Mechanisms Of Carcinogenesis Research Articles

The Relationship of Microsatellite Instability with BRAF and p53 Mutations and Histopathological Parameters in Colorectal Adenocarcinoma.

This study aims to elucidate the associations between microsatellite instability (MSI) status, BRAF mutation, and p53 reactions with pathological parameters and survival outcomes in colorectal carcinoma. MutL homologous 1 (MLH1), Postmeiotic segregation increased 2 (PMS2), MutS homologous 2 (MSH2), MutS homologous 6 (MSH6), BRAF, and p53 antibodies were performed on 130 adenocarcinoma samples, including 65 from the right colon and 65 from the left colon. The relationships of MSI status with BRAF mutation, p53 reaction, clinical and pathological parameters, and survival times were statistically analyzed. A statistically significant relationship was found between MSI and right colon localization, tumor size, histological grade, intraepithelial tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, expansive growth pattern, and BRAF mutation (p < 0.05). No significant correlation was found between MSI status and the disease-free or overall survival times (p > 0.05). In colorectal adenocarcinoma, MSI and BRAF mutation are associated with parameters, indicating the host immune response and prognostic histopathological parameters, including tumor size and histological grade. The evaluation of MSI status and BRAF mutation can be particularly informative for predicting the prognosis and guiding the treatment management in poorly differentiated colorectal adenocarcinoma. Understanding the mechanisms of molecular carcinogenesis in colorectal carcinoma and organizing treatment algorithms based on molecular foundations will increase the success of the treatment.

Prevalence of H. pylori and Gastric Intestinal Metaplasia in BRCA1 and BRCA2 Carriers.

BRCA1 and BRCA2 carriers may be at increased risk for gastric cancer; however, the mechanisms of gastric carcinogenesis remain poorly understood. We sought to determine the prevalence of gastric cancer risk factors Helicobacter pylori (H. pylori) infection and gastric intestinal metaplasia (GIM) among BRCA1/2 carriers to gain insight into the pathogenesis of gastric cancer in this population. A total of 100 unselected BRCA1/2 carriers who underwent endoscopic ultrasound from March 2022 to March 2023 underwent concomitant upper endoscopy with nontargeted gastric antrum and body biopsies. The study population (70% women; mean age 60.1 years) included 66% BRCA2 carriers. H. pylori was detected in one (1%) individual, 7 (7%) had GIM, 2 (2%) had autoimmune atrophic gastritis, and no gastric cancers were diagnosed. Among BRCA1/2 carriers, H. pylori prevalence was low and GIM prevalence was similar to that in the general population; however, identification of H. pylori or GIM may help inform future gastric cancer risk management strategies in BRCA1/2 carriers. Prevention Relevance: Evaluating the burden of H. pylori infection and GIM among BRCA1/2 carriers is warranted to better understand the mechanisms of gastric carcinogenesis and to help inform risk management strategies for gastric cancer among this at-risk population.

Comprehensive DNA methylation profiling by MeDIP-NGS identifies potential genes and pathways for epithelial ovarian cancer.

Ovarian cancer, among all gynecologic malignancies, exhibits the highest incidence and mortality rate, primarily because it is often presents with non-specific or no symptoms during its early stages. For the advancement of Ovarian Cancer Diagnosis, it is crucial to identify the potential molecular signatures that could significantly differentiate between healthy and ovarian cancerous tissues and can be used further as a diagnostic biomarker for detecting ovarian cancer. In this study, we investigated the genome-wide methylation patterns in ovarian cancer patients using Methylated DNA Immunoprecipitation (MeDIP-Seq) followed by NGS. Identified differentially methylated regions (DMRs) were further validated by targeted bisulfite sequencing for CpG site-specific methylation profiles. Furthermore, expression validation of six genes by Quantitative Reverse Transcriptase-PCR was also performed. Out of total 120 differentially methylated genes (DMGs), 68 genes were hypermethylated, and 52 were hypomethylated in their promoter region. After analysis, we identified the top 6 hub genes, namely POLR3B, PLXND1, GIGYF2, STK4, BMP2 and CRKL. Interestingly we observed Non-CpG site methylation in the case of POLR3B and CRKL which was statistically significant in discriminating ovarian cancer samples from normal controls. The most significant pathways identified were focal adhesion, the MAPK signaling pathway, and the Ras signaling pathway. Expression analysis of hypermethylated genes was correlated with the downregulation of the genes. POLR3B and GIGYF2 turned out to be the novel genes associated with the carcinogenesis of EOC. Our study demonstrated that methylation profiling through MeDIP-sequencing has effectively identified six potential hub genes and pathways that might exacerbate our understanding of underlying molecular mechanisms of ovarian carcinogenesis.

