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Pankreas duktal adenokarsinomunda NF-Kappa B ekspresyonu

Year 2019, Volume: 44 Issue: 2, 494 - 501, 30.06.2019
https://doi.org/10.17826/cumj.481396

Abstract

Amaç: Bu çalışmada, NF-KB kompleksinin alt grubu olan p65 ve fosfo-IKB-alfa antikor ile NF-KB’nin aktivasyonu durumu araştırılmıştır.

Gereç ve Yöntem: Doku mikroarray yöntemi ile 107 olgu üzerinden yapılan çalışmada antikorun boyanması, boyanma şiddeti ve yüzdesi beraber değerlendirilerek skorlandı. Cell Signaling Technology ürünlerinden p65 ve fosfo-IKB-alfa(ser32/36) kullanıldı. Boyanma skorlarının arşiv bilgileri doğrultusunda cerrahi sınır, lenf bezi durumu, evre, tümör boyutu ve klinik bilgiler ışığında genel yaşam süresi ile korelasyonu araştırıldı. 

Bulgular: P65 nükleer, p-IkB-alfa sitoplazmik boyanma paterni izledi. Karsinomda, tümör içermeyen bölgelerle kıyaslandığında boyanma belirgin oranda şiddetli olup ve NF-KB aktivitesinde artış mevcuttu. NF-kB(p65) ekspresyonu, lenf bezi durumu ile anlamlı bir korelasyon göstermekle birlikte  yaş, ırk, cinsiyet, tümör lokalizasyonu, tümör boyutu, tümör derecesi ve genel yaşam süresi ile NF-KB(p65), pIkBalfa arasında korelasyon izlenmedi.

Sonuç: Lenf bezi durumu ile NF-KB aktivitesinin korelasyonu tümörün invaziv olma özelliğini ön plana çıkartmakta olup pankreas karsinogenezinde erken aşamalarda görülmesi tedavi açılımlarının geliştirilmesi açısından hedef molekül olabileceğini düşündürmektedir.


References

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  • 25) Brennan M, Moccia R, Klimstra D. Management of adenocarcinoma of the body and tail of the pancreas. Ann Surg. 1996; 223(5):506-11.
  • 26) Luttges J, Vogel I, Menke M, Henne-Bruns D, Kremer B, Kloppel G. The retroperitoneal resection margin and vessel involvement are important factors determining survival after pancreaticoduodenectomy for ductal adenocarcinoma of the head of the pancreas. Virchows Arch. 1998;433(3):237-42.
  • 27) Neoptolemos J, Stocken D, Friess H, Bassi C, Dunn J, Hickey H ve ark. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200-10.
  • 28) Nagakawa T, Nagamori M, Futakami F, Tsukioka Y, Kayahara M, Ohta T ve ark. Results of extensive surgery for pancreatic carcinoma. Cancer.1996;77(4):640-5.
  • 29) Trede M, Schwall G, Saeger H. Survival after pancreatoduodenectomy. 118 consecutive resections without an operative mortality. Ann Surg. 1990; 211(4):447-58.
  • 30) Carpelan-Holmstrom M, Nordling S, Pukkala E, Sankila R, Luttges J, Kloppel G ve ark. Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry. Gut. 2005; 54(3):385-7.
  • 31) Jimeno A, Hidalgo M. Molecular biomarkers: their increasing role in the diagnosis, characterization, and therapy guidance in pancreatic cancer. Mol Cancer Ther. 2006; 5(4):787-96.
  • 32) Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006; 441(7092):431-6.
  • 33) Gilmore T. Introduction to NF-kappaB: players, pathways, perspectives. Oncogene. 2006; 25(51):6680-4.
  • 34) Verma I, Stevenson J, Schwarz E, Van Antwerp D, Miyamoto S. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev. 1995; 9(22):2723-35.
  • 35) Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol. 1994;10:405-55
  • 36) Baldwin, A. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996; 14:649-83.
  • 37) Ghosh, S, May M, Kopp E. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998; 16:225-60.
  • 38) Ghosh, S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell. 2002; 109 Suppl: 81-96.
  • 39) Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000; 18:621-63.
  • 40) Wei H, Wang B, Miyagi M, She Y, Gopalan B, Huang DB ve ark. PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB. Proc Natl Acad Sci. 2013;110(33): 13516–13521.
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  • 45) Sumitomo M, Tachibana M, Ozu C, Asakura H, Murai M, Hayakawa M ve ark. Induction of apoptosis of cytokine-producing bladder cancer cells by adenovirus-mediated IkappaBalpha overexpression. Hum Gene Ther. 1999;10(1):37-47.
  • 46) Sumitomo M, Tachibana M, Nakashima J, Murai M, Miyajima A, Kimura F ve ark. An essential role for nuclear factor kappa B in preventing TNF-alpha-induced cell death in prostate cancer cells. J Urol. 1999; 161(2):674-9.
  • 47) Motokura T, Arnold A. PRAD1/cyclin D1 proto-oncogene: genomic organization, 5' DNA sequence, and sequence of a tumor-specific rearrangement breakpoint. Genes Chromosomes Cancer. 1993;7(2):89-95.
  • 48) Visconti R, Cerutti J, Battista S, Fedele M, Trapasso F, Zeki K ve ark. Expression of the neoplastic phenotype by human thyroid carcinoma cell lines requires NFkappaB p65 protein expression. Oncogene. 1997;15(16):1987-94.
  • 49) Suh J, Payvandi F, Edelstein L, Amenta P, Zong W, Gelinas C ve ark. Mechanisms of constitutive NF-kappaB activation in human prostate cancer cells. Prostate. 2002; 52(3):183-200.
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  • 52) Pham N, Schwock J, Iakovlev V, Pond G, Hedley D, Tsao M. Immunohistochemical analysis of changes in signaling pathway activation downstream of growth factor receptors in pancreatic duct cell carcinogenesis. BMC Cancer. 2008; 8:43.
  • 53) Weichert W, Boehm M, Gekeler V, Bahra M, Langrehr J, Neuhaus P ve ark. High expression of RelA/p65 is associated with activation of nuclear factor-kappaB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis. Br J Cancer. 2007;97(4):523-30.

