Top

Journal of Cancer Research and Clinical Oncology

Published in:

Open Access 01-03-2024 | Colorectal Cancer | Research

Urocortin-1 promotes colorectal cancer cell migration and proliferation and inhibits apoptosis via inhibition of the p53 signaling pathway

Authors: Xiaolan Guo, Ya Li, Xiangyu Chen, Binghua Sun, Xiaolan Guo

Published in: Journal of Cancer Research and Clinical Oncology | Issue 3/2024

Abstract

Purpose

To investigate the effect of urocortin-1 (UCN-1) on growth, migration, and apoptosis in colorectal cancer (CRC) in vivo and vitro and the mechanism by which UCN-1 modulates CRC cells in vitro.

Methods

The correlation between UCN-1 and CRC was evaluated using The Cancer Genome Atlas (TCGA) database and a tissue microarray. The expression of UCN-1 in CRC cells was assessed using quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting. In vitro, the influence of UCN-1 on the proliferation, apoptosis, and migration of HT-29, HCT-116, and RKO cells was explored using the celigo cell counting assay or cell counting kit-8 (CCK8), flow cytometry, and wound healing or Transwell assays, respectively. In vivo, the effect of UCN-1 on CRC growth and progression was evaluated in nude mice. The downstream pathway underlying UCN-1-mediated regulation of CRC was determined using the phospho-kinase profiler array in RKO cells. Lentiviruses were used to knockdown or upregulate UCN-1 expression in cells.

Results

Both the TCGA and tissue microarray results showed that UCN-1 was strongly expressed in the tissues of patients with CRC. Furthermore, the tissue microarray results showed that the expression of UCN-1 was higher in male than in female patients, and high expression of UCN-1 was associated with higher risk of lymphatic metastasis and later pathological stage. UCN-1 knockdown caused a reduction in CRC cell proliferation, migration, and colony formation, as well as an increase in apoptosis. In xenograft experiments, tumors generated from RKO cells with UCN-1 knockdown exhibited reduced volumes and weights. A reduction in the expression of Ki-67 in xenograft tumors indicated that UCN-1 knockdown curbed tumor growth. The human phospho-kinase array showed that the p53 signaling pathway participated in UCN-1-mediated CRC development. The suppression in migration and proliferation caused by UCN-1 knockdown was reversed by inhibitors of p53 signal pathway, while the increase in cell apoptosis was suppressed. On the other hand, overexpression of UCN-1 promoted proliferation and migration and inhibited apoptosis in CRC cells. Overexpression of p53 reversed the effect of UCN-1 overexpression on CRC development.

Conclusion

UCN-1 promotes migration and proliferation and inhibits apoptosis via inhibition of the p53 signaling pathway.

Available only for authorised users

Ayyadurai S, Gibson AJ, D’Costa S, Overman EL, Sommerville LJ, Poopal AC, Mackey E, Li Y, Moeser AJ (2017) Frontline science: corticotropin-releasing factor receptor subtype 1 is a critical modulator of mast cell degranulation and stress-induced pathophysiology. J Leukoc Biol 102:1299–1312PubMedPubMedCentral

Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545PubMed

Balogh B, Vecsernyes M, Veres-Szekely A, Berta G, Stayer-Harci A, Tarjanyi O, Setalo G Jr (2022) Urocortin stimulates ERK1/2 phosphorylation and proliferation but reduces ATP production of MCF7 breast cancer cells. Mol Cell Endocrinol 547:111610PubMed

Brenner H, Kloor M, Pox CP (2014) Colorectal cancer. Lancet 383:1490–1502PubMed

Buckinx R, Adriaensen D, Nassauw LV, Timmermans JP (2011) Corticotrophin-releasing factor, related peptides, and receptors in the normal and inflamed gastrointestinal tract. Front Neurosci 5:54PubMedPubMedCentral

Chang J, Adams MR, Clifton MS, Liao M, Brooks JH, Hasdemir B, Bhargava A (2011) Urocortin 1 modulates immunosignaling in a rat model of colitis via corticotropin-releasing factor receptor 2. Am J Physiol Gastrointest Liver Physiol 300:G884–G894PubMedPubMedCentral

Chatoo M, Li Y, Ma Z, Coote J, Du J, Chen X (2018) Involvement of corticotropin-releasing factor and receptors in immune cells in irritable bowel syndrome. Front Endocrinol (lausanne) 9:21PubMed

Cheng MF, Tsai WC, Hsia KT, Yang YS, Jin JS (2014) Expression of urocortin in pancreatic ductal adenocarcinoma and pancreatic intraepithelial neoplasia. APMIS 122:147–154PubMed

