Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Significance of Suppressor of Cytokine Signaling-3 Expression in Bladder Urothelial Carcinoma in Relation to Proinflammatory Cytokines and Tumor Histopathological Grading

  • Published : 2015.02.04
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Bladder cancer is among the five most common malignancies worldwide. Altered expression of suppressor of cytokine signaling -3 (SOCS-3) has been implicated in various types of human cancers; however, its role in bladder cancer is not well established. Aim: The present study was undertaken to investigate the mRNA expression of SOCS-3 in normal and cancerous bladder tissue and to explore its correlation with urinary levels of some proinflammatory cytokines, cytokeratin-18 (CK -18) and with tumor histopathological grading, in order to evaluate their role as potential diagnostic markers. Materials and Methods: SOCS3 mRNA expression levels were evaluated using quantitative real time PCR. Urinary levels of interleukins 6 and 8 were estimated by enzyme linked immunosorbent assay (ELISA). Cytokeratin-18 expression was analyzed by immuunohistochemistry then validated by ELISA. Results: SOC3 m RNA expression levels were significantly lower in high grade urothelial carcinoma ($0.36{\pm}0.12$) compared to low grade carcinoma ($1.22{\pm}0.38$) and controls ($4.08{\pm}0.88$), (p<0.001). However, in high grade urothelial carcinoma the urinary levels of IL-6, IL-8, total CK-18($221.33{\pm}22.84pg/ml$, $325.2{\pm}53.6pg/ml$, $466.7{\pm}57.40U/L$ respectively) were significantly higher than their levels in low grade carcinoma ($58.6{\pm}18.6pg/ml$, $58.3{\pm}50.2pg/ml$, $185.5{\pm}60.3U/L$ respectively) and controls ($50.9{\pm}23.0pg/ml$, $7.12{\pm}2.74pg/ml$, $106.7{\pm}47.3U/L$ respectively), (p<0.001). Conclusions: Advanced grade of urothelial bladder carcinoma is significantly associated with lowered mRNA expression of SOC3 as well as elevated urinary levels of proinflammatory cytokines and CK-18. Furthermore, our results suggested that urinary IL-8, IL-6 and CK-18 may benefit as noninvasive biomarkers for early detection as well as histopathological subtyping of urothelial carcinoma.

