Evaluation of Notch1 gene expression in prostate carcinoma

Abstract

Aim: Prostate cancer is one of the most common cancers in the world and its incidence is rapidly increasing. Currently, several new treatment strategies that target specific signaling pathways as well as immunotherapy are being explored for prostate cancer. In the current study, we aimed to investigate the frequency and clinicopathologic features associated with Notch1 gene expression using immunohistochemistry and real-time-polymerase chain reaction in patients with prostate cancer.
Methods: This research was planned as a cohort study. Tissue samples of 60 patients with prostate cancer and 20 patients with benign prostatic hyperplasia were selected from the archives. Twenty patients with benign prostatic hyperplasia were used as the control group. The relative expression levels of Notch1 gene were determined by real-time-polymerase chain reaction while Notch1 protein expression was analyzed using immunohistochemistry.
Results: We found Notch1 gene expression at a significant level in 17 (28.3%) of 60 patients with prostate carcinoma. We found a significant correlation between high Gleason scores (P=0.007), high ISUP (International Society of Urologic Pathologists) grade group scores (P=0.008) and high prostate-specific antigen levels (P=0.018) for Notch1 gene expression.
Conclusions: We conclude that Notch1 is important in prostate carcinogenesis. Therefore, determining Notch1 will be an essential step in targeted therapies in patients with prostate carcinoma.

Keywords

• RT-PCR,Immunohistochemistry,Notch1,Prostate cancer,ISUP,PSA

Prostat karsinomunda Notch1 gen ekspresyonunun değerlendirilmesi

Öz

Amaç: Prostat kanseri dünyada en yaygın görülen kanserlerden biridir ve sıklığı giderek artmaktadır. Şu anda, prostat karsinomu için etkin bir tedavi yöntemi olmamakla birlikte immünoterapiyi ve spesifik sinyal yolaklarını hedefleyen yeni tedavi stratejileri araştırılmaktadır. Biz bu çalışmada prostat kanseri hastalarında immünohistokimya ve Real-Time polimeraz zincir reaksiyonu ile Notch1 gen ekspresyonunu ve klinikopatolojik özellikler ile ilişkisini araştırmayı amaçladık.
Yöntemler: Bu araştırma bir kohort çalışma olarak planlandı. Hastane arşivimizden 60 tane prostat kanseri ve 20 tane benign prostat hiperplazisi olan hastaların parafin blokları seçildi. Benign prostat hiperplazisi olan 20 hasta kontrol grubu olarak kullanıldı. Notchl gen ekspresyonu seviyeleri immünohistokimya ve Real-Time polimeraz zincir reaksiyonu kullanılarak analiz edildi.
Bulgular: Çalışmamızda 60 prostat karsinomu tanılı hastamızın 17'sinde (%28,3) Notch1 gen ekspresyonunu anlamlı düzeyde yüksek bulduk. Ayrıca yüksek Gleason skoru (P=0,07), yüksek ISUP skoru (P=0,008) ve yüksek prostat spesifik antijen düzeyi (P=0,018) ile Notch1 ekspresyonu arasında anlamlı bir korelasyon bulduk.
Sonuçlar: Prostat karsinogenezinde Notch1'in önemli olduğu sonucuna vardık. Bu nedenle, Notch1 prostat karsinomlu hastalarda hedefe yönelik tedavilerde önemli bir adım olacaktır.

Anahtar Kelimeler

• RT-PCR,İmmünohistokimya,Notch1,Prostat kanseri,ISUP,PSA

Kaynakça

1. 1. Balistreri CR, Candore G, Lio D, Carruba G. Prostate cancer: from the pathophysiologic implications of some genetic risk factors to translation in personalized cancer treatments. Cancer Gene Therapy. 2014;21(1):2.
2. 2. Mandair D, Rossi RE, Pericleous M, Whyand T, Caplin ME. Prostate cancer and the influence of dietary factors and supplements: a systematic review. Nutrition & Metabolism. 2014;11(1):30.
3. 3. Sherwood ER, Theyer G, Steiner G, Berg LA, Kozlowski JM, Lee C. Differential expression of specific cytokeratin polypeptides in the basal and luminal epithelia of the human prostate. The Prostate. 1991;18(4):303-14.
4. 4. Ghagane SC, Nerli RB, Hiremath MB, Wagh AT, Magdum PV. Incidence of prostate cancer at a single tertiary care center in North Karnataka. Indian Journal of Cancer. 201653(3):429.
5. 5. Humphrey PA. Histological variants of prostatic carcinoma and their significance. Histopathology. 2012;60(1):59-74.
6. 6. Morgan TH. "The theory of the gene." The American Naturalist. 1917;51.609:513-44.
7. 7. Kidd S, Kelley MR, Young MW. Sequence of the notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors. Molecular and cellular biology. 1986;6(9):3094-108.
8. 8. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991;66(4):649-61.

