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Journal of Cancer Research and Clinical Oncology

Published in:

01-09-2020 | Colorectal Cancer | Original Article – Cancer Research

Cholecystokinin type 2 receptor in colorectal cancer: diagnostic and therapeutic target

Authors: Jiang Chang, Zeng-Shan Liu, De-Feng Song, Meng Li, Song Zhang, Ke Zhao, Yu-Ting Guan, Hong-Lin Ren, Yan-Song Li, Yu Zhou, Xi-Lin Liu, Shi-Ying Lu, Pan Hu

Published in: Journal of Cancer Research and Clinical Oncology | Issue 9/2020

Abstract

Introduction

Cholecystokinin type 2 receptor (CCK2R), which mediates the action of gastrin and cholecystokinin (CCK), has been demonstrated to promote the proliferation of colorectal cancer (CRC). A number of studies showed that CCK2R overexpressed in gastric cancer and pancreatic cancer but few in CRC. The correlation between CCK2R expression and clinicopathological characteristics is also not clear.

Methods

This study investigated CCK2R expression in a wide range of cell lines and clinical CRC samples, and explored expression pattern and prognostic value of CCK2R in relation to clinicopathological parameters. The location and expression levels of CCK2R were measured by immunocytochemical (ICC), qRT-PCR and Western blot. The druggability and antineoplastic effects of CCK2R as a therapeutic target were investigated using an anti-CCK2R targeting recombinant toxin named rCCK8PE38 by CCK-8 assay.

Results

Compared with paracarcinoma tissues, tumor samples showed overexpression of CCK2R (p = 0.028) including both CRC tissue and plasma samples, with plasma detection showing a significant indication for CCK2R evaluation. Aberrant expression correlated significantly with histological type (p = 0.032) and p53 status (p < 0.01), and patients with CCK2R overexpression had significantly lower disease-free survival. Application of rCCK8PE38 demonstrated the specificity and druggability of CCK2R as a therapeutic target, providing a strategy for clinical case screening of drugs targeting CCK2R.

Conclusion

This study highlighted the aberrant expression and clinical correlation of CCK2R and reveals its diagnostic, prognostic and treatment value in CRC. We hypothesize that CCK2R serve as a target for the diagnosis and treatment of this cancer.

Akbari B, Farajnia S, Ahdi Khosroshahi S, Safari F, Yousefi M, Dariushnejad H, Rahbarnia L (2017) Immunotoxins in cancer therapy: review and update. Int Rev Immunol 36:201–219. https://doi.org/10.3322/caac.21492 CrossRef

Alewine C, Hassan R, Pastan I (2015) Advances in anticancer immunotoxin therapy. Oncologist 20:176–185. https://doi.org/10.1634/theoncologist.2014-0358 CrossRefPubMedPubMedCentral

Benedix F, Kuester D, Meyer F, Lippert H (2013) Influence of mucinous and signet-ring cell differentiation on epidemiological, histological, molecular biological features, and outcome in patients with colorectal carcinoma. Zentralbl Chir 138:427–433. https://doi.org/10.1055/s-0031-1283870 CrossRefPubMed

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492 CrossRefPubMed

Clawson GA et al (2017) A cholecystokinin B receptor-specific DNA aptamer for targeting pancreatic ductal adenocarcinoma. Nucleic Acid Res 27:23–35. https://doi.org/10.1089/nat.2016.0621 CrossRef

Cowey CL, Rathmell WK (2008) Using molecular biology to develop drugs for renal cell carcinoma. Expert Opin Drug Discov 3:311–327. https://doi.org/10.1517/17460441.3.3.311 CrossRefPubMedPubMedCentral

Dhillon S (2018) Moxetumomab pasudotox: first global approval. Drugs 78:1763–1767. https://doi.org/10.1007/s40265-018-1000-9 CrossRefPubMedPubMedCentral

Edge SB, Compton CC (2010) The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 17:1471–1474. https://doi.org/10.1245/s10434-010-0985-4 CrossRefPubMed

