Molecular Carcinogenesis最新文献

Prostate cancer (PCa) is the second most common cancer and second leading cause of cancer death for American men. Chemoprevention by using phytochemicals offers a promising approach to improve outcomes due to their ability to act on cancer cell metabolism and growth while maintaining low toxicity profiles. The goal of this study was to assess the combination of xanthohumol (XAN) and ursolic acid (UA) given in the diet for synergistic efficacy against PCa progression and identify potential mechanisms of action. PCa cells were treated with the combination to evaluate cell survival and colony formation. Two mouse models of PCa were used to evaluate tolerability and efficacy of dietary administration of the combination and to further understand mechanism(s) of action. The combination of XAN + UA reduced PCa cell survival and colony formation. The combination given in the diet significantly and synergistically inhibited growth of HMVP2 PCa allograft tumors and also inhibited PCa progression in HiMyc mice. Mechanistically, inhibition of polyamine synthesis and epithelial-to-mesenchymal transition contributed to the inhibition of HMVP2 allograft tumor growth, while the inhibition of PCa progression in HiMyc mice was associated with activation of the unfolded protein response pathway and apoptosis. Further studies in cultured PCa cells revealed additional effects of the combination on several oncogenic signaling pathways (e.g, phospho-STAT3) and cell cycle regulatory proteins (e.g, cyclin D1, phospho-Rb).

Epithelial splicing regulatory protein 2 (ESRP2) is a splicing regulator specific to epithelial cell types. Multiple studies have found that its expression is abnormal in various tumors, influencing their occurrence, development, or prognosis. Our previous research indicated that down-regulating ESRP2 can suppress the proliferation of breast cancer (BC) cells, specifically the MCF-7 line. To delve deeper into the role of ESRP2 in BC cells, we investigated its impact on the migration of BC cells in vitro and the underlying molecular mechanisms. The outcomes of the in vitro scratch assay and Transwell assay initially confirmed that ESRP2 hinders the migration of both MCF-7 and MDA-MB-231 cells, and that reducing ESRP2 expression enhances their migratory capacity. We demonstrated that the down-regulation of ESRP2 can boost the migration ability of MCF-7 cells, and increase the mRNA expression of epithelial-mesenchymal transition (EMT) transcription factor ZEB2 and related markers N-cadherin and Vimentin. This suggests that ESRP2 plays a potential regulatory role in inhibiting EMT transcription program. Additionally, results from RNA sequencing and agarose electrophoresis gel experiments predict that down-regulating ESRP2 may promote exon skipping of the ENAH gene by modulating the alternative splicing of genes associated with cell migration, driving the shift of MCF-7 cells from an epithelial to a mesenchymal phenotype. Our research reveals a novel mechanism by which ESRP2 affects BC metastasis through post-transcriptional regulation. ESRP2 may present as a promising biomarker in combating BC cell migration by targeting EMT.

Canine hepatocellular carcinoma (HCC) requires further molecular characterization to identify diagnostic and therapeutic targets, and to establish whether dogs with this condition can model the human disease. Accordingly, we aimed to identify differentially expressed genes (DEGs) in canine HCC and evaluate cross-species transcriptomic dysregulation in canine and human HCC. Liver tissue samples from three dogs with HCC and three healthy dogs were subjected to next-generation sequencing, followed by RT-qPCR validation. Identified DEGs were then targeted in bioinformatics analyses (pathway enrichment, protein-protein interaction network, and hub gene analyses) for molecular characterization and comparison with human HCC datasets. We identified 975 DEGs (upregulated: 604; and downregulated: 371). Extracellular matrix-receptor interaction, focal adhesion, cell adhesion molecule, PI3K/Akt signaling, and cytokine/chemokine-related pathways were enriched. C1R, APOC3, C1QA, APOA1, C1QB, ACTG1, C1QC, CRP, ANXA5, and ANXA2 were identified as hub genes. Canine and human HCCs share 118 DEGs, highlighting conserved alterations in metabolic pathways, PI3K-Akt signaling, focal adhesion, and PPAR signaling pathways. Based on human HCC data, SPP1, NQO1, RRM2, APOA1, APOC3, ALDOB, and IGF1 were identified as prognosticators indicating poor overall survival. This study presents the first cross-species transcriptomic analysis of canine HCC, revealing significant molecular resemblances to human HCC, indicating it may be a promising comparative model for studying tumor biology, drug responses, and novel therapeutic interventions.

