title: An epidemiological and molecular study of the relationship between smoking, risk of nasopharyngeal carcinoma, and Epstein-Barr virus activation.
abstract: BACKGROUND
  Elevated levels of antibodies against antigens in the Epstein-Barr virus (EBV) lytic phase are important predictive markers for nasopharyngeal carcinoma (NPC) risk. Several lifestyle factors, including smoking, have also been associated with NPC risk. We hypothesized that some specific lifestyle factors induce transformation of EBV from the latent to the lytic stage and contribute to NPC occurrence.
  
  
  METHODS
  We conducted a case-control study using data from male case patients (n = 1316) and control subjects (n = 1571) living in Guangdong Province, an area in China at high risk for NPC, to study potential NPC risk factors and EBV inducers. Two independent healthy male populations from a second high-risk area (n = 1657) and a low-risk area (n = 1961) were also included in the analysis of potential EBV inducers using logistic regression models. In vitro assays were performed to investigate the effect of cigarette smoke extract on EBV activation in two EBV-positive cell lines. All statistical tests were two-sided.
  
  
  RESULTS
  Smoking was associated with an increased risk of NPC among the Guangdong participants with 20-40 and 40 or more pack-years vs never smokers (OR = 1.52, 95% CI = 1.22 to 1.88 and OR = 1.76, 95% CI = 1.34 to 2.32, respectively; P (trend) < .001). Smoking was the only factor linked to EBV seropositivity among the expanded control group and the independent low-risk population. In vitro experiments showed that cigarette smoke extract promoted EBV replication, induced the expression of the immediate-early transcriptional activators Zta and Rta, and increased transcriptional expression levels of BFRF3 and gp350 in the lytic phase.
  
  
  CONCLUSIONS
  Smoking is not only associated with NPC risk in individuals from China but is also associated with EBV seropositivity in healthy males and is involved in EBV activation.
authors.affiliation: State Key Laboratory of Oncology in South China, China.
authors.forename: Feng-Hua
authors.initials: FH
authors.lastname: Xu
authors.forename: Dan
authors.initials: D
authors.lastname: Xiong
authors.forename: Ya-Fei
authors.initials: YF
authors.lastname: Xu
authors.forename: Su-Mei
authors.initials: SM
authors.lastname: Cao
authors.forename: Wen-Qiong
authors.initials: WQ
authors.lastname: Xue
authors.forename: Hai-De
authors.initials: HD
authors.lastname: Qin
authors.forename: Wen-Sheng
authors.initials: WS
authors.lastname: Liu
authors.forename: Jing-Yan
authors.initials: JY
authors.lastname: Cao
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qi-Sheng
authors.initials: QS
authors.lastname: Feng
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: Chen
authors.forename: Man-Zhi
authors.initials: MZ
authors.lastname: Li
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Liu
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.forename: Ming-Huang
authors.initials: MH
authors.lastname: Hong
authors.forename: Yin Yao
authors.initials: YY
authors.lastname: Shugart
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Mu-Sheng
authors.initials: MS
authors.lastname: Zeng
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Jia
mesh_terms: D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood*; D044466:Asian People / Q000706:statistics & numerical data*; D002277:Carcinoma; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002681:China / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000276:immunology; D005247:Feeding Behavior; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification* / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D007070:Immunoglobulin A / Q000097:blood; D015994:Incidence; D016015:Logistic Models; D008156:Luciferases / Q000032:analysis; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000453:epidemiology* / Q000209:etiology* / Q000821:virology; D016017:Odds Ratio; D010957:Plasmids; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014775:Virus Activation
chemical_list: D000914:Antibodies, Viral; C068382:BRLF1 protein, Human herpesvirus 4; C063676:BZLF1 protein, Herpesvirus 4, Human; D017874:Immediate-Early Proteins; D007070:Immunoglobulin A; D015534:Trans-Activators; D008156:Luciferases