of fructose for 72 hours. Differentially expressed genes (DEGs) were identified using DESeq2. We identified 4,263 right colon fructose-associated DMRs (FDR<0.05). In contrast, only 24 DMRs survived multiple testing corrections (FDR<0.05) in matched, left colon. Almost 50% of right colon fructose-associated DMRs overlapped regions implicated in CRC in at least one of three datasets. A highly significant enrichment was also observed between genes corresponding to right colon fructose-associated DMRs and DEGs associated with fructose exposure in right colon organoids of AA individuals (P=3.28E-30). Overlapping and significant enrichments for fatty acid metabolism, glycolysis and cell proliferation pathways were also found. Cross-referencing genes within these pathways to DEGs in CRC tumors reveals potential roles for ankyrin repeat domain-containing protein 23 (ANKRD23) and phosphofructokinase, platelet (PFKP) in fructose-mediated CRC risk for AA individuals. Our data support that dietary fructose exerts a greater CRC risk-related effect in right than left colon among AA adults, alluding to its potential role in contributing to racial disparities in CRC.

Chaperonin containing TCP1 subunit 6A may activate Notch and Wnt pathways to facilitate the malignant behaviors and cancer stemness in oral squamous cell carcinoma

ABSTRACT Chaperonin containing TCP1 subunit 6A (CCT6A) was recently discovered to be involved in cancer pathogenesis and stemness; however, its role in oral squamous cell carcinoma (OSCC) has not been reported. The current study aimed to investigate the impact of CCT6A on OSCC cell malignant behaviors and stemness and to explore its potentially interreacted pathways. SCC-15 and HSC-3 cells were transfected with the plasmid loading control overexpression, CCT6A overexpression, control knockout, or CCT6A knockout. Wnt4 overexpression or Notch1 overexpression plasmids were transfected into CCT6A-knockout SCC-15 cells. Cell proliferation, apoptosis, invasion, stemness, Notch, and Wnt pathways were detected in both cell lines, whereas RNA sequencing was only performed in SCC-15 cells. CCT6A was upregulated in five OSCC cell lines, including SCC-15, HSC-3, SAT, SCC-9, and KON, compared to that in the control cell line. In SCC-15 and HSC-3 cells, CCT6A overexpression increased cell proliferation, invasion, sphere formation, CD133, and Sox2 expression, but decreased cell apoptosis; on the contrary, CCT6A knockout exhibited an opposite effect on the above indexes. RNA-sequencing data revealed that the Wnt and Notch pathways were involved in the CCT6A’effect on SCC-15 cell functions. CCT6A positively regulates the Wnt and Notch pathways in SCC-15 and HSC-3 cells. Importantly, it was shown that activation of the Wnt or Notch pathways attenuated the effect of CCT6A knockout on SCC-15 cell survival, invasion, and stemness. CCT6A may promote OSCC malignant behavior and stemness by activating the Wnt and Notch pathways.

Genetic overlap between breast cancer and sarcopenia: exploring the prognostic implications of SLC38A1 gene expression