Feng XL et al (2015) Establishment of a three-step purification scheme for a recombinant protein rG17PE38 and its characteristics identification. J Chromatogr B Analyt Technol Biomed Life Sci 981–982:48–56. https://doi.org/10.1016/j.jchromb.2015.01.008 CrossRefPubMed

Fino KK, Matters GL, McGovern CO, Gilius EL, Smith JP (2012) Downregulation of the CCK-B receptor in pancreatic cancer cells blocks proliferation and promotes apoptosis. Am J Physiol Gastrointest Liver Physiol 302:G1244–1252. https://doi.org/10.1152/ajpgi.00460.2011 CrossRefPubMedPubMedCentral

Fiori S et al (2013) Hepatic pseudocystic metastasis of well-differentiated ileal neuroendocrine tumor: a case report with review of the literature. Diagn Pathol 8:148. https://doi.org/10.1186/1746-1596-8-148 CrossRefPubMedPubMedCentral

Flamand L et al (2008) Multicenter comparison of PCR assays for detection of human herpesvirus 6 DNA in serum. J Clin Microbiol 46:2700–2706. https://doi.org/10.1128/JCM.00370-08 CrossRefPubMedPubMedCentral

Gao S et al (2015) A novel immunotoxin—rCCK8PE38 targeting of CCK-R overexpressed colon cancers. J Drug Target 23:462–468. https://doi.org/10.3109/1061186X.2015.1009073 CrossRefPubMed

Han YM, Park JM, Park SH, Hahm KB, Hong SP, Kim EH (2013) Gastrin promotes intestinal polyposis through cholecystokinin-B receptor-mediated proliferative signaling and fostering tumor microenvironment. J Physiol Pharmacol 64:429–437PubMed

Hellmich MR, Rui XL, Hellmich HL, Fleming RY, Evers BM, Townsend CM Jr (2000) Human colorectal cancers express a constitutively active cholecystokinin-B/gastrin receptor that stimulates cell growth. J Biol Chem 275:32122–32128CrossRef

Hu P et al (2018) An efficient scheme for purification of a novel recombinant immunotoxin, rCCK8PE38, for anti-tumour experiments. Biomed Chromatogr 32:e4197. https://doi.org/10.1002/bmc.4197 CrossRefPubMed

Huang BP, Lin CH, Chen YC, Kao SH (2016) Expression of cholecystokinin receptors in colon cancer and the clinical correlation in Taiwan. Tumour Biol 37:4579–4584. https://doi.org/10.1007/s13277-015-4306-1 CrossRefPubMed

Jessup JM, Stewart A, Greene FL, Minsky BD (2005) Adjuvant chemotherapy for stage III colon cancer: implications of race/ethnicity, age, and differentiation. JAMA 294:2703–2711. https://doi.org/10.1001/jama.294.21.2703 CrossRefPubMed

Jin G et al (2009) Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice. J Clin Invest 119:2691–2701. https://doi.org/10.1172/JCI38918 CrossRefPubMedPubMedCentral

Jin G et al (2017) The G-protein coupled receptor 56, expressed in colonic stem and cancer cells, binds progastrin to promote proliferation and carcinogenesis. Oncotarget 8:40606–40619. https://doi.org/10.18632/oncotarget.16506 CrossRefPubMedPubMedCentral

Jin G et al (2013) Progastrin stimulates colonic cell proliferation via CCK2R- and β-arrestin-dependent suppression of BMP2. Gastroenterology 145:820–830.e810. https://doi.org/10.1053/j.gastro.2013.07.034 CrossRefPubMed

McCawley N, Clancy C, O'Neill BD, Deasy J, McNamara DA, Burke JP (2016) Mucinous rectal adenocarcinoma is associated with a poor response to neoadjuvant chemoradiotherapy: a systematic review and meta-analysis. Dis Colon Rectum 59:1200–1208. https://doi.org/10.1097/dcr.0000000000000635 CrossRefPubMed

Pérez-Portela R, Riesgo A (2013) Optimizing preservation protocols to extract high-quality RNA from different tissues of echinoderms for next-generation sequencing. Mol Ecol Resour 13:884–889. https://doi.org/10.1111/1755-0998.12122 CrossRefPubMed