Deciphering age-specific molecular features in cervical cancer and constructing an angio-immune prognostic model.

Cancer incidence is increasingly seen in younger individuals. Molecular distinctions between young and elderly patients at onset are understudied. This study used public databases to explore genomic, transcriptomic, and immune-related features across age groups in cervical cancer. Additionally, it aims to create a prognostic model applicable across diverse age cohorts, enabling precise patient stratification, and personalized therapies. Gene mutations, expression data, and clinicopathological information were obtained from 317 cervical cancer patients. These patients were divided into a young group and an old group based on the median age of onset. The characteristics of differential gene mutation, gene expression, and immune cells analysis were analyzed by R software. Finally, the prognostic model was constructed by univariate Cox, least absolute shrinkage and selection operator, and multivariate Cox regression analyses of angiogenic and immune gene sets. Its validity was further confirmed using an additional 300 cervical squamous cell carcinoma and endocervical adenocarcinoma tissues. Cervical cancer patients at elderly onset age exhibit a significantly higher frequency of NOTCH1 and TP53 driver mutations compared to young patients, along with a notably higher tumor mutational burden. However, there were no significant differences between the 2 groups in terms of genomic instability and age-related mutational signatures. Differential gene expression analysis revealed that the young group significantly upregulated interferon-alpha and gamma responses and exhibited significantly higher activity in multiple metabolic pathways. Immune microenvironment analysis indicated enrichment of dendritic cells and natural killer cells in the young group, while transforming growth factor-β signature was enriched in the elderly group, indicating a higher degree of immune exclusion. A multigene prognostic model based on angiogenesis and T cell immune gene sets showed excellent prognostic performance independent of clinical factors such as age. High-risk groups identified by the model exhibit significant activation of tumor-promoting processes, such as metastasis and angiogenesis. Our study reveals distinct patterns in cancer-driving mechanisms, biological processes, and immune system status between young and elderly patients at onset with cervical cancer. These findings shed light on the age-specific underlying mechanisms of carcinogenesis. Furthermore, an independent molecular prognostic model is constructed to provide valuable references for patient stratification and the development of potential drug targets.

Retraction Note: Angiopoietin4 (ANGPT4) expression and potential mechanisms in carcinogenesis: current achievements and perspectives

Retraction Note: Angiopoietin4 (ANGPT4) expression and potential mechanisms in carcinogenesis: current achievements and perspectives

Genome-Wide Analysis Identifies Nuclear Factor 1C as a Novel Transcription Factor and Potential Therapeutic Target in SCLC