9. 9. Pear WS, Aster JC, Scott ML, Hasserjian RP, Soffer B, Sklar J, et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. Journal of Experimental Medicine. 1996;183(5):2283-91.
10. 10. Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nature genetics. 1997; 16(3):235.
11. 11. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284(5415):770-6.
12. 12. Kopan R. Notch: a membrane-bound transcription factor. Journal of Cell Science. 2002;115(6):1095-1097.
13. 13. Ohishi K, Varnum-Finney B, Flowers D, Anasetti C, Myerson D, Bernstein ID. Monocytes express high amounts of Notch and undergo cytokine specific apoptosis following interaction with the Notch ligand, Delta-1. Blood. 2000;95(9):2847-54.
14. 14. Yağcı E, Güneş HV. Notch Sinyal Yolağı ve Karsinogenez/Notch Signaling Pathway and Carcinogenesis. Osmangazi Journal of Medicine. 2017;39(1):109-16.
15. 15. Park JW, Lee JK, Phillips JW, Huang P, Cheng D, Huang J, et al. Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay. Proceedings of the National Academy of Sciences. 2016;113(16):4482-7.
16. 16. Schulz W. Molecular biology of human cancers: an advanced student's textbook. Springer Science & Business Media. 2005.
17. 17. Koch U, Radtke F. Dual Function of Notch Signaling in Cancer: Oncogene and Tumor Suppressor. In Targeting Notch in Cancer. Springer, New York, NY. 2018:55-86.
18. 18. Wang XD, Leow CC, Zha J, Tang Z, Modrusan Z, Radtke F, et al. Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation. Developmental Biology. 2006;290(1):66-80.
19. 19. Brown MD, Gilmore PE, Hart CA, Samuel JD, Ramani VA, George NJ, et al. Characterization of benign and malignant prostate epithelial Hoechst 33342 side populations. The Prostate. 2007;67(13):1384-96.
20. 20. Shou J, Ross S, Koeppen H, de Sauvage FJ, Gao WQ. Dynamics of notch expression during murine prostate development and tumorigenesis. Cancer Research. 2001;61(19):7291-7.
21. 21. Carvalho FL, Simons BW, Eberhart CG, Berman DM. Notch signaling in prostate cancer: a moving target. The Prostate. 2014;74(9):933-45.
22. 22. Soylu H, Acar N, Ozbey O, Unal B, Koksal IT, Bassorgun I, et al. Characterization of Notch signalling pathway members in normal prostate, prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma. Pathology & Oncology Research. 2016;22(1):87-94.
23. 23. Kron KJ, Murison A, Zhou S, Huang V, Yamaguchi TN, Shiah YJ, et al. TMPRSS2–ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer. Nature Genetics. 2017;49(9):1336.
24. 24. Zhu H, Zhou X, Redfield S, Lewin J, Miele L. Elevated Jagged-1 and Notch-1 expression in high grade and metastatic prostate cancers. American Journal of Translational Research. 2013;5(3):368.
25. 25. Wang Z, Li Y, Ahmad A, Banerjee S, Azmi AS, Kong D, et al. Down‐regulation of Notch‐1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells. Journal of Cellular Biochemistry. 2011;112(1):78-88.
26. 26. Zayzafoon M, Abdulkadir SA, McDonald JM. Notch signaling and ERK activation are important for the osteomimetic properties of prostate cancer bone metastatic cell lines. Journal of Biological Chemistry. 2004;279(5):3662-70.
27. 27. Sethi N, Kang Y. Notch signalling in cancer progression and bone metastasis. British Journal of Cancer. 2011;105(12):805.
28. 28. Domingo-Domenech J, Vidal SJ, Rodriguez-Bravo V, Castillo-Martin M, Quinn SA, Rodriguez-Barrueco R, et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch-and hedgehog-dependent tumor-initiating cells. Cancer Cell. 2012;22(3):373-88.
29. 29. Çayır D, Bozkurt M, Gültekin S, Turan A. Complete scintigraphic resolution of a bone metastasis after androgen-deprivation therapy. Journal of Surgery and Medicine. 2019;3(12):899-8.