Retraction: D. Chatterjee, P. Bhattacharjee, T. J. Sau, J. K. Das, N. Sarma, A. K. Bandyopadhyay, S. S. Roy, and A. K. Giri, "Arsenic Exposure Through Drinking Water Leads to Senescence and Alteration of Telomere Length in Humans: A Case-Control Study in West Bengal, India," Molecular Carcinogenesis 54, no. 9 (2015): 800-809, https://doi.org/10.1002/mc.22150. The above article, published online on 24 March 2014 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by Wiley Periodicals LLC. The retraction has been agreed upon following concerns raised by a third-party regarding duplication between Figures 1a and 1b. Further investigation revealed multiple instances of similar background patterns in the western blots shown in Figures 1d and 4b. The authors provided an alternative image to correct Figure 1b; however evidence of duplication was also identified in this replacement. Given the nature of the concerns, the Publisher considers the results and conclusions to be unreliable. The authors disagree with the retraction.

The regulation of gene expression and its connection to the dynamics of plasma membrane signaling hubs (lipid rafts) have largely remained unexplored to date. Ras signaling plays crucial roles in the initiation and progression of colon adenocarcinoma (COAD) by regulation of gene expression, including DNA methyltransferase 1 (DNMT1). Gene-specific hypermethylation and genome-wide hypomethylation are well characterized in various cancers, including COAD. In view of this, we have examined how the signaling pathway orchestrated by plasma membrane-associated lipid rafts coordinates with the epigenetic modifications that precisely modulate a specific group of (hub) genes involved. First, we have identified COAD-specific hub genes (COL1A1, COL1A2, COL4A1, SPP1, SPARC, and THBS2) through extensive bioinformatics analyses, which revealed that increased expression of these hub genes facilitates the onset and progression of COAD. Comprehensive computational analyses of methylation patterns confirmed that atypical hypomethylation at these gene loci elevates their expression in COAD. Thereafter, we have explored how the dynamics of plasma membrane signaling hubs', such as lipid rafts, influence gene-specific promoter methylation dynamics within the nucleus of COAD cells. Our experimental analyses indicated that the transient destabilization (TD) of lipid rafts through ectopic cholesterol efflux activates the epidermal growth factor (EGF)-independent lipid raft-associated epidermal growth factor receptor (EGFR)-rat sarcoma (RAS)-mitogen-activated protein kinase (MAPK) signaling pathway, leading to increased expression of DNMTs and decreased expression of hub genes in COAD cells. These results strongly suggest that the plasma membrane lipid raft-associated EGFR-RAS-MAPK axis, functioning from membrane signaling hubs, can regulate genes located in various chromosomal locations. Ectopic expressions of DNMT1 impose an epigenetic checkpoint at those target loci by methylation of promoter DNA of the respective genes. We conclude that, gene specific hypomethylation of some genes, including COL1A1, COL1A2, COL4A1, SPP1, SPARC, and THBS2 drives COAD and would serve as potential markers for COAD screening.

Chemotherapy resistance is the primary cause of clinical treatment failure and unfavorable prognosis among breast cancer patients. Consequently, the exploration of novel molecular targets for chemotherapy resistance is warranted. Here, we demonstrated that Zinc Finger Protein 184 (ZNF184) facilitates chemoresistance in breast cancer. Through integrated bioinformatics and experimental validation, we identified that ZNF184 was highly expressed in paclitaxel-resistant breast cancer cells. Knockdown of ZNF184 inhibited cell proliferation and re-sensitized resistant cells to paclitaxel in vitro and in patients-derived organoids (PDOs). Mechanistically, ZNF184 regulates the expression of stemness-related genes CD44, OCT4, Nanog, SOX2, and ALDH1A1, thereby promoting the proliferation of breast cancer cells and subsequent paclitaxel resistance. Pan-cancer analysis revealed the potential of ZNF184 as a prognostic and predictive biomarker for adverse clinical outcomes. Collectively, these findings reveal a previously unknown role of ZNF184 in breast cancer progression and paclitaxel resistance, providing new insights into ZNF184 as a potential therapeutic target for cancer patients.

Breast cancer represents the leading cause of mortality among women worldwide. Triple negative breast cancer (TNBC) subtype does not express estrogen receptor, progesterone receptor and Her2, as well as presents a high expression of Ki67. In addition, TNBC presents the highest incidence of metastasis. Erythropoietin (EPO) is a hematopoietic cytokine that is produced in the kidney; however, EPO is also produced in non-hematopoietic cells. Treatment of breast cancer patients with EPO is associated with poor prognosis and decrease of survival. Epithelial to mesenchymal transition (EMT) is a reversible process in which epithelial cells decrease or lose their epithelial characteristics and acquire properties of mesenchymal cells. EMT is implicated in normal processes and tumor progression. We previously demonstrated that EPO induces an EMT process in MCF10A mammary non-tumorigenic epithelial cells. In this study, we demonstrate that PI3K activity mediates the EMT process induced by EPO in MCF10A cells. Moreover, Balb/cJ mice inoculated with TNBC 4T1 cells and treated with EPO develop mammary tumors with more weight and volume and an increase in the total number of metastatic nodules in lungs and liver through PI3K activity compared with untreated Balb/cJ mice inoculated with 4T1 cells. In conclusion, PI3K activity mediates the EMT process in MCF10A cells and the growth of mammary tumors and metastasis to lungs and liver induced by EPO in Balb/cJ mice inoculated with TNBC 4T1 cells.

