Abstract
Purpose
Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) represents a central point of convergence for the signal transduction by the TNFR and the IL-lR/TLR superfamilies. We conducted this retrospective clinical study focusing on TRAF6 expression associated with overall survival and chemotherapeutical sensitivity in a large population with advanced non-small cell lung cancer (NSCLC).
Methods
A total of 324 patients with stage III and IV NSCLC were retrospectively enrolled. Immunohistochemistry was performed to evaluate the expression of TRAF6, apoptosis-related proteins Bcl-2, Bax, Fas, and FasL, as well as the density of CD8+ and FOXP3+ tumor infiltrating lymphocytes (TILs) in tumor microenvironment.
Results
A total of 193 carcinomas (59.6 %) were identified as high expression of TRAF6. TRAF6 expression was not significantly related with histology and clinic stage. No obvious correlation of TRAF6 expression with apoptosis-related protein and TILs density was identified. TRAF6 status was correlated inversely with response to chemotherapy in overall patients (response rates 24.9 and 32.8 %, for patients with high-TRAF6 and low-TRAF6 tumors, respectively, P = 0.039). However, multivariate logistic regression analysis could not identify TRAF6 status as an independent predictor for the response to chemotherapy in overall cohort (95 % CI: 0.91–3.32, P = 0.065). The overall survival was not significantly associated with TRAF6 expression (P = 0.616).
Conclusions
Our results provide new insight for the biological properties and clinical relevance of the TRAF6 in NSCLC. TRAF6 is a promise target for therapeutic strategies against cancer.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- FOXP3:
-
Forkhead box P3
- HPF:
-
High power field
- IHC:
-
Immunohistochemistry
- NSCLC:
-
Non-small cell lung cancer
- OS:
-
Overall survival
- TIL:
-
Tumor infiltrating lymphocytes
- TNF:
-
Tumor necrosis factor
- TRAF6:
-
TNF receptor-associated factor 6
- Treg:
-
Regulatory T lymphocytes
References
Bradley JR, Pober JS (2001) Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene 20(44):6482–6491
Cejas PJ, Walsh MC, Pearce EL et al (2010) TRAF6 inhibits Th17 differentiation and TGF-beta-mediated suppression of IL-2. Blood 115(23):4750–4757. doi:10.1182/blood-2009-09-242768
Chiffoleau E, Kobayashi T, Walsh MC et al (2003) TNF receptor-associated factor 6 deficiency during hemopoiesis induces Th2-polarized inflammatory disease. J Immunol 171(11):5751–5759
Elmetwali T, Young LS, Palmer DH (2010) CD40 ligand-induced carcinoma cell death: a balance between activation of TNFR-associated factor (TRAF) 3-dependent death signals and suppression of TRAF6-dependent survival signals. J Immunol 184(2):1111–1120. doi:10.4049/jimmunol.0900528
Gangadharan C, Thoh M, Manna SK (2010) Late phase activation of nuclear transcription factor kappaB by doxorubicin is mediated by interleukin-8 and induction of apoptosis via FasL. Breast Cancer Res Treat 120(3):671–683. doi:10.1007/s10549-009-0493-z
Gibbs A, Thunnissen F (2001) Histological typing of lung and pleural tumours: third edition. J Clin Pathol 54(7):498–499. doi:10.1136/jcp.54.7.498
He L, Wu X, Siegel R, Lipsky PE (2006) TRAF6 regulates cell fate decisions by inducing caspase 8-dependent apoptosis and the activation of NF-kappaB. J Biol Chem 281(16):11235–11249. doi:10.1074/jbc.M508779200
Hirata Y, Ohmae T, Shibata W et al (2006) MyD88 and TNF receptor-associated factor 6 are critical signal transducers in Helicobacter pylori-infected human epithelial cells. J Immunol 176(6):3796–3803
Jundi M, Nadiri A, Al-Zoobi L, Hassan GS, Mourad W (2012) CD40-mediated cell death requires TRAF6 recruitment. Immunobiology 217(3):375–383. doi:10.1016/j.imbio.2011.07.007
King CG, Kobayashi T, Cejas PJ et al (2006) TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis. Nat Med 12(9):1088–1092. doi:10.1038/nm1449
Kobayashi T, Walsh PT, Walsh MC et al (2003) TRAF6 is a critical factor for dendritic cell maturation and development. Immunity 19(3):353–363. doi:10.1016/S1074-7613(03)00230-9
Kobayashi T, Walsh MC, Choi Y (2004) The role of TRAF6 in signal transduction and the immune response. Microbes Infect 6(14):1333–1338. doi:10.1016/j.micinf.2004.09.001
