Molecular Pathways for Nasopharyngeal Carcinoma focused on Acetaldehyde, Nitrosamines and Nicotine Exposures (original) (raw)
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Molecular Carcinogenesis, 2016
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 weeks 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 level of 39 genes in the oral cavity and 69 genes in the esophagus. Validation of RNA sequencing results by qRT-PCR assays revealed a high cross-platform concordance. The most significant impact of exposure to (S)-NNN was alteration of genes involved in immune regulation (Aire, Ctla4 and CD80), inflammation (Ephx2 and Inpp5d) and cancer (Cdkn2a, Dhh, Fetub B, Inpp5d, Ly6E, Nr1d1 and Wnt6). Consistent with the findings in rat tissues, most of the genes were deregulated, albeit to different degrees, in immortalized oral keratinocytes treated with (S)-NNN and in non-treated premalignant oral cells and malignant oral and head and neck squamous cells. Furthermore, interrogation of TCGA data sets showed that genes deregulated by (S)-NNN in rat tissues (Fetub, Ly6e, Nr1d1, Cacna1c, Cd80 and Dgkg) are also altered in esophageal and head and neck tumors. Overall, our findings provide novel insights into early molecular changes induced by (S)-NNN and therefore could contribute to the development of biomarkers for the early detection and prevention of (S)-NNN-associated oral and esophageal cancers.
Relationship Between Cigarette Smoking and Nasopharyngeal Carcinoma
INTERNATIONAL JOURNAL OF NASOPHARYNGEAL CARCINOMA (IJNPC), 2019
Introduciton Since then the pathogenesis of NPC has been intensively studied, specifically aimed at geography and racial variation. In recent years many environmental and biological factors have shown a risky relationship to the occurrence of NPC and the latest research results indicate the role of genetic and viral factors in the development of this disease Objectives Etiology of nasopharyngeal cancer (NPC) is multifactorial, and many of these factors overlap where one factor may occur together with other elements as a cause. Cigarette smoking is thought to also play a role in the development of NPC. Methods The study design was in case of control with an analytical approach during February-October 2007. To find out the relationship between Cigarette smoking NPC, a case-control study was conducted, with a sample of 96 patients with NPC as case and 96 people as a control. Case group and control samples were taken from RSUP H. Adam Malik Medan and RSU Dr. Pirngadi Medan. Results ...
2008
Polymorphisms in nitrosamine metabolism, DNA repair, and immune response genes have been associated with nasopharyngeal carcinoma (NPC). Studies have suggested chromosomal regions involved in NPC. To shed light on NPC etiology, we evaluated host gene expression patterns in 31 NPC and 10 normal nasopharyngeal tissue specimens using the Affymetrix Human Genome U133 Plus 2.0 Array. We focused on genes in five a priori biological pathways and chromosomal locations. Rates of differential expression within these prespecified lists and overall were tested using a bootstrap method. Differential expression was observed for 7.6 % of probe sets overall. Elevations in rate of differential expression were observed within the DNA repair (13.7%; P = 0.01) and nitrosamine metabolism (17.5%; P = 0.04) pathways. Differentially expressed probe sets within the DNA repair pathway were consistently overexpressed (93%), with strong effects observed for PRKDC, PCNA, and CHEK1.
International journal of oncology, 2011
Exposure to tobacco carcinogens is causally associated with head and neck squamous cell carcinoma (HNSCC), but the underlying molecular mechanisms remain unclear. Here, we reported that AKT is activated at a higher frequency in both HNSCC tumors and the adjacent mucosa from HNSCC patients who are smokers than those from HNSCC patients who are non-smokers. Adding physiologically relevant concentrations of 4-(methylnitrosamino)-1-(3-pyridyl)-1-1butanone (NNK), a major tobacco carcinogen, to normal head and neck epithelial cells and HNSCC cell lines, rapidly and constitutively activated AKT through phosphorylation in a dose- and time-dependent manner. AKT phosphorylation was associated with activation of downstream signaling mediators BAD, MDM2, GSK-3β, mTOR. These alterations correlated with increased proliferation and decreased etoposide-induced apoptosis in NNK-exposed cells. Finally, NNK exposure to mouse head and neck epithelia resulted in epithelial hyperproliferation and reduced...
Proceedings of the National Academy of Sciences of the United States of America, 2018
Tobacco smoke (TS) contains numerous cancer-causing agents, with polycyclic aromatic hydrocarbons (PAHs) and nitrosamines being most frequently cited as the major TS human cancer agents. Many lines of evidence seriously question this conclusion. To resolve this issue, we determined DNA adducts induced by the three major TS carcinogens: benzo()pyrene (BP), 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanoe (NNK), and aldehydes in humans and mice. In mice, TS induces abundant aldehyde-induced γ-hydroxy-propano-deoxyguanosine (γ-OH-PdG) and α-methyl-γ-OH-PdG adducts in the lung and bladder, but not in the heart and liver. TS does not induce the BP- and NNK-DNA adducts in lung, heart, liver, and bladder. TS also reduces DNA repair activity and the abundance of repair proteins, XPC and OGG1/2, in lung tissues. These TS effects were greatly reduced by diet with polyphenols. We found that γ-OH-PdG and α-methyl-γ-OH-PdG are the major adducts formed in tobacco smokers' buccal cells as well as...