IntroductionRecent insights regarding mechanisms mediating stemness, heterogeneity, and metastatic potential of lung cancers have yet to be fully translated to effective regimens for the treatment of these malignancies. This study sought to identify novel targets for lung cancer therapy. MethodsTranscriptomes and DNA methylomes of 14 SCLC and 10 NSCLC lines were compared with normal human small airway epithelial cells (SAECs) and induced pluripotent stem cell (iPSC) clones derived from SAEC. SCLC lines, lung iPSC (Lu-iPSC), and SAEC were further evaluated by DNase I hypersensitive site sequencing (DHS-seq). Changes in chromatin accessibility and depths of transcription factor (TF) footprints were quantified using Bivariate analysis of Genomic Footprint. Standard techniques were used to evaluate growth, tumorigenicity, and changes in transcriptomes and glucose metabolism of SCLC cells after NFIC knockdown and to evaluate NFIC expression in SCLC cells after exposure to BET inhibitors. ResultsConsiderable commonality of transcriptomes and DNA methylomes was observed between Lu-iPSC and SCLC; however, this analysis was uninformative regarding pathways unique to lung cancer. Linking results of DHS-seq to RNA sequencing enabled identification of networks not previously associated with SCLC. When combined with footprint depth, NFIC, a transcription factor not previously associated with SCLC, had the highest score of occupancy at open chromatin sites. Knockdown of NFIC impaired glucose metabolism, decreased stemness, and inhibited growth of SCLC cells in vitro and in vivo. ChIP-seq analysis identified numerous sites occupied by BRD4 in the NFIC promoter region. Knockdown of BRD4 or treatment with Bromodomain and extra-terminal domain (BET) inhibitors (BETis) markedly reduced NFIC expression in SCLC cells and SCLC PDX models. Approximately 8% of genes down-regulated by BETi treatment were repressed by NFIC knockdown in SCLC, whereas 34% of genes repressed after NFIC knockdown were also down-regulated in SCLC cells after BETi treatment. ConclusionsNFIC is a key TF and possible mediator of transcriptional regulation by BET family proteins in SCLC. Our findings highlight the potential of genome-wide chromatin accessibility analysis for elucidating mechanisms of pulmonary carcinogenesis and identifying novel targets for lung cancer therapy.

Single-cell transcriptome sequencing analysis reveals intra-tumor heterogeneity in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignant tumor of the digestive system that poses a significant threat to human life and health. It is crucial to thoroughly investigate the mechanisms of esophageal carcinogenesis and identify potential key molecular events in its carcinogenesis. Single-cell transcriptome sequencing is an emerging technology that has gained prominence in recent years for studying molecular mechanisms, which may help to further explore the underlying mechanisms of the ESCC tumor microenvironment in depth. The single-cell dataset was obtained from GSE160269 in the Gene Expression Omnibus database, including 60 tumor samples and four paracancer samples. The single-cell data underwent dimensional reduction clustering analysis to identify clusters and annotate expression profiles. Subcluster analysis was conducted for each cellular taxon. Copy number variation analysis of tumor cell subpopulations was performed to primarily identify malignant cells within them. A proposed chronological analysis was performed to obtain the process of cell differentiation. In addition, cell communication, transcription factor analysis, and tumor pathway analysis were also performed. Relevant risk models and key genes were established by univariate COX regression and LASSO analysis. The key genes obtained from the screen were subjected to appropriate silencing and cellular assays, including CCK-8, 5-ethynyl-2'-deoxyuridine, colony formation, and western blot. Single-cell analysis revealed that normal samples contained a large number of fibroblasts, T cells, and B cells, with fewer other cell types, whereas tumor samples exhibited a relatively balanced distribution of cell types. Subclassification analysis of immune cells, fibroblasts, endothelial cells, and epithelial cells revealed their specific spatial characteristics. The prognostic risk model, we constructed successfully, achieved accurate prognostic stratification for ESCC patients. The screened key gene, UPF3A, was found to be significantly associated with the development of ESCC by cellular assays. This process might be linked to the phosphorylation of ERK and P38. Single-cell transcriptome analysis successfully revealed the distribution of cell types and major expressed factors in ESCC patients, which could facilitate future in-depth studies on the therapeutic mechanisms of ESCC.

Factors of pathogenicity of bacteria of the genus Campylobacter and their role in carcinogenesis

