Annals of Surgical Oncology

, Volume 25, Issue 8, pp 2449–2456 | Cite as

Circulating Interleukin-6 is Associated with Prognosis and Genetic Polymorphisms of MIR608 in Patients with Esophageal Squamous Cell Carcinoma

  • Pei-Wen Yang
  • Pei-Ming Huang
  • Luo-Sheng Yong
  • Ya-Han Chang
  • Chia-Wei Wu
  • Kuo-Tai Hua
  • Min-Shu Hsieh
  • Jang-Ming Lee
Thoracic Oncology



No effective targeted therapy exists for esophageal squamous cell carcinoma (ESCC), the major cell type of esophageal cancer. The pleiotropic cytokine interleukin (IL)-6 is associated with adverse prognosis of some cancers, and the open reading frame of IL-6 contains an miR-608 microRNA-targeted site. We investigated the correlation of circulating IL-6 levels with prognosis and with the mir608:rs4919510 genetic polymorphism in ESCC.


A total of 213 patients with primary ESCC were enrolled. Plasma IL-6 levels of ESCC patients were analyzed by enzyme-linked immunosorbent assay (ELISA). The patients’ genotypes of mir608:rs4919510 were analyzed using the MassARRAY system, and functional assays were performed by transient overexpression in cells. The cytotoxicity of IL-6 signaling blockers in ESCC cells was analyzed by MTT assay.


We found that plasma IL-6 levels significantly correlated with overall survival (p = 0.019), disease recurrence (p = 0.003), and postoperative complications (p =0.002). Patients with the GG genotype of mir608:rs4919510 had a 4.56-fold increased risk of high expression of IL-6 compared with patients with the CC genotype (odds ratio 4.56, 95% confidence interval 1.87–11.09; p =0.001). Transient overexpression of the miR-608 C (miR-608_C) and G variants (miR-608_G) in cancer cells revealed that the miR-608_G variant was less efficient in regulating the expression of IL-6 compared with miR-608_C. Finally, the IL-6 signaling blocker ruxolitinib exhibited effective cytotoxicity in ESCC cells.


The results of this study provide a novel direction for a biomarker-based targeted therapy for ESCC.



The authors thank the staff of the Second Core Laboratory, Department of Medical Research, NTUH, for technical support.


This study was supported by the NTUH (NTUH.105-S3005, NTUH.106-S3439, and NTUH.107-S3867), the Ministry of Science and Technology (MOST 104-2314-B-002-182- MY3 and MOST 106-2320-B-002-029-MY3), and the Taiwan Health Foundation of the Republic of China.


Pei-Wen Yang, Pei-Ming Huang, Luo-Sheng Yong, Ya-Han Chang, Chia-Wei Wu, Kuo-Tai Hua, Min-Shu Hsieh, and Jang-Ming Lee have no conflicts of interest regarding the publication of this study.

Supplementary material

10434_2018_6532_MOESM1_ESM.docx (9.1 mb)
Supplementary material 1 (DOCX 9287 kb)