Ciriello J (2015) Sex and estrogen affect the distribution of urocortin-1 immunoreactivity in brainstem autonomic nuclei of the rat. Brain Res Bull 116:81–92PubMed

Cooks T, Pateras IS, Jenkins LM, Patel KM, Robles AI, Morris J, Forshew T, Appella E, Gorgoulis VG, Harris CC (2018) Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246. Nat Commun 9:771PubMedPubMedCentral

Florio P, De Falco G, Leucci E, Torricelli M, Torres PB, Toti P, Dell’Anna A, Tiso E, Santopietro R, Leoncini L, Petraglia F (2006) Urocortin expression is downregulated in human endometrial carcinoma. J Endocrinol 190:99–105PubMed

Gammie SC, Seasholtz AF, Stevenson SA (2008) Deletion of corticotropin-releasing factor binding protein selectively impairs maternal, but not intermale aggression. Neuroscience 157:502–512PubMed

Gao S, Soares F, Wang S, Wong CC, Chen H, Yang Z, Liu W, Go MYY, Ahmed M, Zeng Y, O’Brien CA, Sung JJY, He HH, Yu J (2021) CRISPR screens identify cholesterol biosynthesis as a therapeutic target on stemness and drug resistance of colon cancer. Oncogene 40:6601–6613PubMedPubMedCentral

Hasbullah HH, Musa M (2021) Gene therapy targeting p53 and KRAS for colorectal cancer treatment: a myth or the way forward? Int J Mol Sci 22:11941PubMedPubMedCentral

Haznadar M, Krausz KW, Margono E, Diehl CM, Bowman ED, Manna SK, Robles AI, Ryan BM, Gonzalez FJ, Harris CC (2018) Inverse association of vitamin D(3) levels with lung cancer mediated by genetic variation. Cancer Med 7:2764–2775PubMedPubMedCentral

Huang D, Sun W, Zhou Y, Li P, Chen F, Chen H, Xia D, Xu E, Lai M, Wu Y, Zhang H (2018) Mutations of key driver genes in colorectal cancer progression and metastasis. Cancer Metastasis Rev 37:173–187PubMed

Kamada M, Ikeda K, Fujioka K, Akiyama N, Akiyoshi K, Inoue Y, Hanada S, Yamamoto K, Tojo K, Manome Y (2012) Expression of mRNAs of urocortin and corticotropin-releasing factor receptors in malignant glioma cell lines. Anticancer Res 32:5299–5307PubMed

Keller DS, Windsor A, Cohen R, Chand M (2019) Colorectal cancer in inflammatory bowel disease: review of the evidence. Tech Coloproctol 23:3–13PubMed

Koido S, Ohkusa T, Kan S, Takakura K, Saito K, Komita H, Ito Z, Kobayashi H, Takami S, Uchiyama K, Arakawa H, Ito M, Okamoto M, Kajihara M, Homma S, Tajiri H (2014) Production of corticotropin-releasing factor and urocortin from human monocyte-derived dendritic cells is stimulated by commensal bacteria in intestine. World J Gastroenterol 20:14420–14429PubMedPubMedCentral

Lewandowska A, Rudzki G, Lewandowski T, Stryjkowska-Gora A, Rudzki S (2022) Risk factors for the diagnosis of colorectal cancer. Cancer Control 29:10732748211056692PubMedPubMedCentral

Li XL, Zhou J, Chen ZR, Chng WJ (2015) P53 mutations in colorectal cancer - molecular pathogenesis and pharmacological reactivation. World J Gastroenterol 21:84–93PubMedPubMedCentral

Li L, Li M, Wang X (2020) Cancer type-dependent correlations between TP53 mutations and antitumor immunity. DNA Repair (amst) 88:102785PubMed

Liebl MC, Hofmann TG (2019) Cell fate regulation upon DNA damage: p53 serine 46 kinases pave the cell death road. BioEssays 41:e1900127PubMed

Liu X, Liu Y, Liu Z, Lin C, Meng F, Xu L, Zhang X, Zhang C, Zhang P, Gong S, Wu N, Ren Z, Song J, Zhang Y (2021) CircMYH9 drives colorectal cancer growth by regulating serine metabolism and redox homeostasis in a p53-dependent manner. Mol Cancer 20:114PubMedPubMedCentral

Liu F, Li X, Yan H, Wu J, Yang Y, He J, Chen J, Jiang Z, Wu F, Jiang Z (2022) Downregulation of CPT2 promotes proliferation and inhibits apoptosis through p53 pathway in colorectal cancer. Cell Signal 92:110267PubMed

