Role of transforming growth factor β1 in the inhibition of gastric cancer cell proliferation by melatonin in vitro and in vivo

  • Authors:
    • Hui Liu
    • Yu Zhu
    • Hui Zhu
    • Rong Cai
    • Kai‑Fang Wang
    • Jun Song
    • Ri‑Xiong Wang
    • Rui‑Xiang Zhou
  • View Affiliations

  • Published online on: June 6, 2019     https://doi.org/10.3892/or.2019.7190
  • Pages: 753-762
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Abstract

Transforming growth factor β (TGF‑β) is a polypeptide growth factor with various biological activities, and is widely distributed in various tissues. In mammals, TGF‑β has three isoforms: TGF‑β1, 2, and 3, of which TGF‑β1 is most abundant in the TGF‑β family. TGF‑β1 is closely related to the occurrence and development of tumors. A large number of previous studies have shown that melatonin can inhibit a variety of malignancies. Thus, the aim of the present study was to investigate the role of TGF‑β1 in the melatonin‑mediated inhibition of the proliferation of gastric cancer cells in vitro and in vivo. TGF‑β1 cytokine stimulation, anti‑TGF‑β1 neutralizing antibody blocking, siRNA TGF‑β1 and other means were utilized to explore the role of TGF‑β1 during the course of anti‑gastric cancer by melatonin. The results showed that melatonin upregulated the expression of TGF‑β1 in tumor tissues during the process of inhibiting gastric cancer tumor growth in vivo. Melatonin inhibited the proliferation of gastric cancer cells in vitro, accompanied by increased expression of TGF‑β1 in a time‑dependent manner. siRNA‑mediated silencing of TGF‑β1 and anti‑TGF‑β1 neutralizing antibody completely blocked the TGF‑β1 pathway, which significantly antagonized the melatonin‑mediated inhibition of the growth and proliferation of gastric cancer cells, and promoted G1 phase to S phase transformation of MFC cells. Our findings suggest that TGF‑β1 is involved in the regulation of the proliferation of tumor cells. One of the ways in which melatonin inhibits the proliferation of gastric cancer cells is dependent on the TGF‑β1 signaling pathway.

References

1 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Sano T, Coit DG, Kim HH, Roviello F, Kassab P, Wittekind C, Yamamoto Y and Ohashi Y: Proposal of a new stage grouping of gastric cancer for TNM classification: International Gastric Cancer Association staging project. Gastric Cancer. 20:217–225. 2017. View Article : Google Scholar : PubMed/NCBI

3 

Bbenik GA: Localization, physiological significance and possible clinical implication of gastrointestinal melatonin. Biol Signals Recept. 10:350–366. 2001. View Article : Google Scholar : PubMed/NCBI

4 

Slominski AT, Zmijewski MA, Semak I, Kim TK, Janjetovic Z, Slominski RM and Zmijewski JW: Melatonin, mitochondria, and the skin. Cell Mol Life Sci. 74:3913–3925. 2017. View Article : Google Scholar : PubMed/NCBI

5 

Slominski AT, Hardeland R, Zmijewski MA, Slominski RM, Reiter RJ and Paus R: Melatonin: A cutaneous perspective on its production, metabolism, and functions. J Invest Dermatol. 138:490–499. 2018. View Article : Google Scholar : PubMed/NCBI

6 

Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS and Slominski AT: Melatonin membrane receptors in peripheral tissues: Distribution and functions. Mol Cell Endocrinol. 351:152–166. 2012. View Article : Google Scholar : PubMed/NCBI

7 

Li T, Ni L, Zhao Z, Liu X, Lai Z, Di X, Xie Z, Song X, Wang X, Zhang R and Liu C: Melatonin attenuates smoking-induced hyperglycemia via preserving insulin secretion and hepatic glycogen synthesis in rats. J Pineal Res. 64:e124752018. View Article : Google Scholar : PubMed/NCBI

8 

Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP and Li HB: Melatonin for the prevention and treatment of cancer. Oncotarget. 8:39896–39921. 2017.PubMed/NCBI

9 

Wei X, Qi Y, Jia N, Zhou Q, Zhang S and Wang Y: Hyperbaric oxygen treatment sensitizes gastric cancer cells to melatonin-induced apoptosis through multiple pathways. J Cell Biochem. 119:6723–6731. 2018. View Article : Google Scholar : PubMed/NCBI