  1. 1.
    Berry MF. Esophageal cancer: staging system and guidelines for staging and treatment. J Thorac Dis. 2014;6 Suppl 3:S289-297.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10-29.CrossRefPubMedGoogle Scholar
  3. 3.
    Napier KJ, Scheerer M, Misra S. Esophageal cancer: A Review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol. 2014;6(5):112-120.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Miyashita M, Tajiri T, Sasajima K, et al. Response to preoperative chemotherapy affects prognosis in esophageal cancer. Dis Esophagus. 2003;16(2):99-101.CrossRefPubMedGoogle Scholar
  5. 5.
    Chang Q, Daly L, Bromberg J. The IL-6 feed-forward loop: A driver of tumorigenesis. Semin Immunol. 2014;26(1):48-53.CrossRefPubMedGoogle Scholar
  6. 6.
    Sansone P, Bromberg J. Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies. J Clin Oncol. 2012;30(9):1005-1014.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Oka M, Yamamoto K, Takahashi M, et al. Relationship between serum levels of interleukin 6, various disease parameters, and malnutrition in patients with esophageal squamous cell carcinoma. Cancer Research. 1996;56(12):2776-2780.PubMedGoogle Scholar
  8. 8.
    Wang LS, Chow KC, Wu CW. Expression and up-regulation of interleukin-6 in oesophageal carcinoma cells by n-sodium butyrate. Brit J Cancer. 1999;80(10):1617-1622.CrossRefPubMedGoogle Scholar
  9. 9.
    Yoneda M, Fujiwara H, Furutani A, et al. Prognostic Impact of Tumor IL-6 Expression after Preoperative Chemoradiotherapy in Patients with Advanced Esophageal Squamous Cell Carcinoma. Anticancer Research. 2013;33(6):2699-2705.PubMedGoogle Scholar
  10. 10.
    Chen MF, Chen PT, Lu MS, Lin PY, Chen WC, Lee KD. IL-6 expression predicts treatment response and outcome in squamous cell carcinoma of the esophagus. Mol Cancer. 2013;12:26.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Fujiwara H, Suchi K, Okamura S, et al. Elevated Serum CRP Levels After Induction Chemoradiotherapy Reflect Poor Treatment Response in Association With IL-6 in Serum and Local Tumor Site in Patients With Advanced Esophageal Cancer. J Surg Oncol. 2011;103(1):62-68.CrossRefPubMedGoogle Scholar
  12. 12.
    Leu CM, Wong FH, Chang C, Huang SF, Hu CP. Interleukin-6 acts as an antiapoptotic factor in human esophageal carcinoma cells through the activation of both STAT3 and mitogen-activated protein kinase pathways. Oncogene. 2003;22(49):7809-7818.CrossRefPubMedGoogle Scholar
  13. 13.
    Mittal RD, George GP . MicroRNAs: potential biomarkers in cancer. Indian Journal of Clinical Biochemistry. 2010;25(1):4-14.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Xu T, Zhu Y, Wei QK, et al. A functional polymorphism in the miR-146a gene is associated with the risk for hepatocellular carcinoma. Carcinogenesis. 2008;29(11):2126-2131.CrossRefPubMedGoogle Scholar
  15. 15.
    Hu Z, Chen J, Tian T, et al. Genetic variants of miRNA sequences and non-small cell lung cancer survival. J Clin Invest. 2008;118(7):2600-2608.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Yang PW, Huang YC, Hsieh CY, et al. Association of miRNA-related genetic polymorphisms and prognosis in patients with esophageal squamous cell carcinoma. Ann Surg Oncol. 2014;21 Suppl 4:S601-609.CrossRefPubMedGoogle Scholar
  17. 17.
    Kang JG, Majerciak V, Uldrick TS, et al. Kaposi’s sarcoma-associated herpesviral IL-6 and human IL-6 open reading frames contain miRNA binding sites and are subject to cellular miRNA regulation. J Pathol. 2011;225(3):378-389.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Kang JG, Pripuzova N, Majerciak V, Kruhlak M, Le SY, Zheng ZM. Kaposi’s sarcoma-associated herpesvirus ORF57 promotes escape of viral and human interleukin-6 from microRNA-mediated suppression. J Virol. 2011;85(6):2620-2630.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (eds). AJCC Cancer Staging Manual, 7th edition. New York: Springer; 2009. pp. 143-159.Google Scholar
  20. 20.
    Hu CP, Hsieh HG, Chien KY, et al. Biologic properties of three newly established human esophageal carcinoma cell lines. J Natl Cancer Inst. 1984;72(3):577-583.PubMedGoogle Scholar
  21. 21.
    Wuu KD, Cheng MY, Wang-Wuu S, Hu CP, Chang CM. Chromosome analysis on a cell line (CE48T/VGH) derived from a human esophageal carcinoma. Cancer Genet Cytogenet. 1986;20(3-4):279-285.CrossRefPubMedGoogle Scholar
  22. 22.
    Shimada Y, Imamura M, Wagata T, Yamaguchi N, Tobe T. Characterization of 21 Newly Established Esophageal Cancer Cell-Lines. Cancer. 1992;69(2):277-284.CrossRefPubMedGoogle Scholar
  23. 23.
    Yang PW, Chiang TH, Hsieh CY, et al. The effect of ephrin-A1 on resistance to Photofrin-mediated photodynamic therapy in esophageal squamous cell carcinoma cells. Lasers Med Sci. 2015;30(9):2353-2361.CrossRefPubMedGoogle Scholar