Quattrone A et al (2012) Promoting role of cholecystokinin 2 receptor (CCK2R) in gastrointestinal stromal tumour pathogenesis. J Pathol 228:565–574. https://doi.org/10.1002/path.4071 CrossRefPubMed

Rao SV, Solum G, Niederdorfer B, Nørsett KG, Bjørkøy G, Thommesen L (2017) Gastrin activates autophagy and increases migration and survival of gastric adenocarcinoma cells. BMC cancer 17:68. https://doi.org/10.1186/s12885-017-3055-5 CrossRefPubMedPubMedCentral

Roy J et al (2016) Assessment of cholecystokinin 2 receptor (CCK2R) in neoplastic tissue. Oncotarget 7:14605–14615. https://doi.org/10.18632/oncotarget.7522 CrossRefPubMedPubMedCentral

Smith AM, Watson SA (2000) Gastrin and gastrin receptor activation: an early event in the adenoma-carcinoma sequence. Gut 47:820–824. https://doi.org/10.1136/gut.47.6.820 CrossRefPubMedPubMedCentral

Song HN et al (2016) Molecular characterization of colorectal cancer patients and concomitant patient-derived tumor cell establishment. Oncotarget 7:19610–19619. https://doi.org/10.18632/oncotarget.7526 CrossRefPubMedPubMedCentral

Veomett N, Dao T, Scheinberg DA (2013) Therapeutic antibodies to intracellular targets in cancer therapy. Expert Opin Biol Ther 13:1485–1488. https://doi.org/10.1517/14712598.2013.833602 CrossRefPubMed

Wang Q, Jin J, Guo Z, Chen F, Qiu Y, Zhu J, Shang Y (2013) Improvements in the primary culture of neonate rat myocardial cells by study of the mechanism of endoplasmic reticulum stress. Cell Stress Chaperones 18:367–375. https://doi.org/10.1007/s12192-012-0390-y CrossRefPubMedPubMedCentral

Washington MC, Williams K, Sayegh AI (2016) The feeding responses evoked by endogenous cholecystokinin are regulated by different gastrointestinal sites. Horm Behav 78:79–85. https://doi.org/10.1016/j.yhbeh.2015.10.019 CrossRefPubMed

Wulaningsih W, Wardhana A, Watkins J, Yoshuantari N, Repana D, VanHemelrijck M (2016) Irinotecan chemotherapy combined with fluoropyrimidines versus irinotecan alone for overall survival and progression-free survival in patients with advanced and/or metastatic colorectal cancer. Cochrane Database Syst Rev. 2:CD008593. https://doi.org/10.1002/14651858.CD008593.pub3 CrossRefPubMed

Xu W et al (2013) Gastrin acting on the cholecystokinin2 receptor induces cyclooxygenase-2 expression through JAK2/STAT3/PI3K/Akt pathway in human gastric cancer cells. Cancer lett 332:11–18. https://doi.org/10.1016/j.canlet.2012.12.030 CrossRefPubMed

Yu HG et al (2006) Enhanced expression of cholecystokinin-2 receptor promotes the progression of colon cancer through activation of focal adhesion kinase. Int J Cancer 119:2724–2732. https://doi.org/10.1002/ijc.22207 CrossRefPubMed

Title: Cholecystokinin type 2 receptor in colorectal cancer: diagnostic and therapeutic target
Authors: Jiang Chang
Zeng-Shan Liu
De-Feng Song
Meng Li
Song Zhang
Ke Zhao
Yu-Ting Guan
Hong-Lin Ren
Yan-Song Li
Yu Zhou
Xi-Lin Liu
Shi-Ying Lu
Pan Hu
Publication date: 01-09-2020
Publisher: Springer Berlin Heidelberg
Keywords: Colorectal Cancer
Colorectal Cancer
Published in: Journal of Cancer Research and Clinical Oncology / Issue 9/2020
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-020-03273-z

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Conclusion

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