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Evaluation of serum level of substance P and tissue distribution of NK-1 receptor in colorectal cancer

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Abstract

Colorectal cancer (CRC) is known as the most common form of malignancies in the world and its occurrence is annually increasing. Due to the relatively high death rates in patients, finding better diagnostic and prognostic factors are required. Substance P (SP) belongs to the tachykinin family that acts as an immunomodulator by binding to the neurokinin-1 receptor (NK1R). The interaction of SP with NK1R might be involved in tumor cell proliferation, angiogenesis, and migration. Hence, this study was aimed to evaluate the serum SP level and tissue distribution of NK1Rs in CRC. Also, we assessed the relationship between tissue distribution of NK1R and some different tumor characteristics, including tumor size, and lymph node status. Recruiting 38 patients primarily diagnosed with CRC, the tissue distribution of NK1R was immunohistochemically evaluated in tumor tissues and their adjacent normal tissue. The serum level of SP was measured using an ELISA method in both cases and healthy control group. The SP value was significantly increased in the serum of patients in comparison with the healthy group (p = 0.001). Tumor tissues expressed a higher number of NK1R than adjacent normal tissues (p = 0.01) considering both the percentage of stained cells and intensity of staining. However, there was not any statistically significant relevance between NK1R distribution and tumor characteristics. The SP/NK1R system is involved in tumorigenesis of CRC, and might be suggested as a potent prognostic or diagnostic factor, or a new target in the treatment of CRC.

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References

  1. Chen XY, Ru GQ, Ma YY, Xie J, Chen WY, Wang HJ, Wang SB, Li L, Jin KT, He XL, Mou XZ (2016) High expression of substance P and its receptor neurokinin-1 receptor in colorectal cancer is associated with tumor progression and prognosis. OncoTargets Ther 9:3595–3602. https://doi.org/10.2147/ott.s102356

    Article  CAS  Google Scholar 

  2. Javid H, Mohammadi F, Zahiri E, Hashemy SI (2019) The emerging role of substance P/neurokinin-1 receptor signaling pathways in growth and development of tumor cells. J Physiol Biochem. https://doi.org/10.1007/s13105-019-00697-1

    Article  PubMed  Google Scholar 

  3. Majkowska-Pilip A, Halik PK, Gniazdowska E (2019) The significance of NK1 receptor ligands and their application in targeted radionuclide tumour therapy. Pharmaceutics. https://doi.org/10.3390/pharmaceutics11090443

    Article  PubMed  PubMed Central  Google Scholar 

  4. Almeida TA, Rojo J, Nieto PM, Pinto FM, Hernandez M, Martin JD, Candenas ML (2004) Tachykinins and tachykinin receptors: structure and activity relationships. Curr Med Chem 11(15):2045–2081

    Article  CAS  PubMed  Google Scholar 

  5. Steinhoff MS, von Mentzer B, Geppetti P, Pothoulakis C, Bunnett NW (2014) Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease. Physiol Rev 94(1):265–301. https://doi.org/10.1152/physrev.00031.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Page NM (2005) New challenges in the study of the mammalian tachykinins. Peptides 26(8):1356–1368. https://doi.org/10.1016/j.peptides.2005.03.030

    Article  CAS  PubMed  Google Scholar 

  7. Koon HW, Zhao D, Na X, Moyer MP, Pothoulakis C (2004) Metalloproteinases and transforming growth factor-alpha mediate substance P-induced mitogen-activated protein kinase activation and proliferation in human colonocytes. J Biol Chem 279(44):45519–45527. https://doi.org/10.1074/jbc.M408523200

    Article  CAS  PubMed  Google Scholar 

  8. Harrison S, Geppetti P (2001) Substance p. Int J Biochem Cell Biol 33(6):555–576

    Article  CAS  PubMed  Google Scholar 

  9. Garcia-Recio S, Gascon P (2015) Biological and pharmacological aspects of the NK1-receptor. BioMed Res Int 2015:495704. https://doi.org/10.1155/2015/495704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rosso M, Robles-Frias MJ, Covenas R, Salinas-Martin MV, Munoz M (2008) The NK-1 receptor is expressed in human primary gastric and colon adenocarcinomas and is involved in the antitumor action of L-733,060 and the mitogenic action of substance P on human gastrointestinal cancer cell lines. Tumour Biol 29(4):245–254. https://doi.org/10.1159/000152942

    Article  CAS  PubMed  Google Scholar 

  11. Friess H, Zhu Z, Liard V, Shi X, Shrikhande SV, Wang L, Lieb K, Korc M, Palma C, Zimmermann A, Reubi JC, Buchler MW (2003) Neurokinin-1 receptor expression and its potential effects on tumor growth in human pancreatic cancer. Lab Investig 83(5):731–742

    Article  CAS  PubMed  Google Scholar 

  12. Munoz M, Gonzalez-Ortega A, Rosso M, Robles-Frias MJ, Carranza A, Salinas-Martin MV, Covenas R (2012) The substance P/neurokinin-1 receptor system in lung cancer: focus on the antitumor action of neurokinin-1 receptor antagonists. Peptides 38(2):318–325. https://doi.org/10.1016/j.peptides.2012.09.024

