Role of DNA mismatch repair genes in lung and head and neck cancer (Review)

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Weakly Acidic Bile Is a Risk Factor for Hypopharyngeal Carcinogenesis Evidenced by DNA Damage, Antiapoptotic Function, and Premalignant Dysplastic Lesions In Vivo

Background: There is recent in vivo discovery documenting the carcinogenic effect of bile at strongly acidic pH 3.0 in hypopharynx, while in vitro data demonstrate that weakly acidic bile (pH 5.5) has a similar oncogenic effect. Because esophageal refluxate often occurs at pH > 4.0, here we aim to determine whether weakly acidic bile is also carcinogenic in vivo. Methods: Using 32 wild-type mice C57B16J, we performed topical application of conjugated primary bile acids with or without unconjugated secondary bile acid, deoxycholic acid (DCA), at pH 5.5 and controls, to hypopharyngeal mucosa (HM) twice per day, for 15 weeks. Results: Chronic exposure of HM to weakly acidic bile, promotes premalignant lesions with microinvasion, preceded by significant DNA/RNA oxidative damage, γH2AX (double strand breaks), NF-κB and p53 expression, overexpression of Bcl-2, and elevated Tnf and Il6 mRNAs, compared to controls. Weakly acidic bile, without DCA, upregulates the “oncomirs”, miR-21 and miR-155. The presence of DCA promotes Egfr, Wnt5a, and Rela overexpression, and a significant downregulation of “tumor suppressor” miR-451a. Conclusion: Weakly acidic pH increases the risk of bile-related hypopharyngeal neoplasia. The oncogenic properties of biliary esophageal reflux on the epithelium of the upper aerodigestive tract may not be fully modified when antacid therapy is applied. We believe that due to bile content, alternative therapeutic strategies using specific inhibitors of relevant molecular pathways or receptors may be considered in patients with refractory GERD

In Vivo Short-Term Topical Application of BAY 11-7082 Prevents the Acidic Bile–Induced mRNA and miRNA Oncogenic Phenotypes in Exposed Murine Hypopharyngeal Mucosa

PURPOSE: Bile-containing gastroesophageal reflux may promote cancer at extraesophageal sites. Acidic bile can accelerate NF-κB activation and molecular events, linked to premalignant changes in murine hypopharyngeal mucosa (HM). We hypothesize that short-term in vivo topical application of NF-κB inhibitor BAY 11-7082 can prevent acidic bile–induced early preneoplastic molecular events, suggesting its potential role in disease prevention. EXPERIMENTAL DESIGN: We topically exposed HM (C57Bl/6j wild-type) to a mixture of bile acids at pH 3.0 with and without BAY 11-7082 3 times/day for 7 days. We used immunofluorescence, Western blotting, immunohistochemistry, quantitative polymerase chain reaction, and polymerase chain reaction microarrays to identify NF-κB activation and its associated oncogenic mRNA and miRNA phenotypes, in murine hypopharyngeal cells in vitro and in murine HM in vivo. RESULTS: Short-term exposure of HM to acidic bile is a potent stimulus accelerating the expression of NF-κB signaling (70 out of 84 genes) and oncogenic molecules. Topical application of BAY 11-7082 sufficiently blocks the effect of acidic bile. BAY 11-7082 eliminates NF-κB activation in regenerating basal cells of acidic bile–treated HM and prevents overexpression of molecules central to head and neck cancer, including bcl-2, STAT3, EGFR, TNF-α, and WNT5A. NF-κB inhibitor reverses the upregulated “oncomirs” miR-155 and miR-192 and the downregulated “tumor suppressors” miR-451a and miR-375 phenotypes in HM affected by acidic bile. CONCLUSION: There is novel evidence that acidic bile–induced NF-κB–related oncogenic mRNA and miRNA phenotypes are generated after short-term 7-day mucosal exposure and that topical mucosal application of BAY 11-7082 can prevent the acidic bile–induced molecular alterations associated with unregulated cell growth and proliferation of hypopharyngeal cells

The Effect of Tobacco Smoke <i>N</i>-Nitrosamines, NNK and NDEA, and Nicotine, on DNA Mismatch Repair Mechanism and miRNA Markers, in Hypopharyngeal Squamous Cell Carcinoma: An In Vivo Model and Clinical Evidence

Deregulation of the DNA mismatch repair (MMR) mechanism has been linked to poor prognosis of upper aerodigestive tract cancers. Our recent in vitro data have provided evidence of crosstalk between deregulated miRNAs and MMR genes, caused by tobacco smoke (TS) N-Nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in hypopharyngeal cells. Here, we explored whether chronic exposure to TS components can affect MMR mechanism and miRNA profiles in hypopharyngeal mucosa. Using a mouse model (C57Bl/6J wild type) of in vivo 14-week exposure to NNK (0.2 mmol/L) and N-Nitrosodiethylamine (NDEA; 0.004 mmol/L), with or without nicotine (0.02 μmol/L), we provide direct evidence that TS components can promote dysplasia, significant downregulation of Msh2 and Mlh1 genes and deregulation of miR-21, miR-155, miR-34a, and miR-451a. By analyzing eight human specimens from tobacco smokers and eight controls, we provide clinical evidence of a significant reduction in hMSH2 and hMLH1 mRNAs in hypopharyngeal squamous cell carcinoma (HSCC). In summary, deregulation of the MMR mechanism and miRNAs is caused by chronic exposure to TS-related N-Nitrosamines, with or without nicotine, in the early stages of upper aerodigestive tract carcinogenesis, and can also be detected in human HSCC. Thus, we encourage future studies to further elucidate a possible in vivo dose-dependent effect of individual or combined N-Nitrosamines, NNK and/or NDEA, and nicotine, on the MMR mechanism and their clinical testing to elaborate prognosis and risk assessment