Inhibition of nitric oxide-induced apoptosis by nicotine in oral epithelial cells
Molecular and Cellular Biochemistry, 2007
Development of oral cancer is clearly linked to the usage of smokeless tobacco. The molecular mechanisms involved in this process are however not well understood. Toward this goal, we investigated the effect of smokeless tobacco exposure on apoptosis of oral epithelial cells. Exposure of oral epithelial cells to smokeless tobacco extract (STE) induces apoptosis in a dose-dependent manner, until a threshold level of nicotine is achieved upon which apoptosis is inhibited. 1 mM of nicotine is able to inhibit apoptosis significantly induced by STE in these oral cells. Exposure of cells to nicotine alone has no effect on apoptosis, but nicotine inhibits apoptosis induced by other agents present in STE. In this study we show that, the antiapoptotic action of nicotine is specifically associated with down-regulation of nitric oxide (NO) production. Using specific inducers of NO, we have demonstrated that inhibition of apoptosis by nicotine is through down-regulation of NO production. Further, we observed that nicotine clearly acts as a sink of NO radicals, shown using peroxynitrite generator (SIN-1) in conjunction or absence of radical scavengers. Nicotine thus causes most damage in transformed epithelial cells as depicted by accumulation of nitrotyrosine in a 3-NT ELISA assay. Inhibition of apoptosis is a hallmark in tumor progression and propels development of cancer. It may further result in functional loss of apoptotic effector mechanisms in the transformed cells. Thus, our data clearly indicates that inhibition of NOinduced apoptosis by nicotine may lead to tobacco-induced oral carcinogenesis, and implies careful development of modalities in tobacco cessation programs. Keywords Nicotine Á Apoptosis Á Nitric oxide Á Inhibition Á Oral epithelial cells Á HCPC-1 Á Fibroblasts Á RPDL Á Reactive oxygen species Á Peroxynitrite radical Á Nitrotyrosination Á 3-NT Abhijit G. Banerjee and Velliyur K. Gopalakrishnan-contributed equally.
Smoking Carcinogens and Lung Cancer – a Review
Asian Journal of Pharmaceutical and Clinical Research, 2021
Smoking ambiguity contributes to a certain revelation regarding the process by which cancer is induced. In the laboratory, carcinogens induce clear lung tumor to lung cancer induction. For instance, carcinogenic chemicals, namely, 4(methyl nitrosomine)-1-(3-pyridyl)-1-butanol, and nitrosonornicotine (NNN) cause tumor malignancy. It is evident from the mechanistic studies that the carcinogens have a stronger tendency to mutate the genes like suppresser gene, a gene that encodes the receptor of the cell surface to the nucleus, thus, giving way to the proliferation of mutation leading to neoplastic cells. In this analysis article, we have discussed molecular mechanics that can cause cancer by nitrosamines such as nicotine-derived nitrosamine ketone and NNN regarding a variety of significant cigarette combustion carcinogens and the effort to introduce a different dimensional approach to the prevention of cancer, by understanding the perspective of various treatments.
Carcinogenesis, 2011
N#-Nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are tobacco-specific nitrosamines. NNN and NNK can induce cancers of the esophagus and lung, respectively, in laboratory animals, but data on human esophageal cancer are lacking. The association between levels of NNN and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), an NNK metabolite, in urine samples collected before diagnosis and risk of esophageal cancer was examined in 77 patients with esophageal cancer and 223 individually matched controls, all current smokers, from a cohort of 18244 Chinese men in Shanghai, China, followed from 1986 to 2008. Urinary total NNN (free NNN plus NNN-N-glucuronide) was significantly higher, whereas the percentage of its detoxification product NNN-N-glucuronide was significantly lower in cases than controls. Odds ratios (95% confidence intervals) of esophageal cancer for the second and third tertiles of total NNN were 3.99 (1.25-12.7) and 17.0 (3.99-72.8), respectively, compared with the first tertile after adjustment for urinary total NNAL and total cotinine and smoking intensity and duration (P trend < 0.001). The corresponding figures for the percentage of NNN-N-glucuronides were 0.37 (0.17-0.80) and 0.27 (0.11-0.62) (P trend 5 0.001). Urinary total NNN and the percentage of NNN-N-glucuronides almost completely accounted for the observed association for urinary total NNAL (free NNAL plus its glucuronides), urinary total cotinine and smoking intensity with esophageal cancer risk. These findings along with results of previous studies in laboratory animals support a significant and unique role of NNN in esophageal carcinogenesis in humans.