Research ArticleClinical Studies

Different Impact of IL10 Haplotype on Prognosis in Lung Squamous Cell Carcinoma and Adenocarcinoma

YAW-CHENG WANG, WEN-WEI SUNG, LEE WANG, YA-WEN CHENG, CHIH-YI CHEN, TZU-CHIN WU, SHWN-HUEY SHIEH and HUEI LEE
Anticancer Research June 2013, 33 (6) 2729-2735;

Abstract

Background: Polymorphisms (1082A>G, - 819C>T, and -592G>A) in the interleukin-10 (IL10) promoter are associated with its transcriptional activity. IL10 induction by cigarette smoking plays a role in smoking-related lung tumor progression. We therefore expected to find a difference in impact of IL10 haplotypes on overall survival (OS) and relapse-free survival (RFS) between squamous cell carcinomas (SCC) and adenocarcinomas (ADC) of lung. Materials and Methods: Normal lung tissues adjacent to resected tumors from 439 lung cancer patients were collected to determine IL10 haplotypes (ATA and non-ATA) by direct sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Kaplan-Meier and multivariate Cox regression models were used to assess the impact of IL10 haplotype on OS and RFS. Resluts: The non-ATA haplotype was more prevalent in patients with nodal metastatic tumors (N1 and N2) than in those with non-nodal metastatic tumors (N0). This observation was only made for patients with SCC and not ADC. Patients with SCC with the non-ATA haplotype had poorer OS and RFS when compared to those with the ATA haplotype, whereas IL10 haplotype was not associated with the clinical outcome of patients with ADC. Conclusion: The IL10 haplotype may independently predict survival and relapse in patients with surgically resected SCC, but not ADC.

Polymorphisms at -1082A>G, -819C>T, and -592G>A in the interleukin-10 (IL10) promoter are associated with its transcriptional activity (1, 2). The involvement of IL10 expression in cancer development is explained by its blockage of tumor immune surveillance via suppressed T-cell immunity (3-7). Several reports have indicated that IL-10 promoter polymorphisms are associated with various cancer risks including lung cancer (8-15). Further studies showed that IL-10 promoter polymorphisms were correlated with tumor progression and clinical outcome in a number of cancers, such as diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, advanced melanoma, breast cancer, skin squamous cell carcinoma after renal transplantation, and NSCLC (16-20).

Non-small cell lung cancer (NSCLC) is categorized into two major histological types: squamous cell carcinoma (SCC) and adenocarcinoma (ADC). SCC is predominantly associated with cigarette smoking, and induction of IL10 production has been reported in response to cigarette smoke extracts and nicotine-derived nitrosamine ketone (NNK), a major carcinogenic compound of cigarette smoke extract (21-25). Recently, we reported that IL10 mRNA levels were significantly higher in lung tumors with the non-ATA IL10 haplotype than with the ATA IL10 haplotype (26). Therefore, we further hypothesized that IL10 haplotype might play a more important role in tumor progression in cases of SCC than in ADC. To this end, we determined the IL10 promoter polymorphisms at -1082A>G, -819C>T, and -592G>A in 439 patients with NSCLC. We analyzed normal lung tissues obtained from areas adjacent to tumors in 245 patients with SCC and 194 with ADC by direct sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in order to verify whether IL10 promoter polymorphisms could have a different impact on overall survival (OS) and relapse-free survival (RFS) between patients with SCC and with ADC.

Materials and Methods

Patients. This study included 439 patients with NSCLC. All patients were unrelated ethnic Chinese and residents of central Taiwan. Patients had been diagnosed with ADC (194; 44.2%) or SCC (245; 55.8%) and underwent surgical resection at the Department of Thoracic Surgery, Taichung Veterans General Hospital, between 1993 and 2004. Samples were immediately frozen at surgery and kept at −80°C until processed. The study was approved by the Institutional Review Board (Institutional Review Board, Chung Shan Medical University Hospital. CSMUH no: CS11177). Cancer relapse data were obtained by chart review and confirmed by thoracic surgeons. Clinical parameters and OS and RFS data were collected from chart reviews (86 patients had no relapse data) and the Taiwan Cancer Registry, Department of Health, Executive Yuan, ROC.