  24. 24.
    Yang PW, Hung MC, Hsieh CY, et al. The effects of Photofrin-mediated photodynamic therapy on the modulation of EGFR in esophageal squamous cell carcinoma cells. Lasers Med Sci. 2013;28(2):605-614.CrossRefPubMedGoogle Scholar
  25. 25.
    Duffy SA, Taylor JMG, Terrell JE, et al. Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer. 2008;113(4):750-757.CrossRefPubMedGoogle Scholar
  26. 26.
    Kita H, Shiraishi Y, Watanabe K, et al. Does Postoperative Serum Interleukin-6 Influence Early Recurrence after Curative Pulmonary Resection of Lung Cancer? Ann Thorac Cardiovas. 2011;17(5):454-460.CrossRefGoogle Scholar
  27. 27.
    Loochtan MJ, Balcarcel D, Carroll E, Foecking EM, Thorpe EJ, Charous SJ. Vocal Fold Paralysis after Esophagectomy for Carcinoma. Otolaryngol Head Neck Surg. 2016;155(1):122-126.CrossRefPubMedGoogle Scholar
  28. 28.
    Sato Y, Kosugi S, Aizawa N, et al. Risk Factors and Clinical Outcomes of Recurrent Laryngeal Nerve Paralysis After Esophagectomy for Thoracic Esophageal Carcinoma. World J Surg. 2016;40(1):129-136.CrossRefPubMedGoogle Scholar
  29. 29.
    Scholtemeijer MG, Seesing MFJ, Brenkman HJF, Janssen LM, van Hillegersberg R, Ruurda JP. Recurrent laryngeal nerve injury after esophagectomy for esophageal cancer: incidence, management, and impact on short- and long-term outcomes. J Thorac Dis. 2017;9 Suppl 8:S868-S878.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sato Y, Kosugi S, Aizawa N, et al. Risk Factors and Clinical Outcomes of Recurrent Laryngeal Nerve Paralysis After Esophagectomy for Thoracic Esophageal Carcinoma. World Journal of Surgery. 2016;40(1):129-136.CrossRefPubMedGoogle Scholar
  31. 31.
    Ryan BM, McClary AC, Valeri N, et al. rs4919510 in hsa-mir-608 is associated with outcome but not risk of colorectal cancer. PLoS One. 2012;7(5):e36306.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Xing J, Wan S, Zhou F, et al. Genetic polymorphisms in pre-microRNA genes as prognostic markers of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2012;21(1):217-227.CrossRefPubMedGoogle Scholar
  33. 33.
    Lin J, Horikawa Y, Tamboli P, Clague J, Wood CG, Wu XF. Genetic variations in microRNA-related genes are associated with survival and recurrence in patients with renal cell carcinoma. Carcinogenesis. 2010;31(10):1805-1812.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Lin MB, Gu J, Eng C, et al. Genetic Polymorphisms in MicroRNA-Related Genes as Predictors of Clinical Outcomes in Colorectal Adenocarcinoma Patients. Clin Cancer Res. 2012;18(14):3982-3991.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ma XP, Yu GP, Chen XB, et al. MiR-608 rs4919510 is associated with prognosis of hepatocellular carcinoma. Tumor Biol. 2016;37(7):9931-9942.CrossRefGoogle Scholar
  36. 36.
    Yang PW, Huang YC, Hsieh CY, et al. Association of miRNA-related Genetic Polymorphisms and Prognosis in Patients with Esophageal Squamous Cell Carcinoma. Annals of Surgical Oncology. 2014;21:S601-S609.CrossRefPubMedGoogle Scholar
  37. 37.
    Hu Y, Hong Y, Xu YJ, Liu P, Guo DH, Chen YB. Inhibition of the JAK/STAT pathway with ruxolitinib overcomes cisplatin resistance in non-small-cell lung cancer NSCLC. Apoptosis. 2014;19(11):1627-1636.CrossRefPubMedGoogle Scholar
  38. 38.
    Pemmaraju N, Kantarjian H, Kadia T, et al. A phase I/II study of the Janus kinase (JAK)1 and 2 inhibitor ruxolitinib in patients with relapsed or refractory acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2015;15(3):171-176.CrossRefPubMedGoogle Scholar
  39. 39.
    Tak PP, Firestein GS. NF-kappaB: a key role in inflammatory diseases. J Clin Invest. 2001;107(1):7-11.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Libermann TA, Baltimore D. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol. 1990;10(5):2327-2334.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Society of Surgical Oncology 2018

Authors and Affiliations

  • Pei-Wen Yang
    • 1
  • Pei-Ming Huang
    • 1
  • Luo-Sheng Yong
    • 1
  • Ya-Han Chang
    • 1
  • Chia-Wei Wu
    • 1
  • Kuo-Tai Hua
    • 2
  • Min-Shu Hsieh
    • 3
    • 4
  • Jang-Ming Lee
    • 1
  1. 1.Department of SurgeryNational Taiwan University Hospital and National Taiwan University College of MedicineTaipeiTaiwan
  2. 2.Graduate Institute of ToxicologyNational Taiwan University HospitalTaipeiTaiwan
  3. 3.Graduate Institute of Pathology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
  4. 4.Department of PathologyNational Taiwan University Hospital and National Taiwan University College of MedicineTaipeiTaiwan

Personalised recommendations