    Article  CAS  PubMed  Google Scholar 

  13. Munoz M, Rosso M, Robles-Frias MJ, Salinas-Martin MV, Rosso R, Gonzalez-Ortega A, Covenas R (2010) The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines. Lab Investig 90(8):1259–1269. https://doi.org/10.1038/labinvest.2010.92

    Article  CAS  PubMed  Google Scholar 

  14. Li Q, Wu X, Yang Y, Zhang Y, He F, Xu X, Zhang Z, Tao L, Luo C (2019) Tachykinin NK1 receptor antagonist L-733,060 and substance P deletion exert neuroprotection through inhibiting oxidative stress and cell death after traumatic brain injury in mice. Int J Biochem Cell Biol 107:154–165. https://doi.org/10.1016/j.biocel.2018.12.018

    Article  CAS  PubMed  Google Scholar 

  15. Davoodian M, Boroumand N, Mehrabi Bahar M, Jafarian AH, Asadi M, Hashemy SI (2019) Evaluation of serum level of substance P and tissue distribution of NK-1 receptor in breast cancer. Mol Biol Rep 46(1):1285–1293. https://doi.org/10.1007/s11033-019-04599-9

    Article  CAS  PubMed  Google Scholar 

  16. Gharaee N, Pourali L, Jafarian AH, Hashemy SI (2018) Evaluation of serum level of substance P and tissue distribution of NK-1 receptor in endometrial cancer. Mol Biol Rep 45(6):2257–2262. https://doi.org/10.1007/s11033-018-4387-1

    Article  CAS  PubMed  Google Scholar 

  17. Covenas R, Munoz M (2014) Cancer progression and substance P. Histol Histopathol 29(7):881–890. https://doi.org/10.14670/hh-29.881

    Article  CAS  PubMed  Google Scholar 

  18. Munoz M, Rosso M, Perez A, Covenas R, Rosso R, Zamarriego C, Piruat JI (2005) The NK1 receptor is involved in the antitumoural action of L-733,060 and in the mitogenic action of substance P on neuroblastoma and glioma cell lines. Neuropeptides 39(4):427–432. https://doi.org/10.1016/j.npep.2005.03.004

    Article  CAS  PubMed  Google Scholar 

  19. Munoz M, Gonzalez-Ortega A, Covenas R (2012) The NK-1 receptor is expressed in human leukemia and is involved in the antitumor action of aprepitant and other NK-1 receptor antagonists on acute lymphoblastic leukemia cell lines. Investig New Drugs 30(2):529–540. https://doi.org/10.1007/s10637-010-9594-0

    Article  CAS  Google Scholar 

  20. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. https://doi.org/10.3322/caac.20107

    Article  PubMed  Google Scholar 

  21. Kraus S, Arber N (2009) Inflammation and colorectal cancer. Curr Opin Pharmacol 9(4):405–410. https://doi.org/10.1016/j.coph.2009.06.006

    Article  CAS  PubMed  Google Scholar 

  22. Rahmani F, Avan A, Hashemy SI, Hassanian SM (2018) Role of Wnt/beta-catenin signaling regulatory microRNAs in the pathogenesis of colorectal cancer. J Cell Physiol 233(2):811–817. https://doi.org/10.1002/jcp.25897

    Article  CAS  PubMed  Google Scholar 

  23. Lorestani S, Hashemy SI, Mojarad M, Keyvanloo Shahrestanaki M, Bahari A, Asadi M, Zahedi Avval F (2018) Increased glutathione reductase expression and activity in colorectal cancer tissue samples: an investigational study in Mashhad. Iran Middle East J Cancer 9(2):99–104

    CAS  Google Scholar 

  24. Soleimani A, Zahiri E, Ehtiati S, Norouzi M, Rahmani F, Fiuji H, Avan A, Ferns GA, Khazaei M, Hashemy SI, Hassanian SM (2019) Therapeutic potency of heat-shock protein-70 in the pathogenesis of colorectal cancer: current status and perspectives. Biochem Cell Biol 97(2):85–90. https://doi.org/10.1139/bcb-2018-0177

    Article  CAS  PubMed  Google Scholar 

  25. Yaghoubi N, Soltani A, Ghazvini K, Hassanian SM, Hashemy SI (2019) PD-1/ PD-L1 blockade as a novel treatment for colorectal cancer. Biomed Pharmacother 110:312–318. https://doi.org/10.1016/j.biopha.2018.11.105

    Article  CAS  PubMed  Google Scholar 

  26. Turner GB, Johnston BT, McCance DR, McGinty A, Watson RGP, Patterson CC, Ardill JES (2006) Circulating markers of prognosis and response to treatment in patients with midgut carcinoid tumours. Gut 55(11):1586–1591. https://doi.org/10.1136/gut.2006.092320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Haggar FA, Boushey RP (2009) Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg 22(4):191–197. https://doi.org/10.1055/s-0029-1242458