Lu Y, Kweon SS, Cai Q, Tanikawa C, Shu XO, Jia WH, Xiang YB, Huyghe JR, Harrison TA, Kim J, Shin A, Kim DH, Matsuo K, Jee SH, Guo X, Wen W, Shi J, Li B, Wang N, Shin MH, Li HL, Ren Z, Oh JH, Oze I, Ahn YO, Jung KJ, Gao J, Gao YT, Pan ZZ, Kamatani Y, Chan AT, Gsur A, Hampe J, Le Marchand L, Li L, Lindblom A, Moreno V, Newcomb PA, Offit K, Pharoah PDP, van Duijnhoven FJB, Van Guelpen B, Vodicka P, Weinstein SJ, Wolk A, Wu AH, Hsu L, Zeng YX, Long J, Peters U, Matsuda K, Zheng W (2020) Identification of novel loci and new risk variant in known loci for colorectal cancer risk in East Asians. Cancer Epidemiol Biomarkers Prev 29:477–486PubMed

Maillot C, Million M, Wei JY, Gauthier A, Tache Y (2000) Peripheral corticotropin-releasing factor and stress-stimulated colonic motor activity involve type 1 receptor in rats. Gastroenterology 119:1569–1579PubMed

Maillot C, Wang L, Million M, Tache Y (2003) Intraperitoneal corticotropin-releasing factor and urocortin induce Fos expression in brain and spinal autonomic nuclei and long lasting stimulation of colonic motility in rats. Brain Res 974:70–81PubMed

Martinez V, Wang L, Rivier JE, Vale W, Tache Y (2002) Differential actions of peripheral corticotropin-releasing factor (CRF), urocortin II, and urocortin III on gastric emptying and colonic transit in mice: role of CRF receptor subtypes 1 and 2. J Pharmacol Exp Ther 301:611–617PubMed

Martinez V, Wang L, Million M, Rivier J, Tache Y (2004) Urocortins and the regulation of gastrointestinal motor function and visceral pain. Peptides 25:1733–1744PubMed

Mattar MC, Lough D, Pishvaian MJ, Charabaty A (2011) Current management of inflammatory bowel disease and colorectal cancer. Gastrointest Cancer Res 4:53–61PubMedPubMedCentral

Or CR, Chang Y, Lin WC, Lee WC, Su HL, Cheung MW, Huang CP, Ho C, Chang CC (2016) Obatoclax a pan-BCL-2 inhibitor, targets cyclin D1 for degradation to induce antiproliferation in human colorectal carcinoma cells. Int J Mol Sci 18:44PubMedPubMedCentral

Owens GL, Lawrence KM, Jackson TR, Crosbie EJ, Sayan BS, Kitchener HC, Townsend PA (2017) Urocortin suppresses endometrial cancer cell migration via CRFR2 and its system components are differentially modulated by estrogen. Cancer Med 6:408–415PubMedPubMedCentral

Peters U, Bien S, Zubair N (2015) Genetic architecture of colorectal cancer. Gut 64:1623–1636PubMed

Saruta M, Takahashi K, Suzuki T, Torii A, Kawakami M, Sasano H (2004) Urocortin 1 in colonic mucosa in patients with ulcerative colitis. J Clin Endocrinol Metab 89:5352–5361PubMed

Schulz-Heddergott R, Stark N, Edmunds SJ, Li J, Conradi LC, Bohnenberger H, Ceteci F, Greten FR, Dobbelstein M, Moll UM (2018) Therapeutic ablation of gain-of-function mutant p53 in colorectal cancer inhibits stat3-mediated tumor growth and invasion. Cancer Cell 34(298–314):e7

Tache Y, Martinez V, Wang L, Million M (2004) CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity: implications for irritable bowel syndrome. Br J Pharmacol 141:1321–1330PubMedPubMedCentral

Uehara I, Tanaka N (2018) ’Role of p53 in the Regulation of the Inflammatory tumor microenvironment and tumor suppression. Cancers (basel) 10:219PubMedPubMedCentral

Vuppaladhadiam L, Ehsan C, Akkati M, Bhargava A (2020) Corticotropin-releasing factor family: a stress hormone-receptor system’s emerging role in mediating sex-specific signaling. Cells 9:839PubMedPubMedCentral

Wang J, Xu Y, Xu Y, Zhu H, Zhang R, Zhang G, Li S (2008) Urocortin’s inhibition of tumor growth and angiogenesis in hepatocellular carcinoma via corticotrophin-releasing factor receptor 2. Cancer Invest 26:359–368PubMed