Bacteria of the genus Campylobacter are a known common cause of gastroenteritis. However, in recent years, there has been more and more evidence in the scientific literature that these bacteria play an essential role in the development of malignant tumors of the human digestive tract. The aim is to systemize data on pathogenicity/virulence factors of Campylobacter spp. and its role in human carcinogenesis. The review provides a general description of the representatives of the genus in question, indicating their current taxonomic position and importance in human infectious pathology. A detailed description of known pathogenicity/virulence factors, including those with species-specific and strain-specific affiliation, is given. The indirect role of Campylobacter spp. in the mechanism of carcinogenesis has been shown due to the effect on individual links of the immune defense of the human body (e.g., on a pool of proinflammatory cytokines), which supports a chronic focus of inflammation and provokes further malignant cell degeneration. The direct effect of cytolethal expanding toxin (CDT) of Campylobacter as an essential link in carcinogenesis is considered. The facts of tumor-associated interaction of Campylobacter spp. with other bacteria of the human digestive tract are presented. Conclusion. The available data indicate a significant contribution of individual factors of Campylobacter spp. pathogenicity to the mechanisms of malignant neoplastic transformation of human digestive tract cells. CDT plays an essential role among other pathogenesis links.

De-Escalated Therapy and Early Treatment of Recurrences in HPV-Associated Head and Neck Cancer: The Potential for Biomarkers to Revolutionize Personalized Therapy.

Human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is the most common HPV-associated cancer in the United States, with a rapid increase in incidence over the last two decades. The burden of HPV+ HNSCC is likely to continue to rise, and given the long latency between infection and the development of HPV+ HNSCC, it is estimated that the effect of the HPV vaccine will not be reflected in HNSCC prevalence until 2060. Efforts have begun to decrease morbidity of standard therapies for this disease, and its improved characterization is being leveraged to identify and target molecular vulnerabilities. Companion biomarkers for new therapies will identify responsive tumors. A more basic understanding of two mechanisms of HPV carcinogenesis in the head and neck has identified subtypes of HPV+ HNSCC that correlate with different carcinogenic programs and that identify tumors with good or poor prognosis. Current development of biomarkers that reliably identify these two subtypes, as well as biomarkers that can detect recurrent disease at an earlier time, will have immediate clinical application.

Telomerase Reverse Transcriptase-Promoter Mutation in Young Patients with Bladder Tumors.

The TERT (Telomerase Reverse Transcriptase) gene promoter mutation is one of the most prevalent mutations in urothelial bladder tumors and this mutation is related to bladder tumor progression. Our purpose was to evaluate the presence of this mutation in a population of patients who were first diagnosed at age ≤ 40 years and to examine its relationship with tumor characteristics and progression. A molecular study was performed to detect the two most prevalent mutations in the TERT promoter (C228T and C250T). The study included 29 patients, with a mean follow-up of 152 months. There were no statistically significant differences in the clinical or tumor characteristics according to the presence or absence of the mutation. Although the mutation group showed poorer recurrence-free survival (RFS), there was no statistically significant difference and there was no difference in progression-free survival by group (p > 0.05). The pTERT mutations in bladder tumor cells occurred less frequently in younger patients than in older patients, a finding that could indicate different mechanisms of carcinogenesis. The trend towards lower RFS in patients with mutated pTERT needs to be confirmed by further studies, given the small number of patients included in these studies due to the low incidence of bladder tumors in this age group.

Hexavalent chromium exposure activates the non-canonical nuclear factor kappa B pathway to promote immune checkpoint protein programmed death-ligand 1 expression and lung carcinogenesis

Lung cancer is the leading cause of cancer-related death worldwide; however, the mechanism of lung carcinogenesis has not been clearly defined. Chronic exposure to hexavalent chromium [Cr(VI)], a common environmental and occupational pollutant, causes lung cancer, representing an important lung cancer etiology factor. The mechanism of how chronic Cr(VI) exposure causes lung cancer remains largely unknown. By using cell culture and mouse models and bioinformatics analyses of human lung cancer gene expression profiles, this study investigated the mechanism of Cr(VI)-induced lung carcinogenesis. A new mouse model of Cr(VI)-induced lung carcinogenesis was developed as evidenced by the findings showing that a 16-week Cr(VI) exposure (CaCrO4, 100 μg per mouse once per week) via oropharyngeal aspiration induced lung adenocarcinomas in male and female A/J mice, whereas none of the sham-exposed control mice had lung tumors. Mechanistic studies revealed that chronic Cr(VI) exposure activated the non-canonical NFκB pathway through the long non-coding RNA (lncRNA) ABHD11-AS1/deubiquitinase USP15-mediated tumor necrosis factor receptor-associated factor 3 (TRAF3) down-regulation. The non-canonical NFκB pathway activation increased the interleukin 6 (IL-6)/Janus kinase (Jak)/signal transducer and activator of transcription 3 (Stat3) signaling. The activation of the IL-6/Jak signaling axis by Cr(VI) exposure not only promoted inflammation but also stabilized the immune checkpoint molecule programmed death-ligand 1 (PD-L1) protein in the lungs, reducing T lymphocyte infiltration to the lungs. Given the well-recognized critical role of PD-L1 in inhibiting anti-tumor immunity, these findings suggested that the lncRNA ABHD11-AS1-mediated non-canonical NFκB pathway activation and PD-L1 up-regulation may play important roles in Cr(VI)-induced lung carcinogenesis.