    Article  PubMed  PubMed Central  Google Scholar 

  28. Javid H, Asadi J, Zahedi Avval F, Afshari AR, Hashemy SI (2020) The role of substance P/neurokinin 1 receptor in the pathogenesis of esophageal squamous cell carcinoma through constitutively active PI3K/Akt/NF-kappaB signal transduction pathways. Mol Biol Rep 47(3):2253–2263. https://doi.org/10.1007/s11033-020-05330-9

    Article  CAS  PubMed  Google Scholar 

  29. Yamaguchi K, Yamazaki S, Kumakura S, Someya A, Iseki M, Inada E, Nagaoka I (2020) Yokukansan, a Japanese Herbal Medicine, suppresses substance P-induced production of interleukin-6 and interleukin-8 by human U373 MG glioblastoma astrocytoma cells. Endocr Metab Immune Disord Drug Targets. https://doi.org/10.2174/1871530320666200131103733

    Article  PubMed  Google Scholar 

  30. Kishi H, Mishima HK, Sakamoto I, Yamashita U (1996) Stimulation of retinal pigment epithelial cell growth by neuropeptides in vitro. Curr Eye Res 15(7):708–713

    Article  CAS  PubMed  Google Scholar 

  31. Reddy BY, Greco SJ, Patel PS, Trzaska KA, Rameshwar P (2009) RE-1-silencing transcription factor shows tumor-suppressor functions and negatively regulates the oncogenic TAC1 in breast cancer cells. Proc Natl Acad Sci USA 106(11):4408–4413. https://doi.org/10.1073/pnas.0809130106

    Article  PubMed  PubMed Central  Google Scholar 

  32. Nakajima Y, Tsuchida K, Negishi M, Ito S, Nakanishi S (1992) Direct linkage of three tachykinin receptors to stimulation of both phosphatidylinositol hydrolysis and cyclic AMP cascades in transfected Chinese hamster ovary cells. J Biol Chem 267(4):2437–2442

    CAS  PubMed  Google Scholar 

  33. Krolicki L, Bruchertseifer F, Kunikowska J, Koziara H, Krolicki B, Jakucinski M, Pawlak D, Apostolidis C, Mirzadeh S, Rola R, Merlo A, Morgenstern A (2019) Safety and efficacy of targeted alpha therapy with (213)Bi-DOTA-substance P in recurrent glioblastoma. Eur J Nucl Med Mol Imaging 46(3):614–622. https://doi.org/10.1007/s00259-018-4225-7

    Article  CAS  PubMed  Google Scholar 

  34. Rosso M, Munoz M, Berger M (2012) The role of neurokinin-1 receptor in the microenvironment of inflammation and cancer. Sci World J 2012:381434. https://doi.org/10.1100/2012/381434

    Article  CAS  Google Scholar 

  35. Koh Y-H, Moochhala S, Bhatia M (2012) Activation of neurokinin-1 receptors up-regulates substance P and neurokinin-1 receptor expression in murine pancreatic acinar cells. J Cell Mol Med 16(7):1582–1592. https://doi.org/10.1111/j.1582-4934.2011.01475.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Castro TA, Cohen MC, Rameshwar P (2005) The expression of neurokinin-1 and preprotachykinin-1 in breast cancer cells depends on the relative degree of invasive and metastatic potential. Clin Exp Metastasis 22(8):621–628. https://doi.org/10.1007/s10585-006-9001-6

    Article  CAS  PubMed  Google Scholar 

  37. Bashash D, Safaroghli-Azar A, Bayati S, Razani E, Pourbagheri-Sigaroodi A, Gharehbaghian A, Momeny M, Sanjadi M, Rezaie-Tavirani M, Ghaffari SH (2018) Neurokinin-1 receptor (NK1R) inhibition sensitizes APL cells to anti-tumor effect of arsenic trioxide via restriction of NF-kappaB axis: shedding new light on resistance to Aprepitant. Int J Biochem Cell Biol 103:105–114. https://doi.org/10.1016/j.biocel.2018.08.010

    Article  CAS  PubMed  Google Scholar 

  38. Bayati S, Razani E, Bashash D, Safaroghli-Azar A, Safa M, Ghaffari SH (2018) Antileukemic effects of neurokinin-1 receptor inhibition on hematologic malignant cells: a novel therapeutic potential for aprepitant. Anticancer Drugs 29(3):243–252. https://doi.org/10.1097/cad.0000000000000591

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are very appreciative of all patients who participated in this research. This study was supported by Grants awarded by the Research Council of Mashhad University of Medical Sciences (Code: 922073).

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Correspondence to Seyed Isaac Hashemy.

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Lorestani, S., Ghahremanloo, A., Jangjoo, A. et al. Evaluation of serum level of substance P and tissue distribution of NK-1 receptor in colorectal cancer. Mol Biol Rep 47, 3469–3474 (2020). https://doi.org/10.1007/s11033-020-05432-4

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