Genomic DNA extraction. Genomic DNA was extracted by conventional methods. Surgically resected normal tissues adjacent to the lung tumor were prepared by proteinase K digestion and phenol-chloroform extraction, followed by ethanol precipitation, as described previously (27).

PCR-RFLP analysis for IL10 -592C/A genetic polymorphism. Genotypes of IL10 -592C/A were determined by PCR-RFLP as described by Rad et al. (28). PCR amplification products from 50 samples were randomly selected for direct sequencing to confirm the genotype analysis by PCR-RFLP.

Direct sequencing for IL10 -1082A/G and -819C/T genetic polymorphisms. Polymorphisms of IL10 -1082G/A and -819C/T were determined by direct sequencing of PCR products amplified from the DNA of normal tissues adjacent to the tumors. Primers used for DNA amplification and direct sequencing were: 5’-ATCCAAGACAACACTACTAA-3’ (forward) and 5’-TAAATATCCTCAAAGTTCC-3’ (reverse). The PCR cycle conditions consisted of an initial denature step at 94°C for 10 min followed by 35 cycles of 30 s at 94°C; 45 s at 56°C; 45 s at 72°C; and a final elongation at 72°C for 10 min. The PCR products were sequenced using an Applied Biosystems 3100 Avant Genetic Analyzer (Applied Biosystems, California, USA).

Statistical analysis. Student's t-test and Chi-square test were applied for continuous or discrete data analysis. The associations between IL10 promoter polymorphisms and patient survival were estimated using the Kaplan Meier method and assessed using the log-rank test. Potential confounders were adjusted by Cox regression models, with IL10 promoter polymorphisms fitted as indicator variables. All statistical analyses were performed using the SPSS statistical software program (version 13.0) (SPSS, Inc., Chicago, IL, USA). All statistical testing was conducted using two-sided tests and p-values <0.05 were considered to be statistically significant.

Results

The non-ATA haplotype in NSCLC is more prevalent in nodal metastatic tumors than in non-nodal metastatic tumors. As previously described, two IL10 haplotypes (ATA and non-ATA) were categorized by three IL10 promoter polymorphisms (-1082A>G, -819C>T, and -592G>A). Our previous study has indicated that patients with non-ATA haplotype had higher IL10 mRNA expression levels than those with ATA haplotype (26). The association of IL10 haplotype with clinical parameters is shown in Table I. Patients with nodal metastatic tumors more frequently had the non-ATA haplotype when compared to patients with non-nodal metastatic tumors (N0) (59.7% vs. 48.4%, p=0.017). The IL10 haplotypes were not associated with other clinical parameters including age, gender, smoking status, stage, T classification, and tumor histology (Table I). When stratified by tumor histology, having a non-ATA IL10 haplotype was not only associated with nodal metastasis but also correlated with tumor stage in SCC (63.0% vs. 40.5%, p<0.001 for nodal metastasis; 59.2% vs. 46.3%, p=0.047; Table II); however, no association was observed with ADC. These results suggest that non-ATA haplotypes might be associated with the clinical outcome in patients with SCC.

View this table:
Table I.

Correlations between interleukin-10 (IL10) haplotype and clinical characteristics in 439 patients with non-small cell lung cancer.

Non-ATA haplotypes may be used as a biomarker for poor prognosis in surgically resected NSCLC. IL10 expression has been shown to promote tumor progression via suppressed tumor immune surveillance (3, 5, 6). We therefore expected that in patients with non-ATA haplotypes tumor, it might show higher IL10 expression to explain its enhanced tumor progression and consequent with poor patient outcome (1, 2). Kaplan-Meier and Cox regression analysis showed that patients with the non-ATA haplotypes had poorer OS and RFS when compared with patients with the ATA haplotype in this study population [hazard ratio (HR)=1.522, 95% confidence interval (CI)=1.191-1.945, p=0.001 for OS; HR=1.611, 95% CI=1.247-2.082, p<0.001 for RFS; Table III]. The median survival duration and 5-year survival rate of patients with non-ATA haplotypes were significantly shorter when compared to those of patients with the ATA haplotype (median OS=25.8 vs. 42.9 months; median RFS=16.8 vs. 30.9 months; 5-year OS=28.6% vs. 44.7%; 5-year RFS=22.2% vs. 36.2%). As expected, tumor stage had a prognostic value for OS and RFS in this study population. After adjusting for various parameters, including age, gender, smoking status, stage, and tumor histology, IL10 haplotype and tumor stage retained their prognostic value for OS and RFS (Table III). These results were consistent with a recent report indicating that IL10 haplotype may be a useful biomarker for predicting survival and relapse of NSCLC.

