∆9‑tetrahydrocannabinol inhibits epithelial‑mesenchymal transition and metastasis by targeting matrix metalloproteinase‑9 in endometrial cancer

Zhang,Yingzhi; Zheng,Wei; Shen,Kewei; Shen,Weiwei

doi:10.3892/ol.2018.8407

∆9‑tetrahydrocannabinol inhibits epithelial‑mesenchymal transition and metastasis by targeting matrix metalloproteinase‑9 in endometrial cancer

Authors:
- Yingzhi Zhang
- Wei Zheng
- Kewei Shen
- Weiwei Shen
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Affiliations: Department of Gynecology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P.R. China, Department of Gynecology, The Affiliated Hospital of School of Medicine of Ningbo University, Hangzhou, Zhejiang 310058, P.R. China
Published online on: April 2, 2018 https://doi.org/10.3892/ol.2018.8407
Pages: 8527-8535
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Limited therapeutic interventions are clinically available for treating aggressive endometrial cancer (EC). Therefore, effective therapies are urgently required. Therefore, the present study investigated the role of ∆9‑tetrahydrocannabinol (THC), which is reported to impact proliferative and migratory activities during impairment of cancer progression. In the present study, cell migration in response to THC was measured using transwell assays. Using western blot analysis, the levels of cannabinoid receptors in EC tissues were detected and pathways leading to the inhibition of cell migration by THC on human EC cells were determined. Results suggested that cannabinoid receptors were highly expressed in EC tissues. Furthermore, THC inhibited EC cell viability and motility by inhibiting epithelial‑mesenchymal transition (EMT) and downregulating matrix metalloproteinase‑9 (MMP‑9) gene expression in aggressive human EC cells. The results have the potential to promote the development of novel compounds for the treatment of EC metastasis. The presnet findings suggest that THC may inhibit human EC cell migration through regulating EMT and MMP‑9 pathways.