10 

Zhang S, Qi Y, Zhang H, He W, Zhou Q, Gui S and Wang Y: Melatonin inhibits cell growth and migration, but promotes apoptosis in gastric cancer cell line, SGC7901. Biotech Histochem. 88:281–289. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Ordoñez R, Carbajo-Pescador S, Prieto-Dominguez N, García-Palomo A, González-Gallego J and Mauriz JL: Inhibition of matrix metalloproteinase 9 and nuclear factor kappa B contribute to melatonin prevention of motility and invasiveness in HepG2 liver cancer cells. J Pineal Res. 56:20–30. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Proietti S, Cucina A, Dobrowolny G, D'Anselmi F, Dinicola S, Masiello MG, Pasqualato A, Palombo A, Morini V, Reiter RJ and Bizzarri M: Melatonin downregulates MDM2 gene expression and enhances p53 acetylation in MCF-7 cells. J Pineal Res. 57:120–129. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Cutando A, López Valverde A, De Vicente J, Gimenez JL, Carcía IA and DE Diego RG: Action of melatonin on squamous cell carcinoma and other tumors of the oral cavity (Review). Oncol Lett. 7:923–926. 2014. View Article : Google Scholar : PubMed/NCBI

14 

Liu H, Xu L, Wei JE, Xie MR, Wang SE and Zhou RX: Role of CD4+CD25+ regulatory T cells in melatonin-mediated inhibition of murine gastric cancer cell growth in vivo and in vitro. Anat Rec (Hoboken). 294:781–788. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Wang RX, Liu H, Xu L, Zhang H and Zhou RX: Melatonin downregulates nuclear receptor RZR/RORγ expression causing growth-inhibitory and anti-angiogenesis activity in human gastric cancer cells in vitro and in vivo. Oncol Lett. 12:897–903. 2016. View Article : Google Scholar : PubMed/NCBI

16 

Song J, Ma SJ, Luo JH, Zhang H, Wang RX, Liu H, Li L, Zhang ZG and Zhou RX: Melatonin induces the apoptosis and inhibits the proliferation of human gastric cancer cells via blockade of the AKT/MDM2 pathway. Oncol Rep. 39:1975–1983. 2018.PubMed/NCBI

17 

Liu H, Jiang JH, Xu L, Gong X and Zhou RX: Proliferation inhibition and apoptosis induction of melatonin in mouse MFC progastric cells in vitro and in vivo. Chin J Anat. 42:794–799. 2011.

18 

Patil AS, Sable RB and Kothari RM: An update on transforming growth factor-β (TGF-β): Sources, types, functionsand clinical applicability for cartilage/bone healing. J Cell Physiol. 226:3094–3103. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Pickup M, Novitskiy S and Moses HL: The roles of TGFβ in the tumour microenvironment. Nat Rev Cancer. 13:788–799. 2013. View Article : Google Scholar : PubMed/NCBI

20 

Proietti S, Cucina A, D'Anselmi F, Dinicola S, Pasqualato A, Lisi E and Bizzarri M: Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFβ-1-dependent growth inhibition of breast cancer cells. J Pineal Res. 50:150–158. 2011.PubMed/NCBI

21 

Xu L, Liu H, Zhang H, Wang RX, Song J and Zhou RX: Growth-inhibitory activity of melatonin on murine foregastric carcinoma cells in vitro and the underlying molecular mechanism. Anat Rec (Hoboken). 296:914–920. 2013. View Article : Google Scholar : PubMed/NCBI

22 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

23 

Liang X, Liang X, Zeng J, Wang L, Shen L, Ma X, Li S, Wu Y, Ma L, Ci X, et al: Histone demethylase RBP2 promotes malignant progression of gastric cancer through TGF-β1-(p-Smad3)-RBP2-E-cadherin-Smad3 feedback circuit. Oncotarget. 6:17661–17674. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Tas F, Yasasever CT, Karabulut S, Tastekin D and Duranyildiz D: Serum transforming growth factor-beta1 levels may have predictive and prognostic roles in patients with gastric cancer. Tumour Biol. 36:2097–2103. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Li C, Song L, Zhang Z, Bai XX, Cui MF and Ma LJ: MicroRNA-21 promotes TGF-β1-induced epithelial-mesenchymal transition in gastric cancer through up-regulating PTEN expression. Oncotarget. 7:66989–67003. 2016.PubMed/NCBI