Abstract 1474: Interleukin-8 and NF-κB mediated signaling axis: A potential driver for cadmium-induced prostate carcinogenesis

Abstract Cadmium (Cd) is a toxic heavy metal, ubiquitous in nature, and an industrial pollutant. Cadmium exposure can cause irreversible damage to lungs, liver and kidney including cancers. Alarmingly, abnormally high levels of cadmium are found in human prostate tissues. Studies on rodents have shown cadmium exposure causes liver, lung, and prostate cancers. The mechanism of carcinogenesis caused by Cd is multifactorial and specific organ carcinogenesis remains unclear. We and others have reported that the CXC-chemokine IL-8 drives cancer progression in prostate cancer (PCa). We tested a hypothesis that chronic cadmium-exposure induces upregulation of proinflammatory cytokines, such as IL-1β, IL-6, and IL-8, which individually or combined promote carcinogenesis and progression. The study used two non-transformed prostate epithelial cell lines (RWPE-1 and NHPrE1) to test whether continuous exposure to Cadmium chloride (CdCl2) perturbs cytokine expression pattern and selective silencing of elevated cytokines delays carcinogenesis and invasive potential. The CdCl2 exposed cells and culture conditioned media were analyzed regularly for changes in inflammatory milieu and for hallmarks of carcinogenesis. These studies measured changes in cell proliferation, production of cytokines (IL-8, IL-1β, IL-6, IFN-γ, TGF-β, and others), activation of Nuclear Factor-kB (NF-κB), and pro-tumorigenic factors, e.g., vascular endothelial growth factors (VEGF-A and B), cellular motility, and invasive potential, etc. Cells exposed to CdCl2 showed increased cell proliferation and clonogenic potential and specifically, increased expression of IL-8, it’s receptors (CXCR1 and CXCR2), IL-1β, and other cytokines &amp; related genes. While un-exposed RWPE-1 cells did not express IL-8, it was the first cytokine to increase when exposed to CdCl2, followed by activation of NF-κB (p65-rel), VEGF-A, &amp; B, CXCR1 and other markers. Gene silencing of IL-8 suppressed motility, invasion, and survival activity. These data supported that immediate-early IL-8 expression probably upregulates NF-κB mediated inflammatory signaling axis which is critical for Cd-induced carcinogenesis and may expose targets for countermeasures to prevent metal-induced toxicity &amp; carcinogenesis. Citation Format: Kunj Bihari Gupta, Rajendra K. Singh, Juliette R. Seremak, Vinata B. Lokeshwar, Bal L. Lokeshwar. Interleukin-8 and NF-κB mediated signaling axis: A potential driver for cadmium-induced prostate carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1474.