BackgroundSarcopenia, an age-related syndrome characterized by a decline in muscle mass, not only affects patients’ quality of life but may also increase the risk of breast cancer recurrence and reduce survival rates. Therefore, investigating the genetic mechanisms shared between breast cancer and sarcopenia is significant for the prevention, diagnosis, and treatment of breast cancer.MethodsThis study downloaded gene expression datasets and clinical data related to breast cancer and skeletal muscle aging from the GEO database. Data preprocessing, integration, differential gene identification, functional enrichment analysis, and construction of protein-protein interaction networks were performed using R language. Subsequently, COX proportional hazards model analysis and survival analysis were conducted, and survival curves and nomograms were generated. The expression levels of genes in tissues were detected using qRT-PCR, and the Radiant DICOM viewer software was used to delineate the pectoralis major muscle area in CT images.ResultsWe identified 152 differentially expressed genes (P < .05) and 226 sarcopenia-related genes (r > .4) associated with skeletal muscle aging. The TCGA-BRCA dataset revealed 106 genes associated with breast cancer (P < .05, logFC = 1). Functional enrichment analysis indicated significant enrichment in cell proliferation and growth pathways. The PPI network identified critical molecules involved in muscle aging and tumor progression. After dimensionality reduction, a strong correlation was observed between the expression of the muscle aging-related gene set and the prognosis of breast cancer patients (P < .01). The expression of SLC38A1 identified through multivariate COX analysis was significantly associated with poor prognosis in breast cancer patients (P = .03). Incorporating SLC38A1 expression, the prognostic model precisely forecasted breast cancer survival (P < .01). External validation confirmed the higher expression of the SLC38A1 gene in breast cancer tissues compared to adjacent non-cancerous tissues (P < .01). The SLC38A1 index, calculated in combination with the patient’s age and BMI, can optimize the prognostic prediction model, providing a powerful tool for personalized treatment of breast cancer.ConclusionHigh SLC38A1 gene expression was significantly associated with poor prognosis in breast cancer patients. The combination of SLC38A1 expression and the pectoralis major muscle area provided an optimized prognostic prediction model, offering a potential tool for personalized breast cancer treatment.

Association of intratumoral microbiome diversity with hepatocellular carcinoma prognosis.

The evidence that intratumoral microbiomes, as a rising hallmark of cancer, have a profound impact on cancer phenotypes is increasingly compelling. However, the impact of the composition and diversity of the intratumoral microbiome on the prognosis of patients undergoing surgical resection for hepatocellular carcinoma (HCC) remains incompletely understood. In this study, we revealed a high abundance of bacteria in the neoplastic tissues. The presence of bacterial lipopolysaccharide and lipoteichoic acid was detected alongside tumor-associated immune cells. By utilizing 16S rRNA gene sequencing, we identified a specific intratumoral microbiome signature that was highly predictive of the prognosis for HCC patients who underwent surgical resection. Specifically, the presence of Intestinimonas, Brachybacterium, and Rothia were identified as independent risk factors for the overall survival of HCC patients who underwent surgical resection.IMPORTANCEAlthough some studies have shown an abundance of bacteria in hepatocellular carcinoma (HCC), there is still limited understanding of the composition and diversity of the intratumoral microbiome that is favorable or adverse to the prognosis of HCC patients. Our results indicated that a greater abundance of bacteria could be observed in the neoplastic tissues than in nonneoplastic tissues. Bacterial cell wall components largely coincided with tumor-associated immune cells. The bacteria in the long overall survival (LOS) group were associated with metabolism and cytokine‒cytokine receptor interaction pathways, while bacteria in the short overall survival (SOS) group were associated with proinflammatory and cell proliferation pathways. Notably, specific taxa could independently predict HCC prognosis. Based on these findings, intratumoral microbiomes facilitate the use of precision medicine in clinical practice.

Comparative liver transcriptome analysis in hamsters infected with food-borne trematodes Opisthorchis felineus, Opisthorchis viverrini, or Clonorchis sinensis.

Epidemiologically important food-borne trematodes Opisthorchis viverrini and Clonorchis sinensis are recognized as biological carcinogens of Group 1A, while Opisthorchis felineus is in Group 3 as noncarcinogenic to humans. Mechanisms of the biological carcinogenesis are still elusive. Some studies highlight chronic inflammation as a key factor and common pathway for cancer initiation and progression. Nonetheless, the chronic inflammation alone does not explain why these three species differ in carcinogenicity. We focused this study on genome-wide landscapes of liver gene expression and activation of cellular pathways in Mesocricetus auratus golden hamsters infected with C. sinensis (South Korea), O. viverrini (Thailand), or O. felineus (Russia) at 1 and 3 months after infection initiation. Liver transcriptomes of golden hamsters (HiSeq Illumina, 2X150 bp) were sequenced at 1 and 3 months postinfection. Data processing was carried out using the following bioinformatic and experimental approaches: analysis of differential gene expression, estimates of proportions of affected liver cell types, liver histopathology, and examination of weighted gene coexpression networks. All infections caused enrichment with inflammatory response signaling pathways, fibrogenesis and cell proliferation, and IL2-STAT5, TNF-NF-κB, TGF-β, Hippo, MAPK, and PI3K-Akt signaling pathways. Nevertheless, species-specific responses to each infection were noted too. We also identified species-specific responses of liver cell types, differentially expressed gene clusters, and cellular pathways associated with structural liver damage (such as periductal fibrosis, epithelial neoplasia, and inflammation). This is the first comparative analysis of gene expression landscapes in the liver of experimental animals infected with O. viverrini, O. felineus, or C. sinensis. The trematodes have species-specific effects on the hepatobiliary system by triggering signaling pathways, thereby leading to differences in the severity of hepatobiliary structural lesions and contributing to the pathogenicity of closely related foodborne trematodes.