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1	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
2	Bokhman JV: Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 15:10–17. 1983. View Article : Google Scholar : PubMed/NCBI
3	Creasman WT, Ali S, Mutch DG, Zaino RJ, Powell MA, Mannel RS, Backes FJ, DiSilvestro PA, Argenta PA, Pearl ML, et al: Surgical-pathological findings in type 1 and 2 endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study on GOG-210 protocol. Gynecol Oncol. 145:519–525. 2017. View Article : Google Scholar : PubMed/NCBI
4	van Bakel H, Stout JM, Cote AG, Tallon CM, Sharpe AG, Hughes TR and Page JE: The draft genome and transcriptome of Cannabis sativa. Genome Biol. 12:R1022011. View Article : Google Scholar : PubMed/NCBI
5	Deiana S: Medical use of cannabis. Cannabidiol: A new light for schizophrenia? Drug Test Anal. 5:46–51. 2013. View Article : Google Scholar : PubMed/NCBI
6	Matsuda LA, Lolait SJ, Brownstein MJ, Young AC and Bonner TI: Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 346:561–564. 1990. View Article : Google Scholar : PubMed/NCBI
7	Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A and Mechoulam R: Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 258:1946–1949. 1992. View Article : Google Scholar : PubMed/NCBI
8	Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, et al: International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: Beyond CB₁ and CB₂. Pharmacol Rev. 62:588–631. 2010. View Article : Google Scholar : PubMed/NCBI
9	Mackie K: Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmaco. 299–325. 2005. View Article : Google Scholar
10	Velasco G, Sánchez C and Guzmán M: Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer. 12:436–444. 2012. View Article : Google Scholar : PubMed/NCBI
11	Caffarel MM, Sarrió D, Palacios J, Guzmán M and Sánchez C: Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. Cancer Res. 66:6615–6621. 2006. View Article : Google Scholar : PubMed/NCBI
12	Casanova ML, Blázquez C, Martínez-Palacio J, Villanueva C, Fernández-Aceñero MJ, Huffman JW, Jorcano JL and Guzmán M: Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest. 111:43–50. 2003. View Article : Google Scholar : PubMed/NCBI
13	Preet A, Qamri Z, Nasser MW, Prasad A, Shilo K, Zou X, Groopman JE and Ganju RK: Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis. Cancer Prev Res (Phila). 4:65–75. 2011. View Article : Google Scholar : PubMed/NCBI
14	Jiang R, Zhang C, Liu G, Gu R and Wu H: MicroRNA-126 inhibits proliferation, migration, invasion, and EMT in osteosarcoma by targeting ZEB1. J Cell Biochem. 118:3765–3774. 2017. View Article : Google Scholar : PubMed/NCBI
15	Xie G, Ji A, Yuan Q, Jin Z, Yuan Y, Ren C, Guo Z, Yao Q, Yang K, Lin X and Chen L: Tumour-initiating capacity is independent of epithelial-mesenchymal transition status in breast cancer cell lines. Br J Cancer. 110:2514–2523. 2014. View Article : Google Scholar : PubMed/NCBI
16	Bauvois B: New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: Outside-in signaling and relationship to tumor progression. Biochim Biophys Acta. 1825:29–36. 2012.PubMed/NCBI
17	Burston JJ, Wiley JL, Craig AA, Selley DE and Sim-Selley LJ: Regional enhancement of cannabinoid CB₁ receptor desensitization in female adolescent rats following repeated Delta-tetrahydrocannabinol exposure. Br J Pharmacol. 161:103–112. 2010. View Article : Google Scholar : PubMed/NCBI
18	Chang X, Bian Y, He Q, Yao J, Zhu J, Wu J, Wang K and Duan T: Suppression of STAT3 signaling by Δ9-Tetrahydrocannabinol (THC) induces trophoblast dysfunction. Cell Physiol Biochem. 42:537–550. 2017. View Article : Google Scholar : PubMed/NCBI
19	Shao R: Progesterone receptor isoforms A and B: New insights into the mechanism of progesterone resistance for the treatment of endometrial carcinoma. Ecancermedicalscience. 7:3812013.PubMed/NCBI
20	Hijiya N, Shibata T, Daa T, Hamanaka R, Uchida T, Matsuura K, Tsukamoto Y, Nakada C, Iha H, Inomata M and Moriyama M: Overexpression of cannabinoid receptor 1 in esophageal squamous cell carcinoma is correlated with metastasis to lymph nodes and distant organs, and poor prognosis. Pathol Int. 67:83–90. 2017. View Article : Google Scholar : PubMed/NCBI
21	Caffarel MM, Andradas C, Pérez-Gómez E, Guzmán M and Sánchez C: Cannabinoids: A new hope for breast cancer therapy? Cancer Treat Rev. 38:911–918. 2012. View Article : Google Scholar : PubMed/NCBI
22	Ramer R, Heinemann K, Merkord J, Rohde H, Salamon A, Linnebacher M and Hinz B: COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells. Mol Cancer Ther. 12:69–82. 2013. View Article : Google Scholar : PubMed/NCBI
23	Salazar M, Carracedo A, Salanueva IJ, Hernández-Tiedra S, Lorente M, Egia A, Vázquez P, Blázquez C, Torres S, García S, et al: Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest. 119:1359–1372. 2009. View Article : Google Scholar : PubMed/NCBI
24	Guzmán M, Duarte MJ, Blázquez C, Ravina J, Rosa MC, Galve-Roperh I, Sánchez C, Velasco G and González-Feria L: A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer. 95:197–203. 2006. View Article : Google Scholar : PubMed/NCBI
25	Kramer JL: Medical marijuana for cancer. CA Cancer J Clin. 65:109–122. 2015. View Article : Google Scholar : PubMed/NCBI
26	Wilkie G, Sakr B and Rizack T: Medical marijuana use in oncology: A review. JAMA Oncol. Mar 17–2016.(Epub ahead of print). View Article : Google Scholar : PubMed/NCBI
27	Araki K, Shimura T, Suzuki H, Tsutsumi S, Wada W, Yajima T, Kobayahi T, Kubo N and Kuwano H: E/N-cadherin switch mediates cancer progression via TGF-β-induced epithelial-to-mesenchymal transition in extrahepatic cholangiocarcinoma. Br J Cancer. 105:1885–1893. 2011. View Article : Google Scholar : PubMed/NCBI
28	Grybos A and Bar J: The relationships between the immunoexpression of KAI1, MMP-2, MMP-9 and steroid receptors expression in endometrial cancer. Folia Histochem Cytobiol. 52:187–194. 2014. View Article : Google Scholar : PubMed/NCBI
29	Ghosh S, Preet A, Groopman JE and Ganju RK: Cannabinoid receptor CB2 modulates the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes. Mol Immunol. 43:2169–2179. 2006. View Article : Google Scholar : PubMed/NCBI
30	McAllister SD, Murase R, Christian RT, Lau D, Zielinski AJ, Allison J, Almanza C, Pakdel A, Lee J, Limbad C, et al: Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat. 129:37–47. 2011. View Article : Google Scholar : PubMed/NCBI
31	Adhikary S, Kocieda VP, Yen JH, Tuma RF and Ganea D: Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression. Blood. 120:3741–3749. 2012. View Article : Google Scholar : PubMed/NCBI