View this table:
Table II.

Correlations between interleukin-10 (IL10) haplotype and clinical characteristics in non-small cell lung cancer according to tumor type.

Differential impacts of the IL10 haplotype on OS and RFS between patients with SCC and those with ADC. Differences in the prognostic value of IL10 haplotype as a predictor of clinical outcome were analyzed by dividing the study population into SCC and ADC groups. As shown in Table III, patients with SCC with the non-ATA haplotype had poorer OS and RFS than did patients with the ATA haplotype (HR=1.727, 95% CI=1.227-2.429, p=0.002 for OS; HR=2.108, 95% CI=1.440-3.087, p<0.001 for RFS). However, no prognostic value of the IL10 haplotype was observed for OS and RFS in patients with ADC (Table III). As expected, the tumor stage was associated with prognosis in both SCC and ADC. Multivariate Cox regression analysis further showed that the IL10 haplotype could independently predict OS and RFS in SCC, although not in ADC. These results suggest that the IL10 haplotype has different impacts on OS and RFS in patients with SCC from those with ADC.

Discussion

The IL10 haplotype has been associated with lung cancer risk (9). Our recent repot showed an association of IL10 haplotype with survival and relapse in lung cancer. In the current study, prognostic value of non-ATA IL10 haplotypes were observed for SCC, but not for ADC. In addition, non-ATA IL10 haplotypes were associated with nodal metastasis and tumor stage in SCC. This finding seemed to be consistent with previous reports indicating that serum IL10 levels were increased with advanced T classification, nodal metastasis, and tumor stage in head and neck SCC (HNSCC) (29-32).

View this table:
Table III.

Univariate and multivariate analysis of the influence of interleukin-10 (IL10) haplotype on overall survival (OS) and relapse-free survival (RFS) in patients with squamous cell carcinoma (SCC) and those with adenocarcinoma (ADC).

Cigarette smoking plays a key role in the development of both SCC and HNSCC (5, 21, 23, 33-36). The induction of IL10 expression by cigarette smoking may have a partial involvement in the progression of SCC and HNSCC, especially in advanced stages (37, 38). Extensive studies have shown an association of IL10 with tumor cell growth and an inhibition of antitumor responses by IL10 through modulation of the functions of antigen-presenting cells and induction of regulatory T-cell generation (38-42). These tumor microenvironmental findings may suggest an underlying mechanism for the association between IL10 haplotype and NSCLC prognosis.

In Taiwan, the majority of smokers with lung cancer are men, because only 4% of women are smokers. Among lung cancer cases, over 70% of male smokers have SCC; conversely, fewer than 30% of the female non-smokers have SCC (43-45). In the present study population, the distribution of SCC and ADC, when stratified by gender, was similar to that described in previous reports (46, 47). Gender stratification revealed that the prognostic value of IL10 haplotype on OS and RFS was observed in male, but not in female patients (Table IV). This finding further supports the differential impact of IL10 haplotype on OS and RFS of patients with SCC compared to those with ADC.

View this table:
Table IV.

Multivariate analysis of the influence of interleukin-10 (IL10) haplotype on overall survival (OS) and relapse free survival (RFS) in patients with non-small cell lung cancer according to gender.