Keywords

References

  1. Al-Jamal HA, Jusoh SA, Yong AC, et al (2014). Silencing of suppressor of cytokine signaling-3 due to methylation results in phosphorylation of STAT3 in imatinib resistant BCR-ABL positive chronic myeloid leukemia cells. Asian Pac J Cancer Prev, 15, 4555-61. https://doi.org/10.7314/APJCP.2014.15.11.4555
  2. Attia FM, Hassan AM, El-Maraghy NN, et al (2011). Clinical significance of suppressor of cytokines signalling-3 mRNA expression from patients with non-Hodgkin lymphoma under chemotherapy. Cancer Biomark, 11, 41-7.
  3. Baltayiannis G, Baltayiannis N, Tsianos EV. (2008). Suppressors of cytokine signaling as tumor repressors. Silencing of SOCS3 facilitates tumor formation and growth in lung and liver. J BUO, 13, 263-5.
  4. Benedict WF, Fisher M, Zhang XQ, et al (2014). Use of monitoring levels of soluble forms of cytokeratin 18 in the urine of patients with superficial bladder cancer following intravesical Ad-$IFN\alpha$/Syn3 treatment in a phase l study. Cancer Gene Ther, 21, 91-4. https://doi.org/10.1038/cgt.2014.1
  5. Chen CL, Cen L, Kohout J, et al (2008). Signal transducer and activator of transcription3 activation is associated with bladder cancercell growth and survival. Mol Cancer, 7, 78. https://doi.org/10.1186/1476-4598-7-78
  6. Chen MF, Lin PY, Wu CF, et al (2013). IL-6 expression regulates tumorigenicity and correlates with prognosis in bladder cancer. PLoS One, 8, 61901. https://doi.org/10.1371/journal.pone.0061901
  7. Culig Z (2013). Suppressors of cytokine signalling-3 and -1 in human carcinogenesis. Front Biosci, 1, 277-83.
  8. da Silva CG, Studer P, Skroch M, et al (2013). A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals. Hepatology, 57, 2014-25. https://doi.org/10.1002/hep.26197
  9. Ebadi N, Jahed M, Mivehchi M, et al (2014). Interleukin-12 and interleukin-6 gene polymorphisms and risk of bladder cancer in the Iranian population. Asian Pac J Cancer Prev, 15, 7869-73. https://doi.org/10.7314/APJCP.2014.15.18.7869
  10. Fajkovic H, Halpern JA, Cha EK, et al (2011). Impact of gender on bladder cancer incidence, staging, and prognosis. World J Urol, 29, 457-63. https://doi.org/10.1007/s00345-011-0709-9
  11. Furqan M, Mukhi N, Lee B, et al (2013). Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application. Biomark Res, 1, 5. https://doi.org/10.1186/2050-7771-1-5
  12. Ghafouri-Fard S, Nekoohesh L, Motevaseli E. (2014). Bladder cancer biomarkers, review and update. Asian Pac J Cancer Prev, 15, 2395-403. https://doi.org/10.7314/APJCP.2014.15.6.2395
  13. Huang WT, Yang SF, Wu CC, et al (2009). Expression of signal transducer and activator of transcription 3 and suppressor of cytokine signaling 3 in urothelial carcinoma. Kaohsiung J Med Sci, 25, 640-6. https://doi.org/10.1016/S1607-551X(09)70569-8
  14. Karantza V. (2011). Keratins in health and cancer, more than mere epithelial cell markers. Oncogene, 30, 127-38. https://doi.org/10.1038/onc.2010.456
  15. Kobeissi LH, Yassine IA, Jabbour ME, et al (2013). Urinary bladder cancer risk factors, a Lebanese case- control study. Asian Pac J Cancer Prev, 14, 3205-11. https://doi.org/10.7314/APJCP.2013.14.5.3205
  16. Li N, Grivennikov SI, Karin M (2011). The unholy trinity, inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell, 19, 429-31. https://doi.org/10.1016/j.ccr.2011.03.018
  17. Li Y, Deuring J, Peppelenbosch MP, et al (2012). IL-6-induced DNMT1 activity mediates SOCS3 promoter hypermethylation in ulcerative colitis-related colorectal cancer. Carcinogenesis, 33, 1889-96. https://doi.org/10.1093/carcin/bgs214
  18. Linossi EM, Babon JJ, Hilton DJ, et al (2013). Suppression of cytokine signaling, the SOCS perspective. Cytokine Growth Factor Rev, 24, 241-8. https://doi.org/10.1016/j.cytogfr.2013.03.005
  19. Lippitz BE. (2013). Cytokine patterns in patients with cancer, a systematic review. Lancet Oncol, 14, 218-28. https://doi.org/10.1016/S1470-2045(12)70582-X
  20. Margel D, Pevsner-Fischer M, Baniel J, et al (2011). Stress proteins and cytokines are urinary biomarkers for diagnosis and staging of bladder cancer. Eur Urol, 59, 113-9. https://doi.org/10.1016/j.eururo.2010.10.008
  21. McConkey DJ, Lee S, Choi W, et al (2010). Molecular genetics of bladder cancer, Emerging mechanisms of tumor initiation and progression. Urol Oncol, 28, 429-40. https://doi.org/10.1016/j.urolonc.2010.04.008
  22. Messai Y1, Noman MZ, Derouiche A, et al (2010). Cytokeratin 18 expression pattern correlates with renal cell carcinoma progression, relationship with Snail. Int J Oncol, 36, 1145-54.
  23. Montironi R, Lopez-Beltran A. (2005). The 2004 WHO classification of bladder tumors, a summary and commentary. Int J Surg Pathol, 13, 143-53. https://doi.org/10.1177/106689690501300203
  24. Paner GP, Annaiah C, Gulmann C, et al (2014). Immunohistochemical evaluation of novel and traditional markers associated with urothelial differentiation in a spectrum of variants of urothelial carcinoma of the urinary bladder. Hum Pathol, 45, 1473-82. https://doi.org/10.1016/j.humpath.2014.02.024
