Dokument: NUCKS1 als Marker der Aggressivität im Pankreaskarzinom
| Titel: | NUCKS1 als Marker der Aggressivität im Pankreaskarzinom | |||||||
| Weiterer Titel: | NUCKS1 protein as a marker of aggressivity in PDAC. | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=69127 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20250407-112500-4 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Dr. Bobe, Remus Catalin [Autor] | |||||||
| Dateien: |
| |||||||
| Beitragende: | Prof. Dr. med. Flügen, Georg [Gutachter] Prof. Dr. med. Roderburg, Christoph [Gutachter] | |||||||
| Stichwörter: | Pankreas, Pankreaskarzinom, Tumormarker | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | S. UntenIntroduction: The ductal adenocarcinoma of the pancreas (PDAC) is an aggressive form of cancer that remains difficult to manage despite intensive research. NUCKS1 (nuclear casein kinase and cyclin dependent kinase substrate 1) is a protein present in almost all human cells with an important role in proliferation and DNA repair, that has been demonstrated to correlate with aggressivity and prognosis in different types of cancer. The objective of this study was to examine the expression of NUCKS1 and p53 protein in a large cohort of PDAC to elucidate if NUCKS1, similar to p53, can be used as a potential marker to determine prognosis.
Methods: The patient collective is comprised of 192 patients with PDAC that underwent surgical treatment at the University Clinic of Düsseldorf between September 2003 and January 2017. Tissue microarrays (TMA) composed of pancreatic tumor tissue, lymph node metastasis and normal pancreatic tissue were stained for NUCS1 and p53 for each patient. The relevant clinicopathological and follow-up data up to 5 years were collected. The IHC staining results were evaluated using the IRS (immune reactive score) in case of the NUCKS1 staining and a proprietary score for the p53 staining. Comparisons were analyzed using Wilcoxon-Tests and Fischer-Freeman-Halton Exact Test. Furthermore, Kaplan-Meier curves were created and the Log-Rank (Mantel Cox) test was used to calculate significance of the overall survival (OS). The Hazard Ratio (HR) was defined at 95% confidence interval (CI). Results: 192 patients were enrolled (93 female and 99 male, mean age 68yrs), and 175 presented with T3 tumors. The patient collective was divided into two groups according to the NUCKS1 staining: above or beneath the median of the IRS. An assessment was made between the two groups concerning the clinical and histopthological factors, and statistical differences were discovered. A significantly higher expression of NUCKS1 was shown in less aberrant (≤G2) tumors, as well as a tendency for a longer survival (p=0,051, Log-Rank Test). Similarly, patients without distant metastases (M0) showed a significantly higher expression of nuclear NUCKS1 in lymph node metastases and the cytoplasm of normal tissue, compared to patients with distant metastases (M1). There was no relevant co-expression of p53 and NUCKS1, as well as no correlation between aberrant p53 protein and clinicopathological characteristics. In our patient collective there was no statistically significant difference in the 5-year OS based on NUCKS1 or p53 expression. Conclusions: The higher NUCKS1 expression seems to correlate to a less aggressive tumor phenotype (≤G2, M0). Surprisingly, an aberrant p53 expression did not correlate with NUCKS1 expression or worse OS. NUCKS1 seems to be rather a protective factor in PDAC patients, possibly due to the known role of NUCKS1 in genome repair. | |||||||
| Quelle: | 1. Michael Schünke u. a. Prometheus. Innere Organe: 1352 Illustrationen, 121
Tabellen. 3., überarbeitete und erweiterte Auflage. Stuttgart New York: Georg Thieme Verlag; 2012. 486 S. 2. Graumann W, Herausgeber. CompactLehrbuch Anatomie. 3: Innere Organsysteme: 13 Tab. / mit Beitr. v. Walther Graumann. Stuttgart: Schattauer; 2004. 552 S. 3. Lüllmann-Rauch R. Taschenlehrbuch Histologie: 10 Tabellen. 3., vollst. überarb. Aufl. Stuttgart: Thieme; 2009. 644 S. (Taschenlehrbuch). 4. Behrends JC, Herausgeber. Physiologie: 93 Tabellen. Stuttgart: Thieme; 2010. 830 S. (Duale Reihe). 5. Nemoda Z, Sahin-Tóth M. CHYMOTRYPSIN C (CALDECRIN) STIMULATES AUTOACTIVATION OF HUMAN CATONIC TRYPSINOGEN. J Biol Chem. 28. April 2006;281(17):11879–86. 6. Witt H. Physiologie und Embryologie des Pankreas. Pädiatr Gastroenterol Hepatol Ernähr. 2013;547–55. 7. Kleine B, Rossmanith WG. Hormone und Hormonsystem: Lehrbuch der Endokrinologie. 3., vollst. überarb. und erw. Aufl. Berlin Heidelberg: Springer Spektrum; 2014. 469 S. (Lehrbuch). 8. Huber W, Schmid RM. Akute Pankreatitis: Evidenzbasierte Diagnostik und Therapie. Dtsch Ärztebl. 2007;12. 9. Siegenthaler W, Battegay E, Aeschlimann A, Herausgeber. Siegenthalers Differenzialdiagnose: innere Krankheiten - vom Symptom zur Diagnose. 20., komplett überarb. und aktualisierte Aufl. Stuttgart New York: Thieme; 2013. 1167 S. 10. Conwell DL, Lee LS, Yadav D, Longnecker DS, Miller FH, Mortele KJ, u. a. American Pancreatic Association Practice Guidelines in Chronic Pancreatitis: Evidence-Based Report on Diagnostic Guidelines. Pancreas. November 2014;43(8):1143–62. 11. Hart PA, Bellin MD, Andersen DK, Bradley D, Cruz-Monserrate Z, Forsmark CE, u. a. Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer. Lancet Gastroenterol Hepatol. November 2016;1(3):226–37. 12. Onkopedia [Internet]. [zitiert 28. April 2022]. Pankreaskarzinom. Verfügbar unter: https://www.onkopedia.com/de/onkopedia/guidelines/pankreaskarzinom 49 13. Ormanns S, Esposito I, Siveke JT, Kirchner T, Neumann J. Pathologie und Molekularpathologie des Pankreaskarzinoms. 2014;6. 14. Krebs - Bauchspeicheldrüsenkrebs [Internet]. [zitiert 1. April 2024]. Verfügbar unter: https://www.krebsdaten.de/Krebs/DE/Content/Krebsarten/Bauchspeicheldruesenkreb s/bauchspeicheldruesenkrebs_node.html 15. Matthaei H, Schulick RD, Hruban RH, Maitra A. Cystic precursors to invasive pancreatic cancer. Nat Rev Gastroenterol Hepatol. März 2011;8(3):141–50. 16. Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, DePinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 15. Mai 2006;20(10):1218– 49. 17. van Lier MGF, Wagner A, Mathus-Vliegen EMH, Kuipers EJ, Steyerberg EW, van Leerdam ME. High Cancer Risk in Peutz–Jeghers Syndrome: A Systematic Review and Surveillance Recommendations. Off J Am Coll Gastroenterol ACG. Juni 2010;105(6):1258–64. 18. Patel J, Madan A, Gammon A, Sossenheimer M, Samadder NJ. Rare hereditary cause of chronic pancreatitis in a young male: SPINK1 mutation. Pan Afr Med J. 4. Oktober 2017;28:110. 19. Rosen MN, Goodwin RA, Vickers MM. BRCA mutated pancreatic cancer: A change is coming. World J Gastroenterol. 7. Mai 2021;27(17):1943–58. 20. Petersen GM. Familial Pancreatic Adenocarcinoma. Hematol Oncol Clin North Am. 1. August 2015;29(4):641–53. 21. Ärzteblatt DÄG Redaktion Deutsches. Deutsches Ärzteblatt. 2011 [zitiert 28. April 2022]. Intraduktale papillär-muzinöse Neoplasie des Pankreas. Verfügbar unter: https://www.aerzteblatt.de/archiv/113222/Intraduktale-papillaer-muzinoeseNeoplasie-des-Pankreas 22. Pape UF, Böhmig M, Tiling N, Wiedenmann B. Diagnostik und Therapie gastroenteropankreatischer neuroendokriner Tumore aus internistischer Sicht. Onkol. 1. Juli 2000;6(7):624–33. 23. Prídavková D, Samoš M, Kyčina R, Adamicová K, Kalman M, Belicová M, u. a. Insulinoma presenting with postprandial hypoglycemia and a low body mass index: A case report. World J Clin Cases. 26. September 2020;8(18):4169–76. 24. Duan S, Rico K, Merchant JL. Gastrin: From Physiology to Gastrointestinal Malignancies. Function. 26. November 2021;3(1):zqab062. 