Many immune cell types are found in the tumor microenvironment, including dendritic cells (DCs) and macrophages in myeloid cells show constitutive activation of signal transducer and activator of transcription 3 (STAT3), which allows efficient cluster of differentiation 8 (CD8+) T cell infiltration into tumors while inhibiting accumulation of regulatory T-cells (42, 48, 49). Activated STAT3 suppresses antitumor immunity by inhibiting the expression of many cytokines and chemokines important for stimulating antitumor immunity, and by up-regulating production of several immunosuppressive factors, including IL10 (49). The activation of the IL6/STAT3 pathway has been shown to play a crucial role in the pathogenesis and progression of lung cancer (48). In addition, IL6 and STAT3 were activated by mainstream cigarette smoke in the lungs of subchronically exposed mice (50). Previous reports indicated that IL6 expression levels were significantly higher in SCC cells than in ADC cells (37). T-cells stimulated by DCs treated with lung tumor cells showed a greater increase in IL10 secretion when the DCs were SCC-DCs rather than ADC-DCs (37). As expected, SCC-DCs were less effective stimulators of T-lymphocyte proliferation when compared with ADC-DCs (37). However, this phenomenon was diminished by neutralization by IL6 (37). Therefore, we suggest that the switch in monocyte differentiation from DCs to macrophage-like cells promoted by SCC, but not by ADC, may occur predominantly through the IL6/STAT3 pathway.

In summary, IL10 may more strongly influence tumor progression in SCC than in ADC. The differential impacts of the IL10 haplotype on the clinical outcome between SCC and ADC observed in the current study seem to support this possibility. However, the underlying mechanisms of IL10 expression in tumor progression of SCC need further investigation.

Acknowledgements

This work was jointly supported by grants from the National Science Council (NSC99-2628-B-038-016-MY3 and NSC100-2314-B-038-043-MY3).

Footnotes

  • ↵* These Authors contributed equally to this work, as did these Authors≠.

  • Received April 16, 2013.
  • Revision received May 2, 2013.
  • Accepted May 9, 2013.

