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Transcriptome profiling in oral cavity and esophagus tissues from (S)-N'-nitrosonornicotine-treated rats reveals candidate genes involved in human oral cavity and esophageal carcinogenesis.

ABSTRACT: Recently, we have shown that (S)-N'-Nitrosonornicotine [(S)-NNN], the major form of NNN in tobacco products, is a potent oral cavity and esophageal carcinogen in rats. To determine the early molecular alterations induced by (S)-NNN in the oral and esophageal mucosa, we administered the carcinogen to rats in the drinking water for 10?wk and global gene expression alterations were analyzed by RNA sequencing. At a false discovery rate P-value?

SUBMITTER: Khammanivong A

PROVIDER: S-EPMC5142294 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Transcriptome profiling in oral cavity and esophagus tissues from (S)-N'-nitrosonornicotine-treated rats reveals candidate genes involved in human oral cavity and esophageal carcinogenesis.

Khammanivong Ali A Anandharaj Arunkumar A Qian Xuemin X Song Jung Min JM Upadhyaya Pramod P Balbo Silvia S Bandyopadhyay Dipankar D Dickerson Erin B EB Hecht Stephen S SS Kassie Fekadu F

Molecular carcinogenesis 20160119 12

Recently, we have shown that (S)-N'-Nitrosonornicotine [(S)-NNN], the major form of NNN in tobacco products, is a potent oral cavity and esophageal carcinogen in rats. To determine the early molecular alterations induced by (S)-NNN in the oral and esophageal mucosa, we administered the carcinogen to rats in the drinking water for 10 wk and global gene expression alterations were analyzed by RNA sequencing. At a false discovery rate P-value < 0.05 and fold-change ≥2, we found alterations in the l ...[more]

PMID: 26785143

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Project description:N'-Nitrosonornicotine (NNN) is one of the most important strong carcinogens in tobacco products and is believed to play a significant role in the induction of esophageal cancer in smokers and oral cavity cancer in snuff dippers. NNN is metabolically activated through cytochrome P450-catalyzed alpha-hydroxylation. 2'-Hydroxylation produces a reactive intermediate 4-(3-pyridyl)-4-oxobutanediazohydroxide (7), which alkylates DNA to form pyridyloxobutyl (POB)-DNA adducts. DNA pyridyloxobutylation from NNN treatment, as measured by released 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB, 8), has been observed in vitro and in vivo. In the present study, we have used liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) to analyze specific POB-DNA adducts in the nasal olfactory, nasal respiratory, and oral mucosa of F344 rats treated chronically with (R)-NNN or (S)-NNN in the drinking water (10 ppm, 1-20 weeks). Adduct levels in the nasal respiratory mucosa exceeded those in the nasal olfactory and oral mucosa. (R)-NNN treatment generated 2-4 times more adducts in the nasal olfactory and respiratory mucosa than did (S)-NNN at most time points. O(2)-[4-(3-Pyridyl)-4-oxobut-1-yl]thymidine (O(2)-POB-dThd, 11) predominated in the nasal olfactory and respiratory mucosa, followed by 7-[4-(3-pyridyl)-4-oxobut-1-yl]guanine (7-POB-Gua, 14). Levels of O(2)-[4-(3-pyridyl)-4-oxobut-1-yl]cytosine (O(2)-POB-Cyt, 13) and O(6)-[4-(3-pyridyl)-4-oxobut-1-yl]-2'-deoxyguanosine (O(6)-POB-dGuo, 12) were significantly lower. In the oral mucosa, the opposite stereoselectivity was observed, with (S)-NNN treatment producing 3-5 times more POB-DNA adducts than did (R)-NNN. O(2)-POB-dThd and 7-POB-dGuo were the two major adducts, and their levels were similar. Overall, POB-DNA adduct formation in the nasal olfactory and nasal respiratory mucosa was similar to that previously observed in the lung, whereas in the oral mucosa, the trend resembled that in the esophagus. These results indicate that different mechanisms are involved in NNN metabolism and tumorigenesis in rat nasal and oral tissues. NNN enters the nasal mucosa through the circulation, and tissue-specific metabolism is important, while in the oral mucosa, direct exposure and local activation both play significant roles. Our results also support the potential importance of NNN as an oral carcinogen in people who use smokeless tobacco products.