FC10 Dysregulation of the SPRY1-DGAT axis alters glyceride metabolism and promotes psoriasis

Abstract Lipids play a crucial role in maintaining skin health. Previous studies have indicated that lipid disorders in psoriasis involve not only systemic dyslipidaemia but also alterations in lipid metabolites within skin tissue. Our study aims to investigate the impact of SPRY1-DGAT axis dysregulation on lipid metabolism in psoriasis, focusing on the role of glycerides, which have been less explored compared with phospholipids, fatty acids, and ceramides. Skin samples from healthy individuals and psoriasis patients were collected to measure the levels of DGAT (Diacylglycerol O-Acyltransferase) and glycerides. Primary cultured keratinocytes were used to assess glyceride content, proliferation, and differentiation. Additionally, we utilized SPRY1 (Sprouty1) overexpression in vitro and SPRY1 knockout (KO) transgenic mice models to observe phenotypic changes and metabolic alterations. The glyceride levels were quantified using lipidomic analyses, while DGAT expression was evaluated via immunofluorescence and Western blotting. Keratinocyte proliferation and differentiation were assessed through cell cycle analysis and marker expression studies. Cytokine secretion was measured using ELISA. Our results demonstrate that psoriasis patients exhibit significant abnormalities in glyceride metabolism, characterized by a notable decrease in the enzyme DGAT in their skin tissues. Our previous studies have indicated a close association between SPRY1 and psoriasis. In SPRY1 KO mice, we observed psoriasis-like phenotypes, including epidermal hyperplasia and inflammation, alongside similar glyceride metabolic abnormalities and reduced DGAT levels. The SPRY1-DGAT pathway was found to have a significant influence on glyceride metabolism, affecting keratinocyte proliferation, differentiation, and the secretion of inflammatory cytokines. Specifically, the downregulation of DGAT in psoriasis patients and SPRY1 KO mice correlated with increased keratinocyte proliferation and aberrant differentiation, contributing to the inflammatory environment characteristic of psoriasis. Metabolic abnormalities in psoriasis involve both systemic dyslipidaemia and localized changes within skin tissue. The downregulation of Spry1 and DGAT is intricately associated with abnormal glyceride metabolism in keratinocytes, leading to altered cell proliferation, differentiation, and inflammatory pathways. Our study highlights the importance of the SPRY1-DGAT axis in maintaining normal lipid metabolism and suggests that its dysregulation may play a critical role in the pathogenesis of psoriasis. Therapeutic strategies aimed at restoring normal glyceride metabolism through modulation of the SPRY1-DGAT pathway could potentially ameliorate psoriasis symptoms and improve skin health.

Thiazolidinedione derivatives in cancer therapy: exploring novel mechanisms, therapeutic potentials, and future horizons in oncology.