26 

Gen Y, Yasui K, Kitaichi T, Iwai N, Terasaki K, Dohi O, Hashimoto H, Fukui H, Inada Y, Fukui A, et al: ASPP2 suppresses invasion and TGF-β1-induced epithelial-mesenchymal transition by inhibiting Smad7 degradation mediated by E3 ubiquitin ligase ITCH in gastric cancer. Cancer Lett. 398:52–61. 2017. View Article : Google Scholar : PubMed/NCBI

27 

Zhu J and Wen K: Astragaloside IV inhibits TGF-β1-induced epithelial- mesenchymal transition through inhibition of the PI3K/Akt/NF-κB pathway in gastric cancer cells. Phytother Re. 32:1289–1296. 2018. View Article : Google Scholar

28 

Ma HY, Liu XZ and Liang CM: Inflammatory microenvironment contributes to epithelial-mesenchymal transition in gastric cancer. World J Gastroenterol. 22:6619–6628. 2016. View Article : Google Scholar : PubMed/NCBI

29 

Gonzalez-Moreno O, Lecanda J, Green JE, Segura V, Catena R, Serrano D and Calvo A: VEGF elicits epithelial-mesenchymal transition (EMT) in prostate intraepithelial neoplasia (PIN)-like cells via an autocrine loop. Exp Cell Res. 316:554–567. 2010. View Article : Google Scholar : PubMed/NCBI

30 

Wu Q, Hou X, Xia J, Qian X, Miele L, Sarkar FH and Wang Z: Emerging roles of PDGF-D in EMT progression during tumorigenesis. Cancer Treat Rev. 39:640–646. 2013. View Article : Google Scholar : PubMed/NCBI

31 

Ma GF, Miao Q, Zeng XQ, Luo TC, Ma LL, Liu YM, Lian JJ, Gao H and Chen SY: Transforming growth factor-β1 and -β2 in gastric precancer and cancer and roles in tumor-cell interactions with peripheral blood mononuclear cells in vitro. PLoS One. 8:e542492013. View Article : Google Scholar : PubMed/NCBI

32 

Yu N, Sun YT, Su XM, He M, Dai B and Kang J: Melatonin attenuates TGFβ1-induced epithelial-mesenchymal transition in lung alveolar epithelial cells. Mol Med Rep. 14:5567–5572. 2016. View Article : Google Scholar : PubMed/NCBI

33 

Wang XG, Meng Q, Qi FM and Yang QF: Blocking TGF-β inhibits breast cancer cell invasiveness via ERK/S100A4 signal. Eur Rev Med Pharmacol Sci. 18:3844–3853. 2014.PubMed/NCBI

34 

Chatterjee A, Mukhopadhyay S, Tung K, Patel D and Foster DA: Rapamycin-induced G1 cell cycle arrest employs both TGF-β and Rb pathways. Cancer Lett. 360:134–140. 2015. View Article : Google Scholar : PubMed/NCBI

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August 2019
Volume 42 Issue 2

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Copy and paste a formatted citation
APA
Liu, H., Zhu, Y., Zhu, H., Cai, R., Wang, K., Song, J. ... Zhou, . (2019). Role of transforming growth factor β1 in the inhibition of gastric cancer cell proliferation by melatonin in vitro and in vivo. Oncology Reports, 42, 753-762. https://doi.org/10.3892/or.2019.7190
MLA
Liu, H., Zhu, Y., Zhu, H., Cai, R., Wang, K., Song, J., Wang, R., Zhou, ."Role of transforming growth factor β1 in the inhibition of gastric cancer cell proliferation by melatonin in vitro and in vivo". Oncology Reports 42.2 (2019): 753-762.
Chicago
Liu, H., Zhu, Y., Zhu, H., Cai, R., Wang, K., Song, J., Wang, R., Zhou, ."Role of transforming growth factor β1 in the inhibition of gastric cancer cell proliferation by melatonin in vitro and in vivo". Oncology Reports 42, no. 2 (2019): 753-762. https://doi.org/10.3892/or.2019.7190