Abstract 5694: Elucidating areca nut-induced miRNA-mRNA regulatory networks in head and neck cancer pathogenesis

Abstract Areca nut has been considered a high-risk carcinogen for head and neck cancer (HNC) in Southeast Asia, while its molecular effects, especially on the miRNA regulatory roles, remain elusive. This study characterized miRNA-mRNA networks associated with areca nut-related HNC. We integratively analyzed the areca nut-induced mRNA profile and TCGA-HNSC gene set. A total of 2575 genes were identified, with 1971 upregulated and 604 downregulated in cancers. The KEGG pathway analysis revealed that these genes were enriched in the cellular functions related to motility and stress response. Experimental studies confirmed that arecoline promoted cell migration, invasion, and chemo-radioresistance. We further cross-analyzed the miRNAs induced by areca nut and dysregulated in TCGA-HNSC data and defined 71 molecules affected, with 35 upregulation and 36 downregulation. Using the multimiR tool to map potential mRNA-miRNA interactions, we uncovered that these miRNAs were connected to 2173 genes. These molecules participated in several oncogenic mechanisms, such as ErbB and PI3K-Akt signaling, cell adhesion, and DNA damage response. We endeavored to establish miRNA-mRNA interaction networks with the functions of cellular motility and stress response via the Cytoscape analytical method. Our data revealed nexus comprising 41 miRNAs with 83 mRNAs, and 38 miRNAs with 66 mRNAs, respectively, co-regulate these two malignant functions. A key miRNA, miR-410-3p, downregulated in HNC and decreased following areca nut treatment, was studied. Ectopic expression of miR-410-3p attenuated areca nut-induced cell invasion and exerted modulatory effects on its target oncogenes, CRK. Thus, our study delineates a comprehensive view of the miRNA-mRNA interplay altered by areca nut, illustrating a sophisticated mechanism of carcinogenesis and suggesting new avenues for diagnostic and therapeutic strategies in HNC. Citation Format: Hung-Han Huang, Guo-Rung You, Kai-Hsin Lin, Yin-Ju Chen, Ann-Joy Cheng. Elucidating areca nut-induced miRNA-mRNA regulatory networks in head and neck cancer pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5694.

Natural Killer Cell Dysfunction in Premenopausal BRCA1 Mutation Carriers: A Potential Mechanism for Ovarian Carcinogenesis.

Tissue-specificity for fimbrial fallopian tube ovarian carcinogenesis remains largely unknown in BRCA1 mutation carriers. We aimed to assess the cell autonomous and cell-nonautonomous implications of a germline BRCA1 mutation in the context of cancer immunosurveillance of CD3- CD56+ natural killer (NK) cells. Premenopausal BRCA1 mutation carriers versus age-matched non-carriers were compared. Daily urinary 5β-pregnanediol levels were used to determine progesterone metabolomics across an ovarian cycle. Using peripherally acquired NK cells the cell-mediated cytotoxicity of tumor targets (OVCAR-3, K-562) was determined using live cellular impedance (xCELLigence®) and multicolor flow cytometry. Hypoxia-inducible factor 1-alpha (HIF-1α) immunohistochemistry of cancer-free fallopian tube specimens allowed a comparison of proximal versus distal portions. Utilizing these findings the role of environmental factors relevant to the fimbrial fallopian tube (progesterone, hypoxia) on NK cell functional activity were studied in an ovarian phase-specific manner. BRCA1 mutation carriers demonstrate a differential progesterone metabolome with a phase-specific reduction of peripheral NK cell functional activity. Progesterone exposure further impairs NK cell-mediated cytotoxicity in a dose-dependent manner, which is reversed with the addition of mifepristone (1.25 µM). The fimbrial fallopian tube demonstrated significantly higher HIF-1α staining, particularly in BRCA1 mutation carriers, reflecting a site-specific 'hypoxic niche'. Exposure to hypoxic conditions (1% O2) can further impair tumor cytotoxicity in high-risk carriers. Phase-specific differential NK cell activity in BRCA1 mutation carriers, either systemically or locally, may favor site-specific pre-invasive carcinogenesis. These cumulative effects across a reproductive lifecycle in high-risk carriers can have a detrimental effect further supporting epidemiological evidence for ovulation inhibition.

Prognostic and predictive role of immune microenvironment in colorectal cancer.

