mRNA expression of CRF family members in urothelial bladder cancer

Mavridis,Charalampos; Venihaki,Maria; Dermitzaki,Eirini; Deiktakis,Michail; Liapakis,Georgios; Mamoulakis,Charalampos

doi:10.3892/ol.2023.14145

mRNA expression of CRF family members in urothelial bladder cancer

This article is part of the special Issue: Clinical and Molecular Insights on Urothelial Carcinoma
Authors:
- Charalampos Mavridis
- Maria Venihaki
- Eirini Dermitzaki
- Michail Deiktakis
- Georgios Liapakis
- Charalampos Mamoulakis
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Affiliations: Department of Urology, University General Hospital of Heraklion, Medical School, University of Crete, Heraklion 71003, Greece, Department of Clinical Chemistry, Medical School, University of Crete, Heraklion 71003, Greece, Department of Pharmacology, Medical School, University of Crete, Heraklion 71003, Greece
Published online on: November 10, 2023 https://doi.org/10.3892/ol.2023.14145
Article Number: 13

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Abstract

The corticotropin‑releasing factor (CRF) gene family includes the three urocortins (UCN1, 2 and 3) and the two receptors (CRFR1 and 2), which play a significant role in the physiology of various organs. The expression of the CRF family of genes and its receptors are shown to participate in the pathogenesis of inflammation and even tumorigenesis. However, data regarding the human urinary tract, especially the bladder, are scarce. To the best of our knowledge, no studies are currently available on the CRF system and bladder cancer. The primary goal of the present study was to investigate the mRNA expression of the CRF family members in bladder cancer. The secondary aim was to analyze the differences with the expression of the same mRNAs in normal bladders. From August 2018 to July 2021, 43 recruited patients were divided into three groups. Group A included healthy patients, group B included patients with bladder cancer and group C included patients with a history of cancer from whom samples were taken from the normal bladder mucosa. Detection of mRNA of the CRF family of genes was performed using reverse transcription‑quantitative PCR. The mRNA of the three urocortins, CRF and the two receptors were predominantly expressed in all three groups of patients. Statistical analysis using the Kruskal‑Wallis test showed that UCN1 was downregulated in patients with bladder cancer and those with possible cancer compared with the healthy group (mean rank group A=24.3 vs. mean rank group B=12.58; P=0.006) and (mean rank group A=24.3 vs. mean rank group C=8.88; P=0.001). The present experiments showed that mRNA of the CRF family of genes was amplified in normal and cancer bladder tissues. Downregulation of the UCN1 gene may be associated with bladder cancer, contributing to the prognosis, diagnosis or therapy of urothelial malignancies.

