Publikationsserver der Universitätsbibliothek Marburg

Titel: Expression des Suppressors zytokiner Signalübertragung 3 (SOCS3) in humanem klarzelligem Nierenzellkarzinom versus gesundem Nierengewebe
Autor: Stumpf, Svenja
Weitere Beteiligte: Urbschat, Anja (PD Dr. med.)
Veröffentlicht: 2017
URN: urn:nbn:de:hebis:04-z2017-05681
DDC: 610 Medizin, Gesundheit
Titel(trans.): Expression of suppressor of cytokine signaling 3 (SOCS3) in human clear cell renal cell carcinoma versus healthy renal tissue
Publikationsdatum: 2017-09-20


STAT3, SOCS3, kidney cancer, suppressor of cytokine signaling 3, Nierenzellkarzinom, renal cell cancer, Hypernephrom

Der suppressor of cytokine signaling 3 (SOCS3) ist ein negativer Gegenspieler des signal transducer and activator of transcription 3 (STAT3). STAT3 selbst ist ein Transkriptionsfaktor und reguliert Zielgene, die bei der Zellproliferation, Differenzierung und Tumorentstehung beteiligt sind. STAT3 liegt im humanen Nierenzellkarzinom phosphoryliert und damit konstitutiv aktiv vor. Wir untersuchten die Expression von SOCS3 in Gewebeproben aus humanem klarzelligen Nierenzellkarzinom sowie dem benachbarten gesunden Nierengewebe von 35 Patienten. Des Weiteren stimulierten wir Caki-1-Zellen, eine kommerziell erhältliche Zelllinie, die aus einem klarzelligen Nierenzellkarzinom stammt, mit den Zytokinen IL-6 und IFN-γ und untersuchten die SOCS3-Expression. SOCS3 wurde in den humanen Gewebeproben auf Genebene mittels Realtime-TaqMan-PCR sowie auf der Ebene des Proteins mittels Westernblot und Immunohistochemie dargestellt. Wir beobachteten eine signifikant niedrigere SOCS3-Expression im Tumorgewebe gegenüber dem gesunden Nierengewebe. Dahingegen zeigte sich das SOCS3-Protein im Tumorgewebe höher exprimiert als im zugehörigen gesunden Nierengewebe. Die Stimulation der Caki-1-Zellen mit IL-6 zeigte keinen Anstieg der SOCS3-Expression. Nach Stimulation mit IFN-γ konnte hingegen ein signifikanter Anstieg festgestellt werden. Aus den Ergebnissen lässt sich entnehmen, dass SOCS3 im klarzelligen Nierenzellkarzinom reguliert ist und daher in der Tumorentstehung und der Tumorausbreitung involviert sein könnte. SOCS3 könnte ein neues Zielprotein in der onkologischen Therapie des klarzelligen Nierenzellkarzinoms sein, da es in der Lage ist, den aktivierten JAK-STAT-Signalweg zu beeinflussen. Ob weitere lokale Faktoren in der Tumormikroumgebung an der SOCS3-Regulation beteiligt sind und welche genaue Funktion SOCS3 auf pSTAT3 im Nierenzellkarzinom hat, lässt sich nur durch weiterführende Untersuchungen beantworten.

The suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of the signal transducer and activator of transcription 3 (STAT3). STAT3 is a transcription factor and controls target genes, which are involved in cell proliferation, differentiation and tumorigenic process. STAT3 is existent in a phosphorylated form in human renal cell carcinoma and is thereby constitutively activated. We investigated the expression of SOCS3 in tissue samples of human clear cell renal cell carcinoma compared with adjacent healthy renal tissue of 35 patients. Furthermore, we stimulated Caki-1-cells, a commercially available cell line which origines from a clear cell renal cell carcinoma, with the cytokines IL-6 and IFN-γ and measured the SOCS3-expression hereafter. The SOCS3-gene was represented by realtime-taqman-PCR in the human tissue samples, the SOCS3-protein was detected by westernblot and immunohistochemistry. We observed a significant lower SOCS3-mRNA-expression in tumor tissue than in adjacent healthy renal tissue. Whereas the SOCS3-protein was higher expressed in tumor tissue than in adjacent healthy renal tissue. The stimulation of Caki-1-cells with IL-6 generated no increase of SOCS3-expression. However, after stimulation with IFN-γ, a significant increase of SOCS3-expression was determined. In conclusion, the results show that SOCS3 is regulated in human clear cell renal cell carcinoma and that it might be involved in tumorigenic process and tumor dissemination. SOCS3 could represent a new target protein in the oncologic therapy of clear cell renal cell carcinoma considering its ability to influence the activated JAK-STAT-pathway. However, further examinations are necessary to investigate whether additional local factors within the tumor microenvironment may be involved in the SOCS3-regulation and to reveal the detailed effect SOCS3 exerts on pSTAT3 in renal cell carcinoma.

Bibliographie / References

  1. 13 Castro, A., Jr., L. C. Jenkins, N. Salas, G. Lorber and R. J. Leveillee (2013). "Ablative therapies for small renal tumours." Nat Rev Urol 10(5): 284-291.
  2. 43 Horiguchi, A., M. Oya, T. Shimada, A. Uchida, K. Marumo and M. Murai (2002). "Activation of signal transducer and activator of transcription 3 in renal cell carcinoma: a study of incidence and its association with pathological features and clinical outcome." J Urol 168(2): 762-765.
  3. 34 Guo, C., G. Yang, K. Khun, X. Kong, D. Levy, P. Lee and J. Melamed (2009). "Activation of Stat3 in renal tumors." Am J Transl Res 1(3): 283-290.
  4. 57 Koebel, C. M., W. Vermi, J. B. Swann, N. Zerafa, S. J. Rodig, L. J. Old, M. J. Smyth and R. D. Schreiber (2007). "Adaptive immunity maintains occult cancer in an equilibrium state." Nature 450(7171): 903-907.
  5. 28 Frank, I., M. L. Blute, J. C. Cheville, C. M. Lohse, A. L. Weaver and H. Zincke (2002). "An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score." J Urol 168(6): 2395-2400.
  6. 70 Mandal, A., Y. Littler and G. Libertiny (2012). "Asymptomatic renal cell carcinoma with metastasis to the skin and duodenum: a case report and review of the literature." BMJ Case Rep 2012.
  7. 56 Kobayashi, A., M. Takahashi, H. Imai, S. Akiyama, S. Sugiyama, K. Komine, K. Saijo, S. Takahashi, H. Shirota, N. Sato, F. Fujishima, T. Shuin, H. Shimodaira and C. Ishioka (2016). "Attainment of a Long-term Favorable Outcome by Sunitinib
  8. 38 Hilvo, M., L. Baranauskiene, A. M. Salzano, A. Scaloni, D. Matulis, A. Innocenti, A. Scozzafava, S. M. Monti, A. Di Fiore, G. De Simone, M. Lindfors, J. Janis, J. Valjakka, S. Pastorekova, J. Pastorek, M. S. Kulomaa, H. R. Nordlund, C. T. Supuran and S. Parkkila (2008). "Biochemical characterization of CA IX, one of the most active carbonic anhydrase isozymes." The Journal of biological chemistry 283(41): 27799-27809.
  9. 32 Glube, N., A. Giessl, U. Wolfrum and P. Langguth (2007). "Caki-1 cells represent an in vitro model system for studying the human proximal tubule epithelium." Nephron Exp Nephrol 107(2): e47-56.
  10. 59 Laemmli, U. K. (1970). "Cleavage of structural proteins during the assembly of the head of bacteriophage T4." Nature 227(5259): 680-685.
  11. 79 Nerich, V., M. Hugues, M. J. Paillard, L. Borowski, T. Nai, U. Stein, T. Nguyen Tan Hon, P. Montcuquet, T. Maurina, G. Mouillet, F. Kleinclauss, X. Pivot, S. Limat and A. Thiery-Vuillemin (2014). "Clinical impact of targeted therapies in patients with metastatic clear-cell renal cell carcinoma." Onco Targets Ther 7: 365- 374.
  12. 50 Jeong, W., K. H. Rha, H. H. Kim, S. S. Byun, T. G. Kwon, I. Y. Seo, G. T. Sung, S. H. Jeon, Y. B. Jeong and S. H. Hong (2011). "Comparison of laparoscopic radical nephrectomy and open radical nephrectomy for pathologic stage T1 and T2 renal cell carcinoma with clear cell histologic features: a multi-institutional study." Urology 77(4): 819-824.
  13. 73 Milonas, D., G. Skulcius, R. Baltrimavicius, S. Auskalnis, M. Kincius, A. Matjosaitis, I. Gudinaviciene, G. Smailyte and M. Jievaltas (2013). "Comparison of long-term results after nephron-sparing surgery and radical nephrectomy in treating 4- to 7-cm renal cell carcinoma." Medicina (Kaunas) 49(5): 223-228.
  14. 20 Dash, A., A. J. Vickers, L. R. Schachter, A. M. Bach, M. E. Snyder and P. Russo (2006). "Comparison of outcomes in elective partial vs radical nephrectomy for clear cell renal cell carcinoma of 4-7 cm." BJU international 97(5): 939-945.
  15. 16 Cheville, J. C., C. M. Lohse, H. Zincke, A. L. Weaver and M. L. Blute (2003). "Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma." Am J Surg Pathol 27(5): 612-624.
  16. 54 King, S. C., L. Pollack, J. Li, J. B. King and V. A. Master (2014). "Continued Rise in Incidence of Renal Cell Carcinoma, Especially in Young and High-Grade Disease-US 2001-2010." J Urol.
  17. 58 Kunkle, D. A. and R. G. Uzzo (2008). "Cryoablation or radiofrequency ablation of the small renal mass : a meta-analysis." Cancer 113(10): 2671-2680.
  18. 27 Flanigan, R. C., G. Mickisch, R. Sylvester, C. Tangen, H. Van Poppel and E. D. Crawford (2004). "Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis." J Urol 171(3): 1071-1076.
  19. 74 Minegishi, Y., M. Saito, S. Tsuchiya, I. Tsuge, H. Takada, T. Hara, N. Kawamura, T. Ariga, S. Pasic, O. Stojkovic, A. Metin and H. Karasuyama (2007). "Dominantnegative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome." Nature 448(7157): 1058-1062.
  20. 26 Evans, M. K., C. R. Yu, A. Lohani, R. M. Mahdi, X. Liu, A. R. Trzeciak and C. E. Egwuagu (2007). "Expression of SOCS1 and SOCS3 genes is differentially regulated in breast cancer cells in response to proinflammatory cytokine and growth factor signals." Oncogene 26(13): 1941-1948.
  21. 18 Clague, J., J. Lin, A. Cassidy, S. Matin, N. M. Tannir, P. Tamboli, C. G. Wood and X. Wu (2009). "Family history and risk of renal cell carcinoma: results from a casecontrol study and systematic meta-analysis." Cancer Epidemiol Biomarkers Prev 18(3): 801-807.
  22. 19 Cobo-Dols, M., I. Ales-Diaz, E. Villar-Chamorro, S. Gil-Calle, J. Alcaide-Garcia, A. Montesa-Pino, V. Gutierrez-Calderon and M. Benavides-Orgaz (2006). "Solitary metastasis in a nasal fossa as the first manifestation of a renal carcinoma." Clin Transl Oncol 8(4): 298-300.
  23. 14 Chang, D. K., R. J. Moniz, Z. Xu, J. Sun, S. Signoretti, Q. Zhu and W. A. Marasco (2015). "Human anti-CAIX antibodies mediate immune cell inhibition of renal cell carcinoma in vitro and in a humanized mouse model in vivo." Mol Cancer 14: 119.
  24. 33 Gore, M. E., C. L. Griffin, B. Hancock, P. M. Patel, L. Pyle, M. Aitchison, N. James, R. T. Oliver, J. Mardiak, T. Hussain, R. Sylvester, M. K. Parmar, P. Royston and P. F. Mulders (2010). "Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial." Lancet 375(9715): 641-648.
  25. 75 Motzer, R. J., J. Bacik, B. A. Murphy, P. Russo and M. Mazumdar (2002). "Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma." J Clin Oncol 20(1): 289-296.
  26. 41 Hong, D. S., L. S. Angelo and R. Kurzrock (2007). "Interleukin-6 and its receptor in cancer: implications for translational therapeutics." Cancer 110(9): 1911-1928.
  27. 46 Hrab, M., K. Olek-Hrab, A. Antczak, Z. Kwias and T. Milecki (2013). "Interleukin6 (IL-6) and C-reactive protein (CRP) concentration prior to total nephrectomy are prognostic factors in localized renal cell carcinoma (RCC)." Rep Pract Oncol Radiother 18(5): 304-309.
  28. 72 Miki, S., M. Iwano, Y. Miki, M. Yamamoto, B. Tang, K. Yokokawa, T. Sonoda, T. Hirano and T. Kishimoto (1989). "Interleukin-6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas." FEBS Lett 250(2): 607-610.
  29. 12 Casneuf, T., A. E. Axel, P. King, J. D. Alvarez, J. L. Werbeck, T. Verhulst, K. Verstraeten, B. M. Hall and A. K. Sasser (2016). "Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-alpha-positive breast cancer." Breast Cancer (Dove Med Press) 8: 13-27.
  30. 21 Decker, T. and A. Meinke (1997). "Jaks, Stats and the immune system." Immunobiology 198(1-3): 99-111.
  31. 31 Ganini, C., A. Lasagna, E. Ferraris, P. Gatti, C. Paglino, I. Imarisio, P. Morbini, M. Benazzo and C. Porta (2012). "Lingual metastasis from renal cell carcinoma: a case report and literature review." Rare Tumors 4(3): e41.
  32. 77 Murakami, Y., K. Kanda, M. Tsuji, H. Kanayama and S. Kagawa (1999). "MN/CA9 gene expression as a potential biomarker in renal cell carcinoma." BJU international 83(7): 743-747.
  33. 60 Lee, C. T., J. Katz, P. A. Fearn and P. Russo (2002). "Mode of presentation of renal cell carcinoma provides prognostic information." Urol Oncol 7(4): 135-140.
  34. 44 Horiuchi, Y., S. J. Bae and I. Katayama (2006). "Overexpression of the suppressor of cytokine signalling 3 (SOCS3) in severe atopic dermatitis." Clin Exp Dermatol 31(1): 100-104.
  35. 37 Heng, D. Y., W. Xie, M. M. Regan, M. A. Warren, A. R. Golshayan, C. Sahi, B. J. Eigl, J. D. Ruether, T. Cheng, S. North, P. Venner, J. J. Knox, K. N. Chi, C. Kollmannsberger, D. F. McDermott, W. K. Oh, M. B. Atkins, R. M. Bukowski, B. I. Rini and T. K. Choueiri (2009). "Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factortargeted agents: results from a large, multicenter study." J Clin Oncol 27(34): 5794- 5799.
  36. 25 Erdogan, F., A. Demirel and O. Polat (2004). "Prognostic significance of morphologic parameters in renal cell carcinoma." Int J Clin Pract 58(4): 333-336.
  37. 39 Hoegl, S., M. Bachmann, P. Scheiermann, I. Goren, C. Hofstetter, J. Pfeilschifter, B. Zwissler and H. Muhl (2011). "Protective properties of inhaled IL-22 in a model of ventilator-induced lung injury." American journal of respiratory cell and molecular biology 44(3): 369-376.
  38. 47 Huguenin, P. U., S. Kieser, C. Glanzmann, R. Capaul and U. M. Lutolf (1998). "Radiotherapy for metastatic carcinomas of the kidney or melanomas: an analysis using palliative end points." Int J Radiat Oncol Biol Phys 41(2): 401-405.
  39. 30 Fujimoto, M. and T. Naka (2003). "Regulation of cytokine signaling by SOCS family molecules." Trends Immunol 24(12): 659-666.
  40. 55 Klatte, T., B. Streubel, F. Wrba, M. Remzi, B. Krammer, M. de Martino, M. Waldert, M. Marberger, M. Susani and A. Haitel (2012). "Renal cell carcinoma associated with transcription factor E3 expression and Xp11.2 translocation: incidence, characteristics, and prognosis." Am J Clin Pathol 137(5): 761-768.
  41. 48 Hwang, E. C., H. S. Yu and D. D. Kwon (2013). "Small renal masses: surgery or surveillance." Korean J Urol 54(5): 283-288.
  42. 36 He, B., L. You, K. Uematsu, K. Zang, Z. Xu, A. Y. Lee, J. F. Costello, F. McCormick and D. M. Jablons (2003). "SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer." Proceedings of the National Academy of Sciences of the United States of America 100(24): 14133- 14138.
  43. 76 Mullis, K., F. Faloona, S. Scharf, R. Saiki, G. Horn and H. Erlich (1986). "Specific enzymatic amplification of DNA in vitro: the polymerase chain reaction." Cold Spring Harb Symp Quant Biol 51 Pt 1: 263-273.
  44. 42 Horiguchi, A., M. Oya, K. Marumo and M. Murai (2002). "STAT3, but not ERKs, mediates the IL-6-induced proliferation of renal cancer cells, ACHN and 769P." Kidney Int 61(3): 926-938.
  45. 22 Dominissini, D., S. Nachtergaele, S. Moshitch-Moshkovitz, E. Peer, N. Kol, M. S. Ben-Haim, Q. Dai, A. Di Segni, M. Salmon-Divon, W. C. Clark, G. Zheng, T. Pan, O. Solomon, E. Eyal, V. Hershkovitz, D. Han, L. C. Dore, N. Amariglio, G. Rechavi and C. He (2016). "The dynamic N(1)-methyladenosine methylome in eukaryotic messenger RNA." Nature 530(7591): 441-446.
  46. 15 Chang, Q., E. Bournazou, P. Sansone, M. Berishaj, S. P. Gao, L. Daly, J. Wels, T. Theilen, S. Granitto, X. Zhang, J. Cotari, M. L. Alpaugh, E. de Stanchina, K. Manova, M. Li, M. Bonafe, C. Ceccarelli, M. Taffurelli, D. Santini, G. AltanBonnet, R. Kaplan, L. Norton, N. Nishimoto, D. Huszar, D. Lyden and J. Bromberg (2013). "The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis." Neoplasia 15(7): 848-862.
  47. 78 Murray, P. J. (2007). "The JAK-STAT signaling pathway: input and output integration." Journal of immunology 178(5): 2623-2629.
  48. 17 Choueiri, T. K., F. A. Schutz, N. D. Hevelone, P. L. Nguyen, S. R. Lipsitz, S. B. Williams, S. G. Silverman and J. C. Hu (2011). "Thermal ablation vs surgery for localized kidney cancer: a Surveillance, Epidemiology, and End Results (SEER) database analysis." Urology 78(1): 93-98.

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