References

  1. ↵
    1. Eskdale J,
    2. Keijsers V,
    3. Huizinga T,
    4. Gallagher G
    : Microsatellite alleles and single nucleotide polymorphisms (SNP) combine to form four major haplotype families at the human interleukin-10 (IL10) locus. Genes Immun 1: 151-155, 1999.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Turner DM,
    2. Williams DM,
    3. Sankaran D,
    4. Lazarus M,
    5. Sinnott PJ,
    6. Hutchinson IV
    : An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 24: 1-8, 1997.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Mosser DM,
    2. Zhang X
    : Interleukin-10: New perspectives on an old cytokine. Immunol Rev 226: 205-218, 2008.
    OpenUrlCrossRefPubMed
    1. Saraiva M,
    2. O'Garra A
    : The regulation of IL10 production by immune cells. Nat Rev Immunol 10: 170-181, 2010.
    OpenUrlCrossRefPubMed
  5. ↵
    1. O'Garra A,
    2. Vieira P
    : T(H)1 cells control themselves by producing interleukin-10. Nat Rev Immunol 7: 425-428, 2007.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Kim R,
    2. Emi M,
    3. Tanabe K,
    4. Arihiro K
    : Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res 66: 5527-5536, 2006.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Brooks DG,
    2. Ha SJ,
    3. Elsaesser H,
    4. Sharpe AH,
    5. Freeman GJ,
    6. Oldstone MB
    : IL10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection. Proc Natl Acad Sci USA 105: 20428-20433, 2008.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Seifart C,
    2. Plagens A,
    3. Dempfle A,
    4. Clostermann U,
    5. Vogelmeier C,
    6. von Wichert P,
    7. Seifart U
    : TNF-α, TNF-β, IL6, and IL10 polymorphisms in patients with lung cancer. Dis Markers 21: 157-165, 2005.
    OpenUrlPubMed
  9. ↵
    1. Shih CM,
    2. Lee YL,
    3. Chiou HL,
    4. Hsu WF,
    5. Chen WE,
    6. Chou MC,
    7. Lin LY
    : The involvement of genetic polymorphism of IL10 promoter in non-small cell lung cancer. Lung Cancer 50: 291-297, 2005.
    OpenUrlCrossRefPubMed
    1. Hart K,
    2. Landvik NE,
    3. Lind H,
    4. Skaug V,
    5. Haugen A,
    6. Zienolddiny S
    : A combination of functional polymorphisms in the CASP8, MMP1, IL10 and SEPS1 genes affects risk of non-small cell lung cancer. Lung Cancer 71: 123-129, 2011.
    OpenUrlCrossRefPubMed
    1. Faupel-Badger JM,
    2. Kidd LC,
    3. Albanes D,
    4. Virtamo J,
    5. Woodson K,
    6. Tangrea JA
    : Association of IL10 polymorphisms with prostate cancer risk and grade of disease. Cancer Causes Control 19: 119-124, 2008.
    OpenUrlCrossRefPubMed
    1. Wei YS,
    2. Kuang XH,
    3. Zhu YH,
    4. Liang WB,
    5. Yang ZH,
    6. Tai SH,
    7. Zhao Y,
    8. Zhang L
    : Interleukin-10 gene promoter polymorphisms and the risk of nasopharyngeal carcinoma. Tissue Antigens 70: 12-17, 2007.
    OpenUrlCrossRefPubMed
    1. Eder T,
    2. Mayer R,
    3. Langsenlehner U,
    4. Renner W,
    5. Krippl P,
    6. Wascher TC,
    7. Pummer K,
    8. Kapp KS
    : Interleukin-10 [ATA] promoter haplotype and prostate cancer risk: A population-based study. Eur J Cancer 43: 472-475, 2007.
    OpenUrlCrossRefPubMed
    1. Yao JG,
    2. Gao LB,
    3. Liu YG,
    4. Li J,
    5. Pang GF
    : Genetic variation in interleukin-10 gene and risk of oral cancer. Clin Chim Acta 388: 84-88, 2008.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Liu J,
    2. Song B,
    3. Bai X,
    4. Liu W,
    5. Li Z,
    6. Wang J,
    7. Zheng Y,
    8. Wang Z
    : Association of genetic polymorphisms in the interleukin-10 promoter with risk of prostate cancer in Chinese. BMC Cancer 10: 456, 2010.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Alonso R,
    2. Suarez A,
    3. Castro P,
    4. Lacave AJ,
    5. Gutierrez C
    : Influence of interleukin-10 genetic polymorphism on survival rates in melanoma patients with advanced disease. Melanoma Res 15: 53-60, 2005.