Wang S, Zhang Y, Huang J, Wong CC, Zhai J, Li C, Wei G, Zhao L, Wang G, Wei H, Zhao Z, Yu J (2019) TRIM67 activates p53 to suppress colorectal cancer initiation and progression. Cancer Res 79:4086–4098PubMed

Wang H, Wang DH, Yang X, Sun Y, Yang CS (2021) Colitis-induced IL11 promotes colon carcinogenesis. Carcinogenesis 42:557–569PubMed

Yang C, Xu Y, Li S (2008) Urocortin: a beneficial or detrimental agent to endothelium? Biochem Biophys Res Commun 371:345–349PubMed

Yin Y, Dong L, Yin D (2008) Peripheral and central administration of exogenous urocortin 1 disrupts the fasted motility pattern of the small intestine in rats via the corticotrophin releasing factor receptor 2 and a cholinergic mechanism. J Gastroenterol Hepatol 23:e79-87PubMed

You IY, Lee S, Kim KB, Lee HS, Jang JS, Yeon M, Han JH, Yoon SM, Chae HB, Park SM, Youn SJ (2015) The effect of urocortin 1 on motility in isolated, vascularly perfused rat colon. Korean J Gastroenterol 65:283–290PubMed

Zeng C, Matsuda K, Jia WH, Chang J, Kweon SS, Xiang YB, Shin A, Jee SH, Kim DH, Zhang B, Cai Q, Guo X, Long J, Wang N, Courtney R, Pan ZZ, Wu C, Takahashi A, Shin MH, Matsuo K, Matsuda F, Gao YT, Oh JH, Kim S, Jung KJ, Ahn YO, Ren Z, Li HL, Wu J, Shi J, Wen W, Yang G, Li B, Ji BT, Genetics, Consortium Epidemiology of Colorectal Cancer, Brenner H, Schoen RE, Kury S, Study Colorectal Transdisciplinary, Gruber SB, Schumacher FR, Stenzel SL, Registry Colon Cancer Family, Casey G, Hopper JL, Jenkins MA, Kim HR, Jeong JY, Park JW, Tajima K, Cho SH, Kubo M, Shu XO, Lin D, Zeng YX, Zheng W (2016) Identification of susceptibility loci and genes for colorectal cancer risk. Gastroenterology 150:1633–1645PubMed

Zhou X, Hao Q, Lu H (2019) Mutant p53 in cancer therapy-the barrier or the path. J Mol Cell Biol 11:293–305PubMed

Zhou M, Thompson TD, Lin HY, Chen VW, Karlitz JJ, Fontham ETH, Theall KP, Zhang L, Hsieh MC, Pollack LA, Wu XC (2022a) Impact of relative dose intensity of FOLFOX adjuvant chemotherapy on risk of death among stage III colon cancer patients. Clin Colorectal Cancer 21:e62–e75PubMed

Zhou Z, Shu Y, Bao H, Han S, Liu Z, Zhao N, Yuan W, Jian C, Shu X (2022b) Stress-induced epinephrine promotes epithelial-to-mesenchymal transition and stemness of CRC through the CEBPB/TRIM2/P53 axis. J Transl Med 20:262PubMedPubMedCentral

Zhu C, Sun Z, Li C, Guo R, Li L, Jin L, Wan R, Li S (2014) Urocortin affects migration of hepatic cancer cell lines via differential regulation of cPLA2 and iPLA2. Cell Signal 26:1125–1134PubMed

Title: Urocortin-1 promotes colorectal cancer cell migration and proliferation and inhibits apoptosis via inhibition of the p53 signaling pathway
Authors: Xiaolan Guo
Ya Li
Xiangyu Chen
Binghua Sun
Xiaolan Guo
Publication date: 01-03-2024
Publisher: Springer Berlin Heidelberg
Keywords: Colorectal Cancer
Colorectal Cancer
Published in: Journal of Cancer Research and Clinical Oncology / Issue 3/2024
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-024-05693-7

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 3/2024

Enzyme-labeled liquid-based cytology (ELLBC): a new noninvasive diagnostic method for bladder cancers

Analyzing the associations between tertiary lymphoid structures and postoperative prognosis, along with immunotherapy response in gastric cancer: findings from pooled cohort studies

Development of a nomogram to predict the prognosis of patients with secondary bone tumors in the intensive care unit: a retrospective analysis based on the MIMIC IV database

Unveiling the role of PYGB in pancreatic cancer: a novel diagnostic biomarker and gene therapy target

PD-(L)1 inhibitors plus bevacizumab and chemotherapy as first-line therapy in PD-L1-negative metastatic lung adenocarcinoma: a real-world data

Alteration of serum bile acid profiles of HBV-related hepatocellular carcinoma identified by LC–MS/MS

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials