Abstract
Substance P (SP), a neuropeptide belonging to the tachykinin family, exerts different biological activities mainly through neurokinin-1 receptor (NK1R). The role of SP/NK1R system in tumoral growth and spread is reported in several cancers. We aimed to evaluate the serum SP concentration and NK1R tissue distribution in endometrial cancer, and to study the relationship between these factors with tumor size, lymph node involvement, disease stage and cancer grade. Recruiting 22 patients with endometrial cancer and 21 patients with leiomyoma as the control group, serum SP concentration was measured using an ELISA method, and NK1R tissue distributions were immunohistochemically analyzed. Serum SP concentration in patients was significantly higher than the control group (p-value = 0.005). The expression level of NK1R in tumoral tissue was more than normal tissue (p-value < 0.001). The NK1R expression had a significant relationship with lymph node involvement (p-value = 0.005) and disease stage (p-value = 0.017). The NK1R expression was higher in more advanced and less-differentiated tumors. SP/NK1R system seems to play a role in tumor growth and development in endometrial cancer. As well, the NK1R expression increased in endometrial cancer, and may be considered as a prognostic factor; but further studies are needed in this field.
Similar content being viewed by others
References
Severini C, Improta G, Falconieri-Erspamer G, Salvadori S, Erspamer V (2002) The tachykinin peptide family. Pharmacol Rev 54(2):285–322
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
Gaddum J (1931) An unidentified depressor substance in certain tissue extracts. J Physiol 72(1):74–87
Garcia-Recio S, Gascón P (2015) Biological and pharmacological aspects of the NK1-Receptor. BioMed Res Int. https://doi.org/10.1155/2015/495704
Datar P, Srivastava S, Coutinho E, Govil G (2004) Substance P: structure, function, and therapeutics. Curr Top Med Chem 4(1):75–103
Bossaller C, Reither K, Hehlert-Friedrich C, Auch-Schwelk W, Graf K, Grafe M, Fleck E (1992) In vivo measurement of endothelium-dependent vasodilation with substance P in man. Herz 17(5):284–290
Eklund B, Jogestrand T, Pernow B (1977) Effect of substance P on resistance and capacitance vessels in the human forearm. In: von Euler US, Pernow B (eds) Substance P. Raven Press, New York
Shimizu Y, Matsuyama H, Shiina T, Takewaki T, Furness J (2008) Tachykinins and their functions in the gastrointestinal tract. Cell Mol Life Sci 65(2):295–311
Saito R, Takano Y, Kamiya HO (2003) Roles of substance P and NK(1) receptor in the brainstem in the development of emesis. J Pharmacol Sci 91(2):87–94
Fields HL, Levine JD (1984) Pain–mechanics and management. West J Med 141(3):347–357
Klassert TE, Patel SA, Rameshwar P (2010) Tachykinins and neurokinin receptors in bone marrow functions: neural-hematopoietic link. J Recept Ligand Channel Res 3:51–61
Nabzdyk LP, Kuchibhotla S, Guthrie P, Chun M, Auster ME, Nabzdyk C, Deso S, Andersen N, Gnardellis C, LoGerfo FW (2013) Expression of neuropeptides and cytokines in a rabbit model of diabetic neuroischemic wound healing. J Vasc Surg 58(3):766–775 (e712)
Rosso M, Robles-Frías MJ, Coveñas R, Salinas-Martín MV, Muñoz 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. Tumor Biol 29(4):245–254
Friess H, Zhu Z, Liard V, Shi X, Shrikhande SV, Wang L, Lieb K, Korc M, Palma C, Zimmermann A (2003) Neurokinin-1 receptor expression and its potential effects on tumor growth in human pancreatic cancer. Lab Investig 83(5):731–742
Singh D, Joshi DD, Hameed M, Qian J, Gascón P, Maloof PB, Mosenthal A, Rameshwar P (2000) Increased expression of preprotachykinin-I and neurokinin receptors in human breast cancer cells: implications for bone marrow metastasis. Proc Natl Acad Sci USA 97(1):388–393