    OpenUrlCrossRefPubMed
    1. Howell WM,
    2. Rose-Zerilli MJ
    : Interleukin-10 polymorphisms, cancer susceptibility and prognosis. Fam Cancer 5: 143-149, 2006.
    OpenUrlCrossRefPubMed
    1. Alamartine E,
    2. Berthoux P,
    3. Mariat C,
    4. Cambazard F,
    5. Berthoux F
    : Interleukin-10 promoter polymorphisms and susceptibility to skin squamous cell carcinoma after renal transplantation. J Invest Dermatol 120: 99-103, 2003.
    OpenUrlCrossRefPubMed
    1. Park YH,
    2. Sohn SK,
    3. Kim JG,
    4. Lee MH,
    5. Song HS,
    6. Kim MK,
    7. Jung JS,
    8. Lee JJ,
    9. Kim HJ,
    10. Kim DH
    : Interaction between BCL2 and interleukin-10 gene polymorphisms alter outcomes of diffuse large B-cell lymphoma following rituximab plus CHOP chemotherapy. Clin Cancer Res 15: 2107-2115, 2009.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Bogunia-Kubik K,
    2. Mazur G,
    3. Wrobel T,
    4. Kuliczkowski K,
    5. Lange A
    : Interleukin-10 gene polymorphisms influence the clinical course of non-Hodgkin's lymphoma. Tissue Antigens 71: 146-150, 2008.
    OpenUrlPubMed
  21. ↵
    1. Kullmann T,
    2. Barta I,
    3. Csiszer E,
    4. Antus B,
    5. Horvath I
    : Differential cytokine pattern in the exhaled breath of patients with lung cancer. Pathol Oncol Res 14: 481-483, 2008.
    OpenUrlCrossRefPubMed
    1. Ray G,
    2. Henson DE,
    3. Schwartz AM
    : Cigarette smoking as a cause of cancers other than lung cancer: an exploratory study using the Surveillance, Epidemiology, and End Results Program. Chest 138: 491-499, 2010.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Stampfli MR,
    2. Anderson GP
    : How cigarette smoke skews immune responses to promote infection, lung disease and cancer. Nat Rev Immunol 9: 377-384, 2009.
    OpenUrlCrossRefPubMed
    1. Pesch B,
    2. Kendzia B,
    3. Gustavsson P,
    4. Jockel KH,
    5. Johnen G,
    6. Pohlabeln H,
    7. Olsson A,
    8. Ahrens W,
    9. Gross IM,
    10. Bruske I,
    11. Wichmann HE,
    12. Merletti F,
    13. Richiardi L,
    14. Simonato L,
    15. Fortes C,
    16. Siemiatycki J,
    17. Parent ME,
    18. Consonni D,
    19. Landi MT,
    20. Caporaso N,
    21. Zaridze D,
    22. Cassidy A,
    23. Szeszenia-Dabrowska N,
    24. Rudnai P,
    25. Lissowska J,
    26. Stucker I,
    27. Fabianova E,
    28. Dumitru RS,
    29. Bencko V,
    30. Foretova L,
    31. Janout V,
    32. Rudin CM,
    33. Brennan P,
    34. Boffetta P,
    35. Straif K,
    36. Bruning T
    : Cigarette smoking and lung cancer-relative risk estimates for the major histological types from a pooled analysis of case control studies. Int J Cancer 2011.
  25. ↵
    1. Therriault MJ,
    2. Proulx LI,
    3. Castonguay A,
    4. Bissonnette EY
    : Immunomodulatory effects of the tobacco-specific carcinogen, NNK, on alveolar macrophages. Clin Exp Immunol 132: 232-238, 2003.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Wang YC,
    2. Sung WW,
    3. Wu TC,
    4. Wang L,
    5. Chien WP,
    6. Cheng YW,
    7. Chen CY,
    8. Shieh SH,
    9. Lee H
    : Interleukin-10 haplotype may predict survival and relapse in resected non-small cell lung cancer. PLoS One 7: e39525, 2012.
    OpenUrlCrossRefPubMed
  27. ↵
    1. Sung WW,
    2. Wang YC,
    3. Cheng YW,
    4. Lee MC,
    5. Yeh KT,
    6. Wang L,
    7. Wang J,
    8. Chen CY,
    9. Lee H
    : A polymorphic -844T/C in FasL promoter predicts survival and relapse in non-small cell lung cancer. Clin Cancer Res 17: 5991-5999, 2011.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Rad R,
    2. Dossumbekova A,
    3. Neu B,
    4. Lang R,
    5. Bauer S,
    6. Saur D,
    7. Gerhard M,
    8. Prinz C
    : Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and host specific colonisation during Helicobacter pylori infection. Gut 53: 1082-1089, 2004.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Lathers DM,