Thiazolidinedione derivatives have shown significant potential as targeted cancer therapies by leveraging their various mechanisms of action. These include suppressing cell proliferation, triggering apoptosis, and influencing signaling pathways associated with tumor development. Their multifaceted effects make them promising candidates for advancing cancer treatment strategies. They have shown significant promise as anti-cancer agents, particularly through their ability to inhibit lipogenesis pathways and apoptosis essential for cancer cell survival and proliferation. This review comprehensively examines the anti-cancer potential of thiazolidinedione derivatives by targeting key aspects of lipid metabolism, apoptosis, and various mechanistic pathways. This review provides an in-depth examination of the anti-cancer potential of TZD derivatives, focusing on their mechanisms of action, therapeutic applications, and future directions in oncology. The anti-tumor effects of TZDs primarily involve the stimulation of peroxisome proliferator-activated receptor gamma (PPAR-γ), suppressing cell proliferation, induction of apoptosis, and inhibition of angiogenesis. Moreover, recent evidence highlights their ability to modulate non-PPAR-γ pathways, such as PI3K/Akt, NF-κB, and MAPK, further expanding their role in overcoming drug resistance and enhancing therapeutic outcomes. This review explores the preclinical (in vitro and in vivo) and clinical research investigating TZD derivatives efficacy in various cancer types. The insights underscore the significance of targeting lipogenesis as a novel anti-cancer strategy, positioning thiazolidinedione derivatives as potent candidates for future cancer therapeutics. As the oncology landscape evolves, TZD derivatives (rosiglitazone, pioglitazone, inolitazone, troglitazone, and 2,4-thiazolidinedione derivatives) represent a promising class of agents with the potential to contribute meaningfully to cancer treatment. By integrating existing knowledge with recent advancements, this study provides valuable insights into the role of thiazolidinedione derivatives in cancer treatment, paving the way for further research and clinical applications.

Investigation of HOTAIR rs12826786, rs920778 and rs4759314 variants with breast cancer susceptibility and clinicopathological characteristics in a Mexican population

BackgroundBreast cancer (BC) is a multifactorial disease of unknown etiology whose major risk factors are genetic alterations of cell proliferation and migration pathways. HOX transcript antisense RNA gene (HOTAIR) is a long non-coding RNA (lncRNA) related to cell proliferation, progression, invasion, metastasis, and poor survival of multiple cancers, including BC. Controversial results have emerged on the association between breast cancer risk in multiple ethnicities. This study explores the association of rs12826786, rs920778, and rs4759314 variants in the HOTAIR gene in BC patients. MethodsDNA of peripheral blood samples was obtained from 588 women (289 patients and 299 control females). Genotypes were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. The association was calculated using the odds ratio (OR) test. P-values were adjusted by the Bonferroni test (0.016). ResultsThe rs12826786 (C>T), rs920778 (T>C), and rs4759314 (A>G) variants were associated with BC and with TNM stage, histologic type, and histologic molecular subtype (P=0.001). Likewise, the haplotype C-T-G in the HOTAIR gene (rs12826786-rs920778-rs4759314) was significantly related to BC (OR= 5.44, 95%, CI= 2.22-13.32, P= 0.001). ConclusionThe results suggest that rs12826786, rs920778, and rs4759314 variants in HOTAIR significantly influence breast cancer risk. Micro-abstractHOX transcript antisense intergenic RNA (HOTAIR) is a long non-coding RNA strongly correlated with the tumor grade and prognosis of various carcinomas, including breast cancer (BC). In this study, we analyzed the association of the rs12826786, rs920778, and rs4759314 variants in the HOTAIR gene and observed an increased susceptibility to BC and clinicopathological characteristics in a Mexican population.

Comprehensive Analysis of RNA Methylation-Regulated Gene Signature and Immune Infiltration in Ischemia/Reperfusion-Induced Acute Kidney Injury

Introduction: The morbidity and mortality of acute kidney injury (AKI) are increasing. Epigenetic regulation and immune cell infiltration are thought to be involved in AKI. However, the relationship between epigenetic regulation and immune cell infiltration in AKI has not been elucidated. This study was conducted to identify the differentially expressed genes (DEGs), differentially expressed RNA methylation genes (DEMGs), and infiltrated immune cells in the kidneys of ischemia-reperfusion induced-acute kidney injury (IRI-AKI) models and further explore their relationships in IRI-AKI. Methods: This is a bioinformatic analysis using R programming language in 3 selected IRI-AKI datasets from the Gene Expression Omnibus (GEO) database, including 16 IRI-AKI kidney tissues and 10 normal kidney tissues. The DEGs were screened, and enrichment pathways were analyzed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The DEMGs and core DEMGs were identified using the R package. The ROC curve was plotted to predict disease occurrence of 7 core DEMGs. The correlation of 7 core DEMGs and other genes was analyzed using Pearson’s correlation test. The gene set enrichment analysis (GSEA) of each DEMG was conducted using the R package. The upstream miRNAs and transcript factors of 7 core DEMGs were predicted based on the RegNetwork database and Cytoscape software. The STITCH database was used to predict the possible binding compounds of the 7 core DEMGs. Immune cell infiltration in kidney tissues between the IRI-AKI group and control group was evaluated using the R package. Results: A total of 2,367 DEGs were obtained, including 1,180 upregulated and 1,187 downregulated genes in IRI-AKI kidney associated with the cell structure, proliferation, molecule binding/interaction, and signaling pathways such as the leukocyte migration and chemokine signaling pathways. Ten DEMGs were identified, with Ythdf1, Rbm15, Trmt6, Hnrnpc, and Dnmt1 being significantly upregulated, while Lrpprc, Cyfip2, Mettl3, Ncbp2, and Nudt7 were significantly downregulated in IRI-AKI tissues. The molecules interacting with 7 core DEMGs were identified. Significant changes in the infiltration of 8 types of immune cells were observed in IRI-AKI kidneys compared to normal controls. The significant correlation between 6 core DEMGs and the infiltration of immune cells was observed. Conclusion: IRI may induce AKI through RNA methylation to regulate the expression of genes involved in immune cell infiltration.

Precision Nanomedicine: Lapatinib-Loaded Chitosan-Gold Nanoparticles Targeting LINC01615 for Lung Cancer Therapy.

Long non-coding RNAs (lncRNAs) play essential roles as oncogenic factors in cancer progression by influencing cell proliferation, apoptosis, and metastasis pathways. This study aims to investigate the expression changes of LINC01615 in prevalent cancers, explore its correlation with patient mortality rates, and introduce a novel therapeutic approach to reduce LINC01615 expression. Using The Cancer Genome Atlas (TCGA) data, the expression changes of LINC01615 in various cancers were analyzed, and its relationship with patient survival rates through Cox regression analysis weas assessed. Co-expressed pathways related to LINC01615 were identified via network analysis. Potential drugs to decrease LINC01615 expression were identified using the GSE38376 study. Besides, chitosan-coated nanoparticles were fabricated and functionalized with the identified drug, Lapatinib, to examine their effect on lung cancer cell lines and changes in LINC01615 expression. Our results indicated elevated LINC01615 expression in various common cancers, particularly in lung cancer, which was associated with poor prognosis in lung, breast, and kidney cancers. Co-expression network analysis suggested links to metastasis-related genes. Lapatinib, identified through GEO data, was found to modulate LINC01615 expression effectively. Chitosan-gold nanoparticles conjugated with Lapatinib significantly reduced LINC01615 expression in lung cancer cell lines while enhancing apoptosis rates. Therefore, these nanoparticles could be considered a promising therapeutic candidate for treating cancers with overexpression of LINC01615.

Abstract PR009: mascRNA directs nutrient-insensitive activation of the LARS-mTOR pathway in breast cancer