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1	Vale W, Spiess J, Rivier C and Rivier J: Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science. 213:1394–1397. 1981. View Article : Google Scholar : PubMed/NCBI
2	Sakamoto R, Matsubara E, Nomura M, Wang L, Kawahara Y, Yanase T, Nawata H and Takayanagi R: Roles for corticotropin-releasing factor receptor type 1 in energy homeostasis in mice. Metabolism. 62:1739–1748. 2013. View Article : Google Scholar : PubMed/NCBI
3	Grammatopoulos DK: Insights into mechanisms of corticotropin-releasing hormone receptor signal transduction. Br J Pharmacol. 166:85–97. 2012. View Article : Google Scholar : PubMed/NCBI
4	Hanna-Mitchell AT, Wolf-Johnston A, Roppolo JR, Buffington TC and Birder LA: Corticotropin-releasing factor family peptide signaling in feline bladder urothelial cells. J Endocrinol. 222:113–121. 2014. View Article : Google Scholar : PubMed/NCBI
5	Hillhouse EW and Grammatopoulos DK: The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: Implications for physiology and pathophysiology. Endocr Rev. 27:260–286. 2006. View Article : Google Scholar : PubMed/NCBI
6	Nozu T, Tsuchiya Y, Kumei S, Takakusaki K and Okumura T: Peripheral corticotropin-releasing factor (CRF) induces stimulation of gastric contractions in freely moving conscious rats: Role of CRF receptor types 1 and 2. Neurogastroenterol Motil. 25:190–197. 2013. View Article : Google Scholar : PubMed/NCBI
7	Ma S, Shen Q, Zhao LH, Mao C, Zhou XE, Shen DD, de Waal PW, Bi P, Li C, Jiang Y, et al: Molecular basis for hormone recognition and activation of corticotropin-releasing factor receptors. Mol Cell. 77:669–680.e664. 2020. View Article : Google Scholar : PubMed/NCBI
8	Fekete EM and Zorrilla EP: Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: Ancient CRF paralogs. Front Neuroendocrinol. 28:1–27. 2007. View Article : Google Scholar : PubMed/NCBI
9	LaBerge J, Malley SE, Zvarova K and Vizzard MA: Expression of corticotropin-releasing factor and CRF receptors in micturition pathways after cyclophosphamide-induced cystitis. Am J Physiol Regul Integr Comp Physiol. 291:R692–R703. 2006. View Article : Google Scholar : PubMed/NCBI
10	Saban MR, Nguyen NB, Hammond TG and Saban R: Gene expression profiling of mouse bladder inflammatory responses to LPS, substance P, and antigen-stimulation. Am J Pathol. 160:2095–2110. 2002. View Article : Google Scholar : PubMed/NCBI
11	Jhang JF, Birder LA, Jiang YH, Hsu YH, Ho HC and Kuo HC: Dysregulation of bladder corticotropin-releasing hormone receptor in the pathogenesis of human interstitial cystitis/bladder pain syndrome. Sci Rep. 9:191692019. View Article : Google Scholar : PubMed/NCBI
12	Kaprara A, Pazaitou-Panayiotou K, Kortsaris A and Chatzaki E: The corticotropin releasing factor system in cancer: Expression and pathophysiological implications. Cell Mol Life Sci. 67:1293–1306. 2010. View Article : Google Scholar : PubMed/NCBI
13	Tezval H, Jurk S, Atschekzei F, Becker JU, Jahn O, Serth J and Kuczyk MA: Urocortin and corticotropin-releasing factor receptor 2 in human renal cell carcinoma: Disruption of an endogenous inhibitor of angiogenesis and proliferation. World J Urol. 27:825–830. 2009. View Article : Google Scholar : PubMed/NCBI
14	Tezval H, Jurk S, Atschekzei F, Serth J, Kuczyk MA and Merseburger AS: The involvement of altered corticotropin releasing factor receptor 2 expression in prostate cancer due to alteration of anti-angiogenic signaling pathways. Prostate. 69:443–448. 2009. View Article : Google Scholar : PubMed/NCBI
15	Jin L, Zhang Q, Guo R, Wang L, Wang J, Wan R, Zhang R, Xu Y and Li S: Different effects of corticotropin-releasing factor and urocortin 2 on apoptosis of prostate cancer cells in vitro. J Mol Endocrinol. 47:219–227. 2011. View Article : Google Scholar : PubMed/NCBI
16	Dahm P and Gschwend JE: Malignant non-urothelial neoplasms of the urinary bladder: A review. Eur Urol. 44:672–681. 2003. View Article : Google Scholar : PubMed/NCBI
17	World Medical Association: World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 310:2191–2194. 2013. View Article : Google Scholar : PubMed/NCBI