  25. Quintas-Cardama A, Verstovsek S (2013). Molecular pathways, Jak/STAT pathway, mutations, inhibitors, and resistance. Clin Cancer Res, 19, 1933-40. https://doi.org/10.1158/1078-0432.CCR-12-0284
  26. Ramazan Sekeroglu M, Aydin S, Dulger H, et al (2002). Diagnostic value of cytokeratin-18 as a tumor marker in bladder cancer. Clin Biochem, 35, 327-31. https://doi.org/10.1016/S0009-9120(02)00321-1
  27. Reis ST, Leite KR, Piovesan LF, et al (2012). Increased expression of MMP-9 and IL-8 are correlated with poor prognosis of Bladder Cancer. BMC Urol, 12, 18. https://doi.org/10.1186/1471-2490-12-18
  28. Rossa C Jr, Sommer G, Spolidorio LC, et al (2012). Loss of expression and function of SOCS3 is an early event in HNSCC, altered subcellular localization as a possible mechanism involved in proliferation, migration and invasion. PLoS One, 7, 45197. https://doi.org/10.1371/journal.pone.0045197
  29. Roth GA, Lebherz-Eichinger D, Ankersmit HJ, et al (2011). Increased total cytokeratin-18 serum and urine levels in chronic kidney disease. Clin Chim Acta, 412, 713-7. https://doi.org/10.1016/j.cca.2010.12.030
  30. Santos CI, Costa-Pereira AP (2011). Signal transducers and activators of transcription-from cytokine signalling to cancer biology. Biochim Biophys Acta, 1816, 38-49.
  31. Sasi W, Jiang WG, Sharma A, et al (2010). Higher expression levels of SOCS 1,3,4,7 are associated with earlier tumour stage and better clinical outcome in human breast cancer. BMC Cancer, 10, 178. https://doi.org/10.1186/1471-2407-10-178
  32. Sharma AK, Mokbel K. (2014). The role of suppressors of cytokine signalling in human neoplasms. Mol Biol Int, 2014, 630797.
  33. Song JW, DU LL, Zhao XW, et al (2009). Expression and clinical significance of nuclear matrix protein 22 and cytokeratin 18 in transitional cell carcinoma of the bladder. Chinese J Oncol, 31, 274-7.
  34. Stahl A, Joyal JS, Chen J, et al (2012). SOCS3 is an endogenous inhibitor of pathologic angiogenesis. Blood, 120, 2925-9. https://doi.org/10.1182/blood-2012-04-422527
  35. Stofas A, Levidou G, Piperi C, et al (2014). The role of CXCchemokine receptor CXCR2 and suppressor of cytokine signaling-3 (SOCS-3) in renal cell carcinoma. BMC Cancer, 14, 149. https://doi.org/10.1186/1471-2407-14-149
  36. Taniguchi K, Karin M. (2014). IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol, 26, 54-74. https://doi.org/10.1016/j.smim.2014.01.001
  37. Topfer K, Kempe S, Muller N, et al (2011). Tumor evasion from T cell surveillance. J Biomed Biotechnol, 2011, 918471.
  38. Tsui KH, Wang SW, Chung LC, et al (2013). Mechanisms by which interleukin-6 attenuates cell invasion and tumorigenesis in human bladder carcinoma cells. Biomed Res Int, 2013, 791212.
  39. Urquidi V, Chang M, Dai Y, et al (2012). IL-8 as a urinary biomarker for the detection of bladder cancer. BMC Urol, 12, 12. https://doi.org/10.1186/1471-2490-12-12
  40. Walsh MJ, Jonsson JR, Richardson MM, et al (2006). Nonresponse to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1. Gut, 55, 529-35. https://doi.org/10.1136/gut.2005.069674
  41. Wang HF, Wang JS. (2012). Research progress in potential urinary markers for the early detection, diagnosis and follow-up of human bladder cancer. Asian Pac J Cancer Prev, 13, 1723-6. https://doi.org/10.7314/APJCP.2012.13.5.1723
  42. Wang J, Zhou H, Han Y, et al (2014). SOCS3 methylation in synergy with Reg3A overexpression promotes cell growth in pancreatic cancer. J Mol Med (Berl), 92, 1257-69. https://doi.org/10.1007/s00109-014-1184-8
  43. Weng YR, Cui Y, Fang JY. (2012). Biological functions of cytokeratin 18 in cancer. Mol Cancer Res, 10, 485-93. https://doi.org/10.1158/1541-7786.MCR-11-0222
  44. Wu WY, Li J, Wu ZS, et al (2011). Prognostic significance of phosphorylated signal transducer and activator of transcription 3 and suppressor of cytokine signaling 3 expression in hepatocellular carcinoma. Exp Ther Med, 2, 647-53.
  45. Ying M, Li D, Yang L, et al (2010). Loss of SOCS3 expression is associated with an increased risk of recurrent disease in breast carcinoma. J Cancer Res Clin Oncol, 136, 1617-26. https://doi.org/10.1007/s00432-010-0819-6
  46. Yu ZB, Bai L, Qian P, et al (2009). Restoration of SOCS3 suppresses human lung adenocarcinoma cell growth by downregulating activation of Erk1/2, Akt apart from STAT3. Cell Biol Int, 33, 995-1001. https://doi.org/10.1016/j.cellbi.2009.06.002
  47. Zarogoulidis P, Katsikogianni F, Tsiouda T, et al (2014). Interleukin-8 and interleukin-17 for cancer. Cancer Invest, 32, 197-205. https://doi.org/10.3109/07357907.2014.898156

Cited by

  1. Editorial Comment from Dr Minardi and Dr Fulvi to Predictive value of urinary interleukin-6 for symptomatic urinary tract infections in a nursing home population vol.23, pp.2, 2016, https://doi.org/10.1111/iju.13053