NF-Kappa B expression in pancreatic ductal carcinoma

Year 2019, Volume: 44 Issue: 2, 494 - 501, 30.06.2019
https://doi.org/10.17826/cumj.481396

Abstract

Purpose: In this study we investigated the expression of the p65 subunit of the nuclear factor-kappaB (NF-kB)  complex and  the activation status of NF-kB by phospho-IkB-alpha antibody.

Materials and Methods: A tissue microarray based on material obtained from 107 patients was utilized. The antibody staining was scored by combining staining intensity with percentage of tumor staining. The antibodies used were NF-kB p65 and phospho-IkB-alpha(ser32/36), both from Cell Signaling Technology. The staining scores were correlated with the archival data available on some patients on margin and lymph node status, stage, tumor size, as well as clinical data including survival.

Results: The staining was nuclear (p65) and cytoplasmic (p-IkBalpha) respectively. In general there was an increased expression and activation of NF-kB in the carcinomas, compared to non-tumoral regions. None of the markers had a significant correlation with the overall survival. NF-kB(p65) expression had a correlation with positive lymph node status.

Conclusion: The correlation with the positive lymph node status suggests a role in invasive properties of the tumor. Activation of NF-kB is most likely an early event in pancreatic carcinogenesis. Despite the lack of an effect on overall survival, due to its increased activation in pancreatic cancer, NF-kB is still a good target for therapeutic interventions.