Lee NK, Lee SY (2002) Modulation of life and death by the tumor necrosis factor receptor-associated factors (TRAFs). J Biochem Mol Biol 35(1):61–66
Li F, Sethi G (2010) Targeting transcription factor NF-kappaB to overcome chemoresistance and radioresistance in cancer therapy. Biochim Biophys Acta 1805(2):167–180. doi:10.1016/j.bbcan.2010.01.002
Liu H, Zhang T, Li X et al (2008) Predictive value of MMP-7 expression for response to chemotherapy and survival in patients with non-small cell lung cancer. Cancer Sci 99:2185–2192. doi:10.1111/j.1349-7006.2008.00922.x
Ma Y, Aymeric L, Locher C et al (2011a) Contribution of IL-17-producing gamma delta T cells to the efficacy of anticancer chemotherapy. J Exp Med 208(3):491–503. doi:10.1084/jem.20100269
Ma T, Wang N, Su Z et al (2011b) Characterization of apoptosis and proliferation in esophageal carcinoma EC109 cells following siRNA-induced down-regulation of TRAF6. Mol Cell Biochem 352(1–2):77–85. doi:10.1007/s11010-011-0741-5
Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47(1):207–214
Paik JH, Jang JY, Jeon YK et al (2011) MicroRNA-146a downregulates NFκB activity via targeting TRAF6 and functions as a tumor suppressor having strong prognostic implications in NK/T cell lymphoma. Clin Cancer Res 17(14):4761–4771. doi:10.1158/1078-0432.CCR-11-0494
Peng G, Wang HY, Peng W, Kiniwa Y, Seo KH, Wang RF (2007) Tumor-infiltrating gammadelta T cells suppress T and dendritic cell function via mechanisms controlled by a unique toll-like receptor signaling pathway. Immunity 27(2):334–348. doi:10.1016/j.immuni.2007.05.020
Rajandram R, Bennett NC, Morais C, Johnson DW, Gobe GC (2012) Renal cell carcinoma: resistance to therapy, role of apoptosis, and the prognostic and therapeutic target potential of TRAF proteins. Med Hypotheses 78(2):330–336. doi:10.1016/j.mehy.2011.11.014
Rowland SL, Tremblay MM, Ellison JM, Stunz LL, Bishop GA, Hostager BS (2007) A novel mechanism for TNFR-associated factor 6-dependent CD40 signaling. J Immunol 179(7):4645–4653
Santarpia M, Magri I, Sanchez-Ronco M et al (2011) mRNA expression levels and genetic status of genes involved in the EGFR and NF-κB pathways in metastatic non-small-cell lung cancer patients. J Transl Med 9:163. doi:10.1186/1479-5876-9-163
Shimo Y, Yanai H, Ohshima D et al (2011) TRAF6 directs commitment to regulatory T cells in thymocytes. Genes Cells 16(4):437–447. doi:10.1111/j.1365-2443.2011.01500.x
Siervo-Sassi RR, Marrangoni AM, Feng X et al (2003) Physiological and molecular effects of Apo2L/TRAIL and cisplatin in ovarian carcinoma cell lines. Cancer Lett 190(1):61–72. doi:10.1016/S0304-3835(02)00579-7
Starczynowski DT, Lockwood WW, Deléhouzée S et al (2011) TRAF6 is an amplified oncogene bridging the RAS and NF-kB pathways in human lung cancer. J Clin Invest 121(10):4095–4105. doi:10.1172/JCI58818
Starska K, Forma E, Lewy-Trenda I et al (2009) The expression of SOCS1 and TLR4-NFkappaB pathway molecules in neoplastic cells as potential biomarker for the aggressive tumor phenotype in laryngeal carcinoma. Folia Histochem Cytobiol 47(3):401–410. doi:10.2478/v10042-009-0075-2
Trauzold A, Röder C, Sipos B et al (2005) CD95 and TRAF2 promote invasiveness of pancreatic cancer cells. FASEB J 19(6):620–622. doi:10.1096/fj.04-2984fje
Zapata JM, Krajewska M, Krajewski S et al (2000) TNFR-associated factor family protein expression in normal tissues and lymphoid malignancies. J Immunol 165(9):5084–5096
Zapata JM, Lefebvre S, Reed JC (2007) Targeting TRAfs for therapeutic intervention. Adv Exp Med Biol 597:188–201. doi:10.1007/978-0-387-70630-6_15
Zheng M, Morgan-Lappe SE, Yang J et al (2008) Growth inhibition and radiosensitization of glioblastoma and lung cancer cells by small interfering RNA silencing of tumor necrosis factor receptor-associated factor 2. Cancer Res 68(18):7570–7578. doi:10.1158/0008-5472.CAN-08-0632
Acknowledgments
This work was supported by grants from the National Science Foundation of China (Grants 81000986).
Conflict of interest
All other authors indicated no potential conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Liu, H., Zhang, T., Ye, J. et al. TNF receptor-associated factor 6 in advanced non-small cell lung cancer: clinical and prognostic implications. J Cancer Res Clin Oncol 138, 1853–1863 (2012). https://doi.org/10.1007/s00432-012-1255-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-012-1255-6