Colorectal cancer (CRC) represents a molecularly heterogeneous disease and one of the most frequent causes of cancer-related death worldwide. The traditional classification of CRC is based on pathomorphological and molecular characteristics of tumor cells (mucinous, ring-cell carcinomas, etc.), analysis of mechanisms of carcinogenesis involved (chromosomal instability, microsatellite instability, CpG island methylator phenotype) and mutational statuses of commonly altered genes (KRAS, NRAS, BRAF, APC, etc.), as well as expression signatures (CMS 1-4). It is also suggested that the tumor microenvironment is a key player in tumor progression and metastasis in CRC. According to the latest data, the immune microenvironment can also be predictive of the response to immune checkpoint inhibitors. In this review, we highlight how the immune environment influences CRC prognosis and sensitivity to systemic therapy.

Transcriptomic analysis reveals particulate hexavalent chromium regulates key inflammatory pathways in human lung fibroblasts as a possible mechanism of carcinogenesis

Hexavalent chromium [Cr(VI)] is considered a major environmental health concern and lung carcinogen. However, the exact mechanism by which Cr(VI) causes lung cancer in humans remains unclear. Since several reports have demonstrated a role for inflammation in Cr(VI) toxicity, the present study aimed to apply transcriptomics to examine the global mRNA expression in human lung fibroblasts after acute (24 h) or prolonged (72 and 120 h) exposure to 0.1, 0.2 and 0.3 μg/cm2 zinc chromate, with a particular emphasis on inflammatory pathways. The results showed Cr(VI) affected the expression of multiple genes and these effects varied according to Cr(VI) concentration and exposure time. Bioinformatic analysis of RNA-Seq data based on the Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and MetaCore databases revealed multiple inflammatory pathways were affected by Cr(VI) treatment. qRT-PCR data corroborated RNA-Seq findings. This study showed for the first time that Cr(VI) regulates key inflammatory pathways in human lung fibroblasts, providing novel insights into the mechanisms by which Cr(VI) causes lung cancer.

Endogenous Microbacteria Can Contribute to Ovarian Carcinogenesis by Reducing Iron Concentration in Cysts: A Pilot Study.

Among epithelial ovarian cancer, clear cell carcinoma is common for chemo-resistance and high mortality. This cancer arises from benign ovarian endometrioma (OE), which is a high oxidative stress environment due to the cystic retention of menstrual blood produced during menstruation and the "iron" liberated from the cyst. There has been strong evidence that the iron concentration in OE decreases when they become cancerous. A decrease in iron concentration is a necessary condition for the formation of cancer. However, the mechanism of carcinogenesis is not yet clear. In the current study, the bacterial flora in endometriosis-associated ovarian cancer (EAOC), including clear cell carcinoma, and their origin, OE, were investigated using next-generation sequencing. The Shannon index in the genus level was significantly higher in EAOC than in OE fluids. Among several bacterial flora that were more abundant than benign chocolate cysts, a number of bacterial species that correlate very well with iron concentrations in the cysts were identified. These bacterial species are likely to be associated with decreased iron concentrations and cancer development.

Content-aware Nakagami morphing for incremental brain MRI

Within the carcinogenesis mechanism, from the initiation of the very first tumor cell to the preneoplastic and neoplastic cancer cell groups, cancer cells omnidirectionally and unpredictably proliferate in three-dimensional (3D) space during the promotion and progression steps. Whole tumors areas, consisting of edema, necrosis, enhancing and non-enhancing tumor subareas, could easily be identified by the typical sequences of magnetic resonance imaging (MRI), mostly by FLAIR, the fluid attenuated inversion recovery sequence. Depending on the increment value of the scanner, not every scan could be contiguous though, which might create some gaps between the slices and cause some crucial loss of information. Shape-based morphing by erosion and dilation operations might be inadequate when the source or target lesions are not found on the MRI slices, which might emerge due to unpredictable shape of tumors. Furthermore, the real trajectories and genuine shapes of the tumors in spatial view might not be seen in the planar MRI slices due to approximations during the voxel-to-pixel transformations executed in MRI devices. Therefore, we propose a novel content-aware morphing procedure to generate imaginary slices by m-parametric Nakagami imaging. The mathematical and parametric design in our framework not only leads to precise segmentation of the whole tumors according to the ground truth images; but also, to realistic morphing, based on the content of tumor footprints in MRI slices. For testing purposes, a total number of 5133 morphs are created using 1831 genuine images containing at least one lesion taken from the Brats 2012 dataset. Given the average dice score coefficients (DSC), we obtained an average of 88.44% DSC with our morphing framework outperforming the conventional dilation-based morphing result which is 83.25%. Besides being a novel morphing methodology, the outcomes of this research could also be very beneficial in smoother 3D reconstruction and more realistic volumetric calculations of lesions to help the experts working on assessment of lesions.

Human Endogenous Retroviruses in Breast Cancer: Altered Expression Pattern Implicates Divergent Roles in Carcinogenesis

Introduction: Breast cancer is the most common cancer and the leading cause of cancer death in women. Recent research indicates that human endogenous retroviruses (HERVs) may be linked to carcinogenesis, but the data remain controversial. Methods: HERVs’ expression was evaluated to show the differences between breast cancer and control samples, and their associations with clinicopathological parameters. Gene expression of 12 HERVs, i.e., ERVE-4, ERVW-1, ERVFRD-1, ERVV-1, ERV3-1, ERVH48-1, ERVMER34-1, ERVK-7, ERVK13-1, ERVK11-1, ERVK3-1, and HCP5, was analyzed by qPCR and/or TCGA datasets for breast cancer. Results: ERV3-1, ERVFRD-1, ERVH48-1, and ERVW-1 provided data to support their tumor suppressor roles in breast cancer. ERV3-1 evinced the best performing diagnostic data based on qPCR, i.e., AUC: 0.819 (p < 0.0001), sensitivity of 72.41%, and specificity of 89.66%. Lower levels of ERV3-1 were noted in advanced stage and higher grades, and significant negative association was found in relation to Ki-67 levels. Oncogenic roles may be inferred for ERVK13-1, ERVV-1, and ERVMER34-1. Data for ERVK-7, ERVE-4, ERVK11-1, and HCP5 remain inconclusive. Conclusion: Differential HERV expression may be applicable to evaluate novel biomarkers for breast cancer. However, more research is needed to reveal their real clinical impact, the biological roles, and regulatory mechanisms in breast carcinogenesis.

Genetic susceptibility to prostate cancer in Taiwan: A genome-wide association study.

We conducted the first genome-wide association study (GWAS) of prostate cancer (PCa) in Taiwan with 1844 cases and 80,709 controls. Thirteen independent single-nucleotide polymorphisms (SNPs) reached genome-wide significance (p < 5 × 10-8 ). Among these, three were distinct from previously identified loci: rs76072851 in CORO2B gene (15q23), odds ratio (OR) = 1.54, 95% confidence interval (CI), 1.36-1.76, p = 5.30 × 10-11 ; rs7837051, near two long noncoding RNA (lncRNA) genes, PRNCR1 and PCAT2 (8q24.21), OR = 1.41 (95% CI, 1.31-1.51), p = 8.77 × 10-21 ; and rs56339048, near an lncRNA gene, CASC8 (8q24.21), OR = 1.25 (95% CI, 1.16-1.35), p = 2.14 × 10-8 . We refined the lead SNPs for two previously identified SNPs in Taiwanese: rs13255059 (near CASC8), p = 9.02 × 10-43 , and rs1456315 (inside PRNCR1), p = 4.33 × 10-42 . We confirmed 35 out of 49 GWAS-identified East Asian PCa susceptibility SNPs. In addition, we identified twoSNPs more specific to Taiwanese than East Asians: rs34295433 in LAMC1 (1q25.3) and rs6853490 in PDLIM5 (4q22.3). A weighted genetic risk score (GRS) was developed using the 40 validated SNPs and the area under the receiver-operating characteristiccurvefor the GRS to predict PCa was 0.67 (95% CI, 0.63-0.71). These identified SNPs provide valuable insights into the molecular mechanisms of prostate carcinogenesis in Taiwan and underscore the significant role of genetic susceptibility in regional differences in PCa incidence.