The Progressive Mutagenic Effects of Acidic Bile Refluxate in Hypopharyngeal Squamous Cell Carcinogenesis: New Insights

Cancers of the laryngopharynx represent the most devastating of the head and neck malignancies and additional risk factors are now epidemiologically linked to this disease. Using an in vivo model (Mus musculus C57Bl/6J), we provide novel evidence that acidic bile (pH 3.0) progressively promotes invasive cancer in the hypopharynx. Malignant lesions are characterized by increasing: (i) oxidative DNA-damage, (ii) &gamma;H2AX expression, (iii) NF-&kappa;B activation, and (iv) p53 expression. Histopathological changes observed in murine hypopharyngeal mucosa exposed to acidic bile were preceded by the overexpression of Tnf, Il6, Bcl2, Egfr, Rela, Stat3, and the deregulation of miR-21, miR-155, miR-192, miR-34a, miR-375, and miR-451a. This is the first study to document that acidic bile is carcinogenic in the upper aerodigestive tract. We showed that oxidative DNA-damage produced by acidic bile in combination with NF-&kappa;B-related anti-apoptotic deregulation further supports the underlying two-hit hypothesized mechanism. Just as importantly, we reproduced the role of several biomarkers of progression that served as valuable indicators of early neoplasia in our experimental model. These findings provide a sound basis for proposing translational studies in humans by exposing new opportunities for early detection and prevention

Pepsin Promotes Activation of Epidermal Growth Factor Receptor and Downstream Oncogenic Pathways, at Slightly Acidic and Neutral pH, in Exposed Hypopharyngeal Cells

Pepsin refluxate is considered a risk factor for laryngopharyngeal carcinogenesis. Non-acidic pepsin was previously linked to an inflammatory and tumorigenic effect on laryngopharyngeal cells in vitro. Yet there is no clear evidence of the pepsin-effect on a specific oncogenic pathway and the importance of pH in this process. We hypothesized that less acidic pepsin triggers the activation of a specific oncogenic factor and related-signalling pathway. To explore the pepsin-effect in vitro, we performed intermittent exposure of 15 min, once per day, for a 5-day period, of human hypopharyngeal primary cells (HCs) to pepsin (1 mg/mL), at a weakly acidic pH of 5.0, a slightly acidic pH of 6.0, and a neutral pH of 7.0. We have documented that the extracellular environment at pH 6.0, and particularly pH 7.0, vs. pH 5.0, promotes the pepsin-effect on HCs, causing increased internalized pepsin and cell viability, a pronounced activation of EGFR accompanied by NF-κB and STAT3 activation, and a significant upregulation of EGFR, AKT1, mTOR, IL1β, TNF-α, RELA(p65), BCL-2, IL6 and STAT3. We herein provide new evidence of the pepsin-effect on oncogenic EGFR activation and its related-signaling pathway at neutral and slightly acidic pH in HCs, opening a window to further explore the prevention and therapeutic approach of laryngopharyngeal reflux disease

Novel non‐invasive molecular signatures for oral cavity cancer, by whole transcriptome and small non‐coding RNA sequencing analyses: Predicted association with PI3K/AKT/mTOR pathway

Abstract Introduction Identification of molecular biomarkers in the saliva and serum of oral cavity cancer patients represents a first step in the development of essential and efficient clinical tools for early detection and post‐treatment monitoring. We hypothesized that molecular analyses of paired saliva and serum samples from an individual would likely yield better results than analyses of either serum or saliva alone. Materials and Methods We performed whole‐transcriptome and small non‐coding RNA sequencing analyses on 32 samples of saliva and serum collected from the same patients with oral squamous cell carcinoma (OSCC) and healthy controls (HC). Results We identified 12 novel saliva and serum miRNAs and a panel of unique miRNA and mRNA signatures, significantly differentially expressed in OSCC patients relative to HC (log2 fold change: 2.6–26.8; DE: 0.02–0.000001). We utilized a combined panel of the 10 top‐deregulated miRNAs and mRNAs and evaluated their putative diagnostic potential (>87% sensitivity; 100% specificity), recommending seven of them for further validation. We also identified unique saliva and serum miRNAs associated with OSCC and smoking history (OSCC smokers vs. never‐smokers or HC: log2 fold change: 22–23; DE: 0.00003–0.000000001). Functional and pathway analyses indicated interactions between the discovered OSCC‐related non‐invasive miRNAs and mRNAs and their targets, through PI3K/AKT/mTOR signaling. Conclusion Our data support our hypothesis that using paired saliva and serum from the same individuals and deep sequencing analyses can provide unique combined mRNA and miRNA signatures associated with canonical pathways that may have a diagnostic advantage relative to saliva or serum alone and may be useful for clinical testing. We believe this data will contribute to effective preventive care by post‐treatment monitoring of patients, as well as suggesting potential targets for therapeutic approaches

Resource demands in telco data centers

Abstract Telecommunication (telco) cloud services have emerged as crucial components in the modern digital landscape, offering extensive capabilities for data management, connectivity, and service provision. However, research on telco clouds lacks comprehensive data on the characteristics of production workloads, which is fundamental for designing effective resource management systems, such as workload schedulers and power management mechanisms. To this end, this paper addresses a substantial gap in telco cloud research by creating a comprehensive dataset that encapsulates crucial information regarding the pattern demands of applications within telco data centers. In addition, the proposed dataset contributes to the field by enabling strategic network configuration, optimizing data center sizing, facilitating proactive decision-making for data center operations, but its applicability extends beyond these cases. These examples illustrate the practical value of the dataset in enhancing efficiency, reducing operational costs, and ensuring optimal performance within telecommunication data centers