    2. Young MR
    : Increased aberrance of cytokine expression in plasma of patients with more advanced squamous cell carcinoma of the head and neck. Cytokine 25: 220-228, 2004.
    OpenUrlCrossRefPubMed
    1. Gunaydin RO,
    2. Kesikli SA,
    3. Kansu E,
    4. Hosal AS
    : Identification of the peripheral blood levels of interleukin-12, interleukin-10, and transforming growth factor-beta in patients with laryngeal squamous cell carcinoma. Head Neck 34: 393-397, 2012.
    OpenUrlPubMed
    1. Alhamarneh O,
    2. Agada F,
    3. Madden L,
    4. Stafford N,
    5. Greenman J
    : Serum IL10 and circulating CD4(+) CD25(high) regulatory T cell numbers as predictors of clinical outcome and survival in patients with head and neck squamous cell carcinoma. Head Neck 33: 415-423, 2011.
    OpenUrlPubMed
  32. ↵
    1. Jebreel A,
    2. Mistry D,
    3. Loke D,
    4. Dunn G,
    5. Hough V,
    6. Oliver K,
    7. Stafford N,
    8. Greenman J
    : Investigation of interleukin 10, 12 and 18 levels in patients with head and neck cancer. J Laryngol Otol 121: 246-252, 2007.
    OpenUrlCrossRefPubMed
  33. ↵
    1. Muscat JE,
    2. Ahn K,
    3. Richie JP Jr..,
    4. Stellman SD
    : Nicotine dependence phenotype, time to first cigarette, and risk of head and neck cancer. Cancer 117: 5377-5382, 2011.
    OpenUrlCrossRefPubMed
    1. Hashibe M,
    2. Brennan P,
    3. Benhamou S,
    4. Castellsague X,
    5. Chen C,
    6. Curado MP,
    7. Dal Maso L,
    8. Daudt AW,
    9. Fabianova E,
    10. Fernandez L,
    11. Wunsch-Filho V,
    12. Franceschi S,
    13. Hayes RB,
    14. Herrero R,
    15. Koifman S,
    16. La Vecchia C,
    17. Lazarus P,
    18. Levi F,
    19. Mates D,
    20. Matos E,
    21. Menezes A,
    22. Muscat J,
    23. Eluf-Neto J,
    24. Olshan AF,
    25. Rudnai P,
    26. Schwartz SM,
    27. Smith E,
    28. Sturgis EM,
    29. Szeszenia-Dabrowska N,
    30. Talamini R,
    31. Wei Q,
    32. Winn DM,
    33. Zaridze D,
    34. Zatonski W,
    35. Zhang ZF,
    36. Berthiller J,
    37. Boffetta P
    : Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: Pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst 99: 777-789, 2007.
    OpenUrlCrossRefPubMed
    1. Brennan JA,
    2. Boyle JO,
    3. Koch WM,
    4. Goodman SN,
    5. Hruban RH,
    6. Eby YJ,
    7. Couch MJ,
    8. Forastiere AA,
    9. Sidransky D
    : Association between cigarette smoking and mutation of the p53 gene in squamous cell carcinoma of the head and neck. N Engl J Med 332: 712-717, 1995.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Browman GP,
    2. Wong G,
    3. Hodson I,
    4. Sathya J,
    5. Russell R,
    6. McAlpine L,
    7. Skingley P,
    8. Levine MN
    : Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 328: 159-163, 1993.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Avila-Moreno F,
    2. Lopez-Gonzalez JS,
    3. Galindo-Rodriguez G,
    4. Prado-Garcia H,
    5. Bajana S,
    6. Sanchez-Torres C
    : Lung squamous cell carcinoma and adenocarcinoma cell lines use different mediators to induce comparable phenotypic and functional changes in human monocyte-derived dendritic cells. Cancer Immunol Immunother 55: 598-611, 2006.
    OpenUrlCrossRefPubMed
  38. ↵
    1. Clark RA,
    2. Huang SJ,
    3. Murphy GF,
    4. Mollet IG,
    5. Hijnen D,
    6. Muthukuru M,
    7. Schanbacher CF,
    8. Edwards V,
    9. Miller DM,
    10. Kim JE,
    11. Lambert J,
    12. Kupper TS
    : Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T-cells. J Exp Med 205: 2221-2234, 2008.
    OpenUrlAbstract/FREE Full Text
    1. Ramos RN,
    2. Oliveira CE,
    3. Gasparoto TH,
    4. Malaspina TS,
    5. Belai EB,
    6. Cavassani KA,
    7. Garlet GP,
    8. Silva JS,
    9. Campanelli AP