50 25. Grundt K, Haga IV, Aleporou-Marinou V, Drosos Y, Wanvik B, Østvold AC. Characterisation of the NUCKS gene on human chromosome 1q32.1 and the presence of a homologous gene in different species. Biochem Biophys Res Commun. 22. Oktober 2004;323(3):796–801. 26. Østvold AC, Grundt K, Wiese C. NUCKS1 is a highly modified, chromatinassociated protein involved in a diverse set of biological and pathophysiological processes. Biochem J. 17. Juni 2022;479(11):1205–20. 27. Drosos Y, Kouloukoussa M, Østvold AC, Havaki S, Katsantoni E, Marinos E, u. a. Dynamic expression of the vertebrate-specific protein Nucks during rodent embryonic development. Gene Expr Patterns. 1. Januar 2014;14(1):19–29. 28. Huang P, Cai Y, Zhao B, Cui L. Roles of NUCKS1 in Diseases: Susceptibility, Potential Biomarker, and Regulatory Mechanisms. BioMed Res Int. 29. Januar 2018;2018:7969068. 29. Hume S, Grou CP, Lascaux P, D’Angiolella V, Legrand AJ, Ramadan K, u. a. The NUCKS1-SKP2-p21/p27 axis controls S phase entry. Nat Commun. 29. November 2021;12:6959. 30. Qiu B, Han W, Tergaonkar V. NUCKS: a potential biomarker in cancer and metabolic disease. Clin Sci. 10. März 2015;128(10):715–21. 31. Zheng S, Ji R, He H, Li N, Han C, Han J, u. a. NUCKS1, a LINC00629- upregulated gene, facilitated osteosarcoma progression and metastasis by elevating asparagine synthesis. Cell Death Dis. 1. August 2023;14(8):489. 32. Zhang X, Zhang X, Li X, Bao H, Li G, Li N, u. a. NUCKS1 Acts as a Promising Novel Biomarker for the Prognosis of Patients with Hepatocellular Carcinoma. Cancer Biother Radiopharm. Dezember 2023;38(10):720–5. 33. Liebl MC, Hofmann TG. The Role of p53 Signaling in Colorectal Cancer. Cancers. 28. April 2021;13(9):2125. 34. Chen X, Zeh HJ, Kang R, Kroemer G, Tang D. Cell death in pancreatic cancer: from pathogenesis to therapy. Nat Rev Gastroenterol Hepatol. November 2021;18(11):804–23. 35. Mello SS, Flowers BM, Mazur PK, Lee JJ, Müller F, Denny SK, u. a. Multifaceted role for p53 in pancreatic cancer suppression. Proc Natl Acad Sci. 7. März 2023;120(10):e2211937120. 51 36. Remmele W, Stegner HE. [Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue]. Pathol. Mai 1987;8(3):138–40. 37. Symonowicz K, Duś-Szachniewicz K, Woźniak M, Murawski M, Kołodziej P, Osiecka B, u. a. Immunohistochemical study of nuclear ubiquitous casein and cyclindependent kinase substrate 1 in invasive breast carcinoma of no special type. Exp Ther Med. 1. Oktober 2014;8(4):1039–46. 38. Ziółkowski P, Gamian E, Osiecka B, Zougman A, Wiśniewski JR. Immunohistochemical and proteomic evaluation of nuclear ubiquitous casein and cyclin-dependent kinases substrate in invasive ductal carcinoma of the breast. J Biomed Biotechnol. 2009;2009:919645. 39. Shi C, Qin L, Gao H, Gu L, Yang C, Liu H, u. a. NUCKS nuclear elevated expression indicates progression and prognosis of ovarian cancer. Tumor Biol. 1. September 2017;39(9):1010428317714631. 40. Gu L, Xia B, Zhong L, Ma Y, Liu L, Yang L, u. a. NUCKS1 overexpression is a novel biomarker for recurrence-free survival in cervical squamous cell carcinoma. Tumor Biol. 1. August 2014;35(8):7831–6. 41. Yang M, Wang X, Zhao Q, Liu T, Yao G, Chen W, u. a. Combined evaluation of the expression of NUCKS and Ki-67 proteins as independent prognostic factors for patients with gastric adenocarcinoma. Tumor Biol. August 2014;35(8):7505–12. 42. Voutsadakis IA. Mutations of p53 associated with pancreatic cancer and therapeutic implications. Ann Hepato-Biliary-Pancreat Surg. 31. August 2021;25(3):315–27. 43. Wenning AS, Ryser CO, Andreou A, Gloor B, Berger MD. Neues zur Therapie des Pankreaskarzinoms: Hoffnung am Horizont? Schweiz Gastroenterol. 1. Dezember 2021;2(4):138–47. | |||||||
| Rechtliche Vermerke: | - | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Bezug: | - | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 07.04.2025 | |||||||
| Dateien geändert am: | 07.04.2025 | |||||||
| Promotionsantrag am: | 11.10.2024 | |||||||
| Datum der Promotion: | 13.03.2025 |