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
Muñoz M, Rosso M, Robles-Frias MJ, Salinas-Martín MV, Rosso R, González-Ortega A, Coveñas 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
Harkins J, Roper M, Ham RG, Stewart JM (1978) Biosynthesis of substance P in cultured mouse neuroblastoma and rat glioma cells. Brain Res 147(2):405–409
Ma J, Yuan S, Cheng J, Kang S, Zhao W, Zhang J (2016) Substance P promotes the progression of endometrial adenocarcinoma. Int J Gynecol Cancer: Off J Int Gynecol Cancer Soc 26(5):845–850. https://doi.org/10.1097/igc.0000000000000683
Akazawa T, Kwatra SG, Goldsmith LE, Richardson MD, Cox EA, Sampson JH, Kwatra MM (2009) A constitutively active form of neurokinin 1 receptor and neurokinin 1 receptor-mediated apoptosis in glioblastomas. J Neurochem 109(4):1079–1086
Bigioni M, Benzo A, Irrissuto C, Maggi CA, Goso C (2005) Role of NK-1 and NK-2 tachykinin receptor antagonism on the growth of human breast carcinoma cell line MDA-MB-231. Anti-Cancer Drugs 16(10):1083–1089
Entschladen F, Lang K, Drell TL, Joseph J, Zaenker KS (2002) Neurotransmitters are regulators for the migration of tumor cells and leukocytes. Cancer Immunol Immunother 51(9):467–482
Guha S, Eibl G, Kisfalvi K, Fan RS, Burdick M, Reber H, Hines OJ, Strieter R, Rozengurt E (2005) Broad-spectrum G protein-coupled receptor antagonist, [D-Arg1,D-Trp5,7,9,Leu11]SP: a dual inhibitor of growth and angiogenesis in pancreatic cancer. Cancer Res 65(7):2738–2745. https://doi.org/10.1158/0008-5472.can-04-3197
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
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
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386. https://doi.org/10.1002/ijc.29210
Arab M, Noghabaei G, Kazemi SN (2014) Comparison of crude and age-specific incidence rates of breast, ovary, endometrium and cervix cancers in Iran, 2005. Asian Pac J Cancer Prevent: APJCP 15(6):2461–2464
Plataniotis G, Castiglione M, Group EGW (2010) Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(suppl 5):v41–v45
Faria SC, Sagebiel T, Balachandran A, Devine C, Lal C, Bhosale PR (2015) Imaging in endometrial carcinoma. Indian J Radiol Imaging 25(2):137–147. https://doi.org/10.4103/0971-3026.155857
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. https://doi.org/10.1073/pnas.0809130106
Rosso M, Munoz M, Berger M (2012) The role of neurokinin-1 receptor in the microenvironment of inflammation and cancer. Sci World J. https://doi.org/10.1100/2012/381434
Simeonidis S, Castagliuolo I, Pan A, Liu J, Wang CC, Mykoniatis A, Pasha A, Valenick L, Sougioultzis S, Zhao D, Pothoulakis C (2003) Regulation of the NK-1 receptor gene expression in human macrophage cells via an NF-kappa B site on its promoter. Proc Natl Acad Sci USA 100(5):2957–2962. https://doi.org/10.1073/pnas.0530112100
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: A J Tech Methods Pathol 83(5):731–742
Acknowledgements
We would like to thank all patients who participated in this study. We acknowledge Samaneh Shoghi Motlagh and Zohrehsadat Hosseinzadeh for their technical assistance. We also express our gratitude towards the Research Council of Mashhad University of Medical Sciences for financially granting this project. This work was written based on the master thesis of Naghmeh Gharaee (Code: 930603).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Gharaee, N., Pourali, L., Jafarian, A.H. et al. Evaluation of serum level of substance P and tissue distribution of NK-1 receptor in endometrial cancer. Mol Biol Rep 45, 2257–2262 (2018). https://doi.org/10.1007/s11033-018-4387-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-018-4387-1