18	Sylvester RJ, Rodríguez O, Hernández V, Turturica D, Bauerová L, Bruins HM, Bründl J, van der Kwast TH, Brisuda A, Rubio-Briones J, et al: European association of urology (EAU) prognostic factor risk groups for non-muscle-invasive bladder cancer (NMIBC) incorporating the WHO 2004/2016 and WHO 1973 classification systems for grade: An update from the EAU NMIBC guidelines panel. Eur Urol. 79:480–488. 2021. View Article : Google Scholar : PubMed/NCBI
19	Poulaki S, Rassouli O, Liapakis G, Gravanis A and Venihaki M: Analgesic and anti-inflammatory effects of the synthetic neurosteroid analogue BNN27 during CFA-induced hyperalgesia. Biomedicines. 9:11852021. View Article : Google Scholar : PubMed/NCBI
20	Zhang C, Wang YQ, Jin G, Wu S, Cui J and Wang RF: Selection of reference genes for gene expression studies in human bladder cancer using SYBR-Green quantitative polymerase chain reaction. Oncol Lett. 14:6001–6011. 2017.PubMed/NCBI
21	De Spiegelaere W, Dern-Wieloch J, Weigel R, Schumacher V, Schorle H, Nettersheim D, Bergmann M, Brehm R, Kliesch S, Vandekerckhove L and Fink C: Reference gene validation for RT-qPCR, a note on different available software packages. PLoS One. 10:e01225152015. View Article : Google Scholar : PubMed/NCBI
22	Ikeda K, Akiyoshi K, Kamada M, Fujioka K, Tojo K and Manome Y: Expression of urocortin I in normal tissues and malignant tumors. Cancer Cell & Microenvironment. 1:45–50. 2014.PubMed/NCBI
23	Owens GL, Lawrence KM, Jackson TR, Crosbie EJ, Sayan BS, Kitchener HC and Townsend PA: Urocortin suppresses endometrial cancer cell migration via CRFR2 and its system components are differentially modulated by estrogen. Cancer Med. 6:408–415. 2017. View Article : Google Scholar : PubMed/NCBI
24	Graziani G, Tentori L, Portarena I, Barbarino M, Tringali G, Pozzoli G and Navarra P: CRH inhibits cell growth of human endometrial adenocarcinoma cells via CRH-receptor 1-mediated activation of cAMP-PKA pathway. Endocrinology. 143:807–813. 2002. View Article : Google Scholar : PubMed/NCBI
25	Carlson KW, Nawy SS, Wei ET, Sadée W, Filov VA, Rezsova VV, Slominski A and Quillan JM: Inhibition of mouse melanoma cell proliferation by corticotropin-releasing hormone and its analogs. Anticancer Res. 21:1173–1179. 2001.PubMed/NCBI
26	Wang J, Xu Y, Xu Y, Zhu H, Zhang R, Zhang G and Li S: Urocortin's inhibition of tumor growth and angiogenesis in hepatocellular carcinoma via corticotrophin-releasing factor receptor 2. Cancer Invest. 26:359–368. 2008. View Article : Google Scholar : PubMed/NCBI
27	Reyes TM, Lewis K, Perrin MH, Kunitake KS, Vaughan J, Arias CA, Hogenesch JB, Gulyas J, Rivier J, Vale WW and Sawchenko PE: Urocortin II: A member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proc Natl Acad Sci USA. 98:2843–2848. 2001. View Article : Google Scholar : PubMed/NCBI
28	Ou Y, Zheng X, Gao Y, Shu M, Leng T, Li Y, Yin W, Zhu W, Huang Y, Zhou Y, et al: Activation of cyclic AMP/PKA pathway inhibits bladder cancer cell invasion by targeting MAP4-dependent microtubule dynamics. Urol Oncol. 32:47.e21–48. 2014. View Article : Google Scholar : PubMed/NCBI
29	Goto T and Miyamoto H: The role of estrogen receptors in urothelial cancer. Front Endocrinol (Lausanne). 12:6438702021. View Article : Google Scholar : PubMed/NCBI
30	Stewart TA, Yapa KT and Monteith GR: Altered calcium signaling in cancer cells. Biochim Biophys Acta. 1848:2502–2511. 2015. View Article : Google Scholar : PubMed/NCBI
31	Cai H, Chiorean EG, Chiorean MV, Rex DK, Robb BW, Hahn NM, Liu Z, Loehrer PJ, Harrison ML and Xu Y: Elevated phospholipase A2 activities in plasma samples from multiple cancers. PLoS One. 8:e570812013. View Article : Google Scholar : PubMed/NCBI
32	Kopparapu PK, Boorjian SA, Robinson BD, Downes M, Gudas LJ, Mongan NP and Persson JL: Expression of VEGF and its receptors VEGFR1/VEGFR2 is associated with invasiveness of bladder cancer. Anticancer Res. 33:2381–2390. 2013.PubMed/NCBI
33	Paner GP, Ro JY, Wojcik EM, Venkataraman G, Datta MW and Amin MB: Further characterization of the muscle layers and lamina propria of the urinary bladder by systematic histologic mapping: Implications for pathologic staging of invasive urothelial carcinoma. Am J Surg Pathol. 31:1420–1429. 2007. View Article : Google Scholar : PubMed/NCBI