References

  • 1) Siegel R, Miller K, Jemal A. Cancer statistics. 2018. CA Cancer J Clin. 2018;68(1):7-30.
  • 2 ) Garcea G, Neal C, Pattenden C, Steward W, Berry D, Molecular prognostic markers in pancreatic cancer: a systematic review. Eur J Cancer. 2005; 41(15):2213-36.
  • 3) Ghaneh, P, Kawesha A, Evans J, Neoptolemos J. Molecular prognostic markers in pancreatic cancer. J Hepatobiliary Pancreat Surg. 2002; 9(1):1-11.
  • 4) Mimeault M, Brand R, Sasson A, Batra S. Recent advances on the molecular mechanisms involved in pancreatic cancer progression and therapies. Pancreas. 2005; 31(4):301-16.
  • 5) Haller D. New perspectives in the management of pancreas cancer. Semin Oncol. 2003; 30(Suppl 11):3-10.
  • 6) Hezel A, Kimmelman A, Stanger B, Bardeesy N, Depinho R. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2006; 20(10):1218-49.
  • 7) Khan M, Azim S, Zubair H, Bhardwaj A, Patel G, Khushman M ve ark. Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward. Int J Mol Sci. 2017;18(4):779.
  • 8) Ling J, Kang Y, Zhao R, Xia Q, Lee DF, Chang Z ve ark. KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21(1):105-20.
  • 9) Prabhu L, Mundade R, Korc M, Loehrer P, Lu T. Critical role of NF-κB in pancreatic cancer. Oncotarget. 2014; 5:22.
  • 10) Sarkar F, Li Y. Targeting multiple signal pathways by chemopreventive agents for cancer prevention and therapy. Acta Pharmacol Sin. 2007;28(9):1305-15.
  • 11) Burris H, Storniolo A. Assessing clinical benefit in the treatment of pancreas cancer: gemcitabine compared to 5-fluorouracil. Eur J Cancer. 1997;33(Suppl 1):18-22.
  • 12) Burris H, Moore M, Andersen J, Green M, Rothenberg M, Modiano M ve ark. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997; 15(6):2403-13.
  • 13) Park J, Ryu J, Yoon W, Lee S, Kim Y, Yoon Y. Gemcitabine chemotherapy versus 5-fluorouracil-based concurrent chemotherapy in locally advanced unresectable pancreatic cancer. Pancreas. 2006;33(4):397-402.
  • 14) Arlt A, Gehrz A, Muerkoster S, Vorndamm J, Kruse M, Folsch U ve ark. Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene. 2003;22(21):3243-51.
  • 15) Chandler N, Canete J, Callery M. Increased expression of NF-kappa B subunits in human pancreatic cancer cells. J Surg Res. 2004;118(1):9-14.
  • 16) Li L, Braiteh F, Kurzrock R. Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer. 2005;104(6):1322-31.
  • 17) Nagaraju G, Benton L, Bethi S, Shoji M, El-Rayes B. Curcumin analog: their roles in pancreatic cancer growth and metastasis. Int J Cancer. 2018; Sep 18 (epub ahead of print)
  • 18) www.cancer.gov/clinicaltrials
  • 19) Hruban R, Boffetta P, Hiraoka N, Iacobuzio-Donahue C, Kato Y, Kern SE ve ark. Ductal adenocarcinoma of the pancreas, in Pathology and genetics of tumors of the digestive system. WHO classification of the tumors of the Digestive System. Eds F. Bosman, F. Carneiro, R. Hruban, N. Theise: 281-291.IARC Press: Lyon, 2010.
  • 20) Adsay N, Klimstra D. Benign and malignant tumors of the pancreas. In Textbook of Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. Eds R. Odze, J. Goldblum, J. Crawford): 699-736. Philadelphia, Saunders, 2004.
  • 21) Blackbourne L, Jones R, Catalano C, Iezzoni J, Bourgeois F. Pancreatic adenocarcinoma in the pregnant patient: case report and review of the literature. Cancer. 1997;79(9):1776-9.
  • 22) Luttges J, Stigge C, Pacena M, Kloppel G. Rare ductal adenocarcinoma of the pancreas in patients younger than age 40 years. Cancer. 2004;100(1):173-82.
  • 23) Pernick N, Eldean Z, Kabbani W, Philip P, Shields A, Vaitkevicius V ve ark. Pancreatic ductal adenocarcinoma in young patients (abstract). Modern Pathology. 2001; 14(1): 201A.
  • 24) Evans D, Abruzzese J, Rich T. Cancer of the pancreas. In Textbook of Cancer: Principles and practice of oncology. (Eds V.T. Devita, S. Hellman, S.A. Rosenberg) 1126-1161. Lippincott-Raven ,MA, 2001.
  • 25) Brennan M, Moccia R, Klimstra D. Management of adenocarcinoma of the body and tail of the pancreas. Ann Surg. 1996; 223(5):506-11.
  • 26) Luttges J, Vogel I, Menke M, Henne-Bruns D, Kremer B, Kloppel G. The retroperitoneal resection margin and vessel involvement are important factors determining survival after pancreaticoduodenectomy for ductal adenocarcinoma of the head of the pancreas. Virchows Arch. 1998;433(3):237-42.
  • 27) Neoptolemos J, Stocken D, Friess H, Bassi C, Dunn J, Hickey H ve ark. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200-10.
  • 28) Nagakawa T, Nagamori M, Futakami F, Tsukioka Y, Kayahara M, Ohta T ve ark. Results of extensive surgery for pancreatic carcinoma. Cancer.1996;77(4):640-5.