Project description:Background & aimsObesity is associated with neoplasia, possibly via insulin-mediated cell pathways that affect cell proliferation. Metformin has been proposed to protect against obesity-associated cancers by decreasing serum insulin. We conducted a randomized, double-blind, placebo-controlled, phase 2 study of patients with Barrett's esophagus (BE) to assess the effect of metformin on phosphorylated S6 kinase (pS6K1), a biomarker of insulin pathway activation.MethodsSeventy-four subjects with BE (mean age, 58.7 years; 58 men [78%; 52 with BE >2 cm [70%]) were recruited through 8 participating organizations of the Cancer Prevention Network. Participants were randomly assigned to groups given metformin daily (increasing to 2000 mg/day by week 4, n = 38) or placebo (n = 36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 via esophagogastroduodenoscopy. We calculated and compared percent changes in median levels of pS6K1 between subjects given metformin vs placebo as the primary end point.ResultsThe percent change in median level of pS6K1 did not differ significantly between groups (1.4% among subjects given metformin vs -14.7% among subjects given placebo; 1-sided P = .80). Metformin was associated with an almost significant reduction in serum levels of insulin (median -4.7% among subjects given metformin vs 23.6% increase among those given placebo, P = .08) as well as in homeostatic model assessments of insulin resistance (median -7.2% among subjects given metformin vs 38% increase among those given placebo, P = .06). Metformin had no effects on cell proliferation (on the basis of assays for KI67) or apoptosis (on the basis of levels of caspase 3).ConclusionsIn a chemoprevention trial of patients with BE, daily administration of metformin for 12 weeks, compared with placebo, did not cause major reductions in esophageal levels of pS6K1. Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues. These findings do not support metformin as a chemopreventive agent for BE-associated carcinogenesis. ClinicalTrials.gov number, NCT01447927.

Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is among the most prevalent causes of cancer-related death in adults. Tumor microenvironment (TME) has been associated with therapeutic failure and lethal outcomes for patients. However, published reports on the heterogeneity and TME in ESCC are scanty.MethodsFive tumor samples and five corresponding non-malignant samples were subjected to scRNA-seq analysis. Bulk RNA sequencing data were retrieved in publicly available databases.FindingsFrom the scRNA-seq data, a total of 128,688 cells were enrolled for subsequent analyses. Gene expression and CNV status exhibited high heterogeneity of tumor cells. We further identified a list of tumor-specific genes and four malignant signatures, which are potential new markers for ESCC. Metabolic analysis revealed that energy supply-related pathways are pivotal in cancer metabolic reprogramming. Moreover, significant differences were found in stromal and immune cells between the esophagus normal and tumor tissues, which promoted carcinogenesis at both cellular and molecular levels in ESCC. Immune checkpoints, regarded as potential targets for immunotherapy in ESCC were significantly highly expressed in ESCC, including LAG3 and HAVCR2. Eventually, we constructed a cell-to-cell communication atlas based on cancer cells and immune cells and performed the flow cytometry, qRT-PCR, immunofluorescence, and immunohistochemistry analyses to validate the results.InterpretationThis study demonstrates a widespread reprogramming across multiple cellular elements within the TME in ESCC, particularly in transcriptional states, cellular functions, and cell-to-cell interactions. The findings offer an insight into the exploration of TME and heterogeneity in the ESCC and provide new therapeutic targets for its clinical management in the future.FundingThe work was supported by the Shanghai Pujiang Program (2020PJD009) and Research Development Fund of Zhongshan Hospital, Fudan University (2019ZSFZ002 and 2019ZSFZ19).

Dataset Information

Transcriptome profiling in oral cavity and esophagus tissues from (S)-N'-nitrosonornicotine-treated rats reveals candidate genes involved in human oral cavity and esophageal carcinogenesis.

Publications

Transcriptome profiling in oral cavity and esophagus tissues from (S)-N'-nitrosonornicotine-treated rats reveals candidate genes involved in human oral cavity and esophageal carcinogenesis.

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