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.
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References
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
Alewine C, Hassan R, Pastan I (2015) Advances in anticancer immunotoxin therapy. Oncologist 20:176–185. https://doi.org/10.1634/theoncologist.2014-0358
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
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
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
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
Dhillon S (2018) Moxetumomab pasudotox: first global approval. Drugs 78:1763–1767. https://doi.org/10.1007/s40265-018-1000-9
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
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
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
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
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
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
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 64:429–437
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 275:32122–32128
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Acknowledgements
This work was supported by the Project of Science and Technology Development Plan of Jilin Province (No. 20190304043YY; No. 20200404123YY).
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Chang, J., Liu, ZS., Song, DF. et al. Cholecystokinin type 2 receptor in colorectal cancer: diagnostic and therapeutic target. J Cancer Res Clin Oncol 146, 2205–2217 (2020). https://doi.org/10.1007/s00432-020-03273-z
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DOI: https://doi.org/10.1007/s00432-020-03273-z