  • 29) Trede M, Schwall G, Saeger H. Survival after pancreatoduodenectomy. 118 consecutive resections without an operative mortality. Ann Surg. 1990; 211(4):447-58.
  • 30) Carpelan-Holmstrom M, Nordling S, Pukkala E, Sankila R, Luttges J, Kloppel G ve ark. Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry. Gut. 2005; 54(3):385-7.
  • 31) Jimeno A, Hidalgo M. Molecular biomarkers: their increasing role in the diagnosis, characterization, and therapy guidance in pancreatic cancer. Mol Cancer Ther. 2006; 5(4):787-96.
  • 32) Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006; 441(7092):431-6.
  • 33) Gilmore T. Introduction to NF-kappaB: players, pathways, perspectives. Oncogene. 2006; 25(51):6680-4.
  • 34) Verma I, Stevenson J, Schwarz E, Van Antwerp D, Miyamoto S. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev. 1995; 9(22):2723-35.
  • 35) Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol. 1994;10:405-55
  • 36) Baldwin, A. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996; 14:649-83.
  • 37) Ghosh, S, May M, Kopp E. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998; 16:225-60.
  • 38) Ghosh, S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell. 2002; 109 Suppl: 81-96.
  • 39) Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000; 18:621-63.
  • 40) Wei H, Wang B, Miyagi M, She Y, Gopalan B, Huang DB ve ark. PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB. Proc Natl Acad Sci. 2013;110(33): 13516–13521.
  • 41) Mukhopadhyay T, Roth J, Maxwell S. Altered expression of the p50 subunit of the NF-kappa B transcription factor complex in non-small cell lung carcinoma. Oncogene. 1995;11(5):999-1003
  • 42) Dejardin E, Deregowski V, Chapelier M, Jacobs N, Gielen J, Merville M ve ark. Regulation of NF-kappaB activity by I kappaB-related proteins in adenocarcinoma cells. Oncogene. 1999;18(16):2567-77
  • 43) Nakshatri H, Bhat-Nakshatri P, Martin D, Goulet R, Sledge G. Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol. 1997;17(7):3629-39.
  • 44) Sovak M, Bellas R, Kim D, Zanieski G, Rogers A, Traish A ve ark. Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer. J Clin Invest. 1997;100(12):2952-60.
  • 45) Sumitomo M, Tachibana M, Ozu C, Asakura H, Murai M, Hayakawa M ve ark. Induction of apoptosis of cytokine-producing bladder cancer cells by adenovirus-mediated IkappaBalpha overexpression. Hum Gene Ther. 1999;10(1):37-47.
  • 46) Sumitomo M, Tachibana M, Nakashima J, Murai M, Miyajima A, Kimura F ve ark. An essential role for nuclear factor kappa B in preventing TNF-alpha-induced cell death in prostate cancer cells. J Urol. 1999; 161(2):674-9.
  • 47) Motokura T, Arnold A. PRAD1/cyclin D1 proto-oncogene: genomic organization, 5' DNA sequence, and sequence of a tumor-specific rearrangement breakpoint. Genes Chromosomes Cancer. 1993;7(2):89-95.
  • 48) Visconti R, Cerutti J, Battista S, Fedele M, Trapasso F, Zeki K ve ark. Expression of the neoplastic phenotype by human thyroid carcinoma cell lines requires NFkappaB p65 protein expression. Oncogene. 1997;15(16):1987-94.
  • 49) Suh J, Payvandi F, Edelstein L, Amenta P, Zong W, Gelinas C ve ark. Mechanisms of constitutive NF-kappaB activation in human prostate cancer cells. Prostate. 2002; 52(3):183-200.
  • 50) Herrmann J, Beham A, Sarkiss M, Chiao P, Rands M, Bruckheimer E ve ark. Bcl-2 suppresses apoptosis resulting from disruption of the NF-kappa B survival pathway. Exp Cell Res. 1997; 237(1):101-9.
  • 51) Bours V, Dejardin E, Goujon-Letawe F, Merville M, Castronovo V. The NF-kappa B transcription factor and cancer: high expression of NF-kappa B- and I kappa B-related proteins in tumor cell lines. Biochem Pharmacol. 1994;47(1):145-9.
  • 52) Pham N, Schwock J, Iakovlev V, Pond G, Hedley D, Tsao M. Immunohistochemical analysis of changes in signaling pathway activation downstream of growth factor receptors in pancreatic duct cell carcinogenesis. BMC Cancer. 2008; 8:43.
  • 53) Weichert W, Boehm M, Gekeler V, Bahra M, Langrehr J, Neuhaus P ve ark. High expression of RelA/p65 is associated with activation of nuclear factor-kappaB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis. Br J Cancer. 2007;97(4):523-30.
There are 53 citations in total.

Details

Primary Language English
Subjects Health Care Administration
Journal Section Research
Authors

Deniz Tunçel 0000-0001-6025-9733

N. Ümit Bayol This is me 0000-0002-7424-5268

Publication Date June 30, 2019
Acceptance Date December 14, 2018
Published in Issue Year 2019 Volume: 44 Issue: 2

Cite

MLA Tunçel, Deniz and N. Ümit Bayol. “NF-Kappa B Expression in Pancreatic Ductal Carcinoma”. Cukurova Medical Journal, vol. 44, no. 2, 2019, pp. 494-01, doi:10.17826/cumj.481396.