    : CD25+ T-cell depletion impairs murine squamous cell carcinoma development via modulation of antitumor immune responses. Carcinogenesis 33: 902-909, 2012.
    OpenUrlCrossRefPubMed
    1. Fukuyama T,
    2. Ichiki Y,
    3. Yamada S,
    4. Shigematsu Y,
    5. Baba T,
    6. Nagata Y,
    7. Mizukami M,
    8. Sugaya M,
    9. Takenoyama M,
    10. Hanagiri T,
    11. Sugio K,
    12. Yasumoto K
    : Cytokine production of lung cancer cell lines: Correlation between their production and the inflammatory/immunological responses both in vivo and in vitro. Cancer Sci 98: 1048-1054, 2007.
    OpenUrlCrossRefPubMed
    1. Jarnicki AG,
    2. Lysaght J,
    3. Todryk S,
    4. Mills KH
    : Suppression of antitumor immunity by IL10 and TGF-β-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells. J Immunol 177: 896-904, 2006.
    OpenUrlAbstract/FREE Full Text
  42. ↵
    1. Bluth MJ,
    2. Zaba LC,
    3. Moussai D,
    4. Suarez-Farinas M,
    5. Kaporis H,
    6. Fan L,
    7. Pierson KC,
    8. White TR,
    9. Pitts-Kiefer A,
    10. Fuentes-Duculan J,
    11. Guttman-Yassky E,
    12. Krueger JG,
    13. Lowes MA,
    14. Carucci JA
    : Myeloid dendritic cells from human cutaneous squamous cell carcinoma are poor stimulators of T-cell proliferation. J Invest Dermatol 129: 2451-2462, 2009.
    OpenUrlCrossRefPubMed
  43. ↵
    1. Papadopoulos A,
    2. Guida F,
    3. Cenee S,
    4. Cyr D,
    5. Schmaus A,
    6. Radoi L,
    7. Paget-Bailly S,
    8. Carton M,
    9. Tarnaud C,
    10. Menvielle G,
    11. Delafosse P,
    12. Molinie F,
    13. Luce D,
    14. Stucker I
    : Cigarette smoking and lung cancer in women: results of the French ICARE case control study. Lung Cancer 74: 369-377, 2011.
    OpenUrlCrossRefPubMed
    1. Lubin JH,
    2. Blot WJ
    : Assessment of lung cancer risk factors by histologic category. J Natl Cancer Inst 73: 383-389, 1984.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Brownson RC,
    2. Chang JC,
    3. Davis JR
    : Gender and histologic type variations in smoking-related risk of lung cancer. Epidemiology 3: 61-64, 1992.
    OpenUrlCrossRefPubMed
  46. ↵
    1. Chen KY,
    2. Chang CH,
    3. Yu CJ,
    4. Kuo SH,
    5. Yang PC
    : Distribution according to histologic type and outcome by gender and age group in Taiwanese patients with lung carcinoma. Cancer 103: 2566-2574, 2005.
    OpenUrlCrossRefPubMed
  47. ↵
    1. Chien CR,
    2. Chen TH
    : A Bayesian model for age, period, and cohort effects on mortality trends for lung cancer, in association with gender-specific incidence and case-fatality rates. J Thorac Oncol 4: 167-171, 2009.
    OpenUrlPubMed
  48. ↵
    1. Wu L,
    2. Du H,
    3. Li Y,
    4. Qu P,
    5. Yan C
    : Signal transducer and activator of transcription 3 (STAT3C) promotes myeloid-derived suppressor cell expansion and immune suppression during lung tumorigenesis. Am J Pathol 179: 2131-2141, 2011.
    OpenUrlCrossRefPubMed
  49. ↵
    1. Herbeuval JP,
    2. Lelievre E,
    3. Lambert C,
    4. Dy M,
    5. Genin C
    : Recruitment of STAT3 for production of IL10 by colon carcinoma cells induced by macrophage-derived IL6. J Immunol 172: 4630-4636, 2004.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    1. Halappanavar S,
    2. Russell M,
    3. Stampfli MR,
    4. Williams A,
    5. Yauk CL
    : Induction of the interleukin 6/signal transducer and activator of transcription pathway in the lungs of mice subchronically exposed to mainstream tobacco smoke. BMC Med Genomics 2: 56, 2009.
    OpenUrlCrossRefPubMed
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Different Impact of IL10 Haplotype on Prognosis in Lung Squamous Cell Carcinoma and Adenocarcinoma
YAW-CHENG WANG, WEN-WEI SUNG, LEE WANG, YA-WEN CHENG, CHIH-YI CHEN, TZU-CHIN WU, SHWN-HUEY SHIEH, HUEI LEE
Anticancer Research Jun 2013, 33 (6) 2729-2735;
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