Cyclin L1 (CCNL1) is highly expressed in multiple cancer types and has been linked to poor prognosis. However, the expression pattern of CCNL1 in breast cancer and its specific role in regulating breast cancer progression remain largely unknown. This study used cell and molecular biology techniques to examine how CCNL1 regulates the proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) of breast cancer cells. The applied methods encompassed plasmid transfection, Transwell assay, wound-healing assay, Western blot analysis, co-immunoprecipitation (Co-IP), and rescue assay. For the analysis of CCNL1-related factors and pathways, bioinformatics platforms including Metascape and HURI were also employed. CCNL1 is highly expressed in breast cancer cells and is associated with a poor prognosis. CCNL1 overexpression increased breast cancer cell invasion and migration and accelerated proliferation. Overexpression of CCNL1 was found to upregulate the mesenchymal marker Vimentin and downregulate the epithelial marker E-cadherin expression. There is close relationship between CCNL1, the NF-κB and PI3K/AKT signaling pathways. The direct interaction is verified between CCNL1 and DVL3 by Co-IP, indicating a negative correlation between the two proteins. CCNL1 overexpression affects breast cancer cells' paclitaxel sensitivity through the PI3K/AKT pathway. CCNL1 activates the NF-κB signaling pathway through its interaction with DVL3; additionally, it promotes the PI3K/AKT pathway. Together, these two mechanisms enable CCNL1 to exert a regulatory role in the progression of breast cancer.

Glioblastoma (GBM) represents an exceedingly malignant and invasive type of brain tumor, known for its significant tendency to recur and its unfavorable clinical outcome. Despite significant advancements in research and therapeutic strategies, the survival rates for patients with GBM remain low. Synthesis of 1,4,5,6,7,8-hexahydropyridine [4,3-d] pyrimidine (PPM) has emerged as a promising avenue for the development of novel therapeutic agents with potent anti-glioma efficacy and minimal toxicity. Although previous studies have demonstrated the ability of PPM to inhibit HepG2 cell proliferation and suppress liver cancer, its potential anti-glioma effects and the underlying mechanisms remain largely unexplored. Using a comprehensive array of experimental approaches, this study was designed to elucidate both the therapeutic potential and underlying molecular mechanisms of PPM in GBM, including western blotting, flow cytometry, EdU assay, clone formation analysis, immunofluorescence, qRT-PCR, wound healing assay, Transwell migration/invasion assay, and a dual-luciferase reporter gene system. In vitro experiments demonstrated that PPM exhibited significant inhibitory effects on tumor cell proliferation, migration, and invasion. Furthermore, PPM treatment induced cell cycle arrest and promoted both apoptosis and autophagy, and its antitumor effects were mediated by the inhibition of autophagosome degradation. Mechanistically, PPM exerted its anti-glioma effects through the upregulation of miR-873-3p, which subsequently inhibited the PI3K/AKT/mTOR signaling pathway. Through the integration of proteomic profiling and bioinformatics approaches, PTBP1 was identified as a putative downstream target gene regulated by miR-873-3p. Suppression of miR-873-3p upregulates PTBP1 expression, thereby facilitating the progression and development of glioma cells. These findings suggest that PPM is a promising therapeutic candidate for GBM treatment and offer novel insights into glioma therapy. The identification of the miR-873-3p/PTBP1 axis as a potential therapeutic target provides a new direction for future clinical applications and GBM treatment strategies.

Hepatocellular carcinoma is a leading cause of cancer-related mortality worldwide, with metabolic syndrome emerging as a major risk factor. However, the molecular mechanisms underlying the association between metabolic syndrome and hepatocellular carcinoma progression are not fully understood. Here, we investigated the role of kisspeptin signaling in hepatocellular carcinoma progression under metabolic dysregulation. High-fat diet feeding significantly decreased hepatic kisspeptin receptor expression in mice. Integrated transcriptomic and metabolomic analyses revealed that kisspeptin primarily regulated glycolysis-related pathways. In a N-Nitrosodiethylamine-induced hepatocellular carcinoma mouse model, high-fat diet accelerated tumor progression accompanied by kisspeptin receptor downregulation. Treatment with kisspeptin-10 attenuated high-fat diet-promoted hepatocellular carcinoma progression and decreased the expression of key glycolytic enzymes HK, PFKM, and PKM2. In vitro studies using HepG2 cells further confirmed that kisspeptin-10 inhibited these glycolytic enzymes in a dose-dependent manner. The integration of transcriptomic and metabolomic data demonstrated that kisspeptin exerts broad inhibitory effects on metabolism, particularly glucose metabolism, also suggesting potential antitumor effect. Our results suggest kisspeptin as a potential therapeutic target for hepatocellular carcinoma in patients with metabolic syndrome.