Abstract Cellular growth and metabolism are tightly regulated by nutrient availability, yet cancer cells frequently lose these controls, enabling unchecked proliferation even in the absence of sufficient nutrients. While non-coding RNAs are known to regulate metabolic enzyme expression, their direct role in nutrient-sensing pathways in cancer remains unclear. MALAT1-associated small cytoplasmic RNA (mascRNA) is a 61-nucleotide small RNA with a tRNA-like structure, cleaved from the 3’ end of the long non-coding RNA MALAT1. mascRNA has been shown to promote hepatocellular carcinoma proliferation and enhance protein translation in HEK293 cells, though its underlying molecular mechanism is not fully understood. We assessed mascRNA levels in over 70 human breast cancer patient samples using BaseScope assays and found that mascRNA is detectable in the cytoplasm of tumor cells, but not in normal mammary tissues or stromal cells adjacent to tumors. However, the levels of mascRNA varied significantly among patient samples, irrespective of molecular subtypes or tumor stages, suggesting that mascRNA is associated with other aspects of tumor biology. Functional studies in breast cancer cell lines revealed that mascRNA overexpression promotes cell proliferation, invasion, and metabolic pathways linked to ATP generation. Specifically, mascRNA increases basal glycolysis and mitochondrial oxidative phosphorylation and significantly enhances mitochondrial spare capacity, particularly in triple-negative breast cancer (TNBC) cell lines. We also found that mascRNA overexpression activates both mTORC1 and AMPK, indicating a deviation from the normal negative feedback loop between these two pathways. To dissect the molecular mechanism, we performed mascRNA pull-down assays and mass-spectrometric analyses. We identified RNA splicing factors, tRNA-modifying enzymes, and several aminoacyl-tRNA synthetases as mascRNA-interacting proteins. Among these, leucyl-tRNA synthetase (LARS), a component of the multi-tRNA synthetase complex, is known for its non-canonical role in activating mTORC1 at the lysosomal membrane. We found that, in MDA-MB-231 TNBC cells, mascRNA overexpression led to increased LARS localization to the lysosomal membrane where it can activate mTORC1. Interestingly, while control MDA-MB-231 cells responded to glucose and leucine availability to regulate the lysosomal localization of LARS and mTOR, mascRNA- overexpressing cells constitutively maintained LARS and mTOR localization to the lysosome, as well as mTORC1 phosphorylation, regardless of nutrient status. In summary, our data demonstrate that mascRNA aberrantly activates the LARS-mTORC1 axis in breast cancer cells independent of nutrient levels, likely through direct interaction with LARS, promoting its localization to the lysosome. This suggests that mascRNA enables breast cancer cells, and possibly other cancer types, to sustain uncontrolled growth even in nutrient-deprived conditions. Elevated mascRNA levels may thus represent a highly efficient metabolic adaptation of cancer cells. Citation Format: Bohye Park, Joshua K Stone, Steve Lim, Shuko Harada, Erin Ahn. mascRNA directs nutrient-insensitive activation of the LARS-mTOR pathway in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR009.

Probiotic-facilitated cytokine-induced killer cells suppress peritoneal carcinomatosis and liver metastasis in colorectal cancer cells.

Background: This study tested the hypothesis that combined therapy with probiotics and cytokine-induced killer (CIK) cells was superior to merely one on suppressing the peritoneal carcinomatosis and liver metastasis of colorectal cancer (CRC) cells in nude mice. Methods and Results: The in vitro study revealed that in HCT 116/SW620 CRC cell lines, cell viability, proliferation, colony formation, migratory ability, wound healing, and protein expression of PD-L1 and FAK were significantly and comparably suppressed and that apoptosis was significantly and comparably increased by probiotics and CIK cells, and these effects were further significantly enhanced by combined probiotics + CIK cell therapy (all p<0.001). Nude mice were categorized into Groups 1 (SC), 2 (HCT 116), 3 (HCT 116 + probiotics), 4 (HCT 116 + CIK cells), and 5 (HCT 116 + probiotics + CIK cells). CRC cells were intraperitoneally implanted into Groups 2 to 5, and the animals were euthanized by Day 28. The results demonstrated that the abdominal dissemination of CRC cells, tumor numbers, tumor weights, liver weights, liver necrosis areas and the expression of γ-H2AX/PD-L1/FAK in harvested liver tumors were lowest in Group 1, highest in Group 2, and significantly and progressively decreased in Groups 3 to 5 (all p<0.0001). The protein expression levels of apoptotic and DNA damage biomarkers (Bax/c-caspase 3/c-PARP/γ-H2AX), a metastatic biomarker (FAK) and three tumor proliferation and survival signaling biomarkers (JAK-STAT1, PI3K/Akt/m-TOR and Ras/Raf/MEK/ERK) exhibited identical patterns to that of a tumor immune escape biomarker (PD-L1) among the groups (all p<0.0001). Conclusion: The combination of probiotics and CIK cells was superior to either therapy alone in suppressing CRC cell growth, proliferation, liver metastasis and survival, mainly through downregulating cell proliferation and survival signaling pathways.