Baicalein inhibits migration and invasion of gastric cancer cells through suppression of the TGF‑β signaling pathway

Chen,Fenglin; Zhuang,Mingkai; Peng,Jun; Wang,Xiaozhong; Huang,Tingxuan; Li,Sanmei; Lin,Manqiang; Lin,Hongming; Xu,Yating; Li,Jianying; Chen,Zhixin; Huang,Yuehong

doi:10.3892/mmr.2014.2452

Baicalein inhibits migration and invasion of gastric cancer cells through suppression of the TGF‑β signaling pathway

Authors:
- Fenglin Chen
- Mingkai Zhuang
- Jun Peng
- Xiaozhong Wang
- Tingxuan Huang
- Sanmei Li
- Manqiang Lin
- Hongming Lin
- Yating Xu
- Jianying Li
- Zhixin Chen
- Yuehong Huang
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Affiliations: Department of Gastroenterology, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China, College of Union Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China, Academy of Integrative Medicine Biomedical Research Center, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350001, P.R. China, College of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
Published online on: August 5, 2014 https://doi.org/10.3892/mmr.2014.2452
Pages: 1999-2003

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Abstract

The transforming growth factor‑β (TGF‑β) signaling pathway exhibits an important role in cancer invasion and metastasis. Excessive expression of TGF‑β activates Smad4, leading to the upregulation of downstream metastasis-associated genes. Thus, the inhibition of the TGF‑β/Smad4 signaling pathway may be a novel strategy for treatment of cancer metastasis. Baicalein, a flavonoid derived from the root of Scutellaria baicalensis, has been reported to exert strong anti‑tumor activity towards various types of cancer. In the present study the effect of baicalein on migration and invasion of cancer cells was evaluated using wound‑healing and Transwell assays. In order to investigate the possible molecular mechanisms of the anti‑metastatic effects of baicalein, quantitative polymerase chain reaction (qPCR) and western blot analyses were performed to examine the effect on the expression of TGF‑β, Smad4, N‑cadherin, vimentin, ZEB1 and ZEB2. It was determined that baicalein inhibited the migration and invasion of AGS cells by suppressing the TGF‑β/Smad4 signaling pathway. In addition, baicalein treatment reduced the expression of the metastasis‑associated N‑cadherin, vimentin, ZEB1 and ZEB2, downstream target genes of the TGF‑β/Smad4 signaling pathway. Collectively, these results suggest that inhibition of the metastasis of cancer cells via inactivation of TGF‑β/Smad4 signaling is one of the mechanisms by which baicalein may treat cancer.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	Hartgrink HH, Jansen EP, van Grieken NC and van de Velde CJ: Gastric cancer. Lancet. 374:477–490. 2009. View Article : Google Scholar
3	Derynck R and Akhurst RJ: Differentiation plasticity regulated by TGF-beta family proteins in development and disease. Nat Cell Biol. 9:1000–1004. 2007. View Article : Google Scholar : PubMed/NCBI
4	Saito H, Tsujitani S, Oka S, et al: The expression of transforming growth factor-beta1 is significantly correlated with the expression of vascular endothelial growth factor and poor prognosis of patients with advanced gastric carcinoma. Cancer. 86:1455–1462. 1999. View Article : Google Scholar
5	Maehara Y, Kakeji Y, Kabashima A, et al: Role of transforming growth factor-beta 1 in invasion and metastasis in gastric carcinoma. J Clin Oncol. 17:607–614. 1999.PubMed/NCBI
6	Ijichi H, Ikenoue T, Kato N, et al: Systematic analysis of the TGF-beta-Smad signaling pathway in gastrointestinal cancer cells. Biochem Biophys Res Commun. 289:350–357. 2001. View Article : Google Scholar : PubMed/NCBI
7	Wang KS, Hu ZL, Li JH, Xiao DS and Wen JF: Enhancement of metastatic and invasive capacity of gastric cancer cells by transforming growth factor-beta1. Acta Biochim Biophys Sin (Shanghai). 38:179–186. 2006. View Article : Google Scholar : PubMed/NCBI
8	Parajuli P, Joshee N, Rimando AM, Mittal S and Yadav AK: In vitro antitumor mechanisms of various Scutellaria extracts and constituent flavonoids. Planta Med. 75:41–48. 2009. View Article : Google Scholar : PubMed/NCBI
9	Li-Weber M: New therapeutic aspects of flavones: the anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin. Cancer Treat Rev. 35:57–68. 2009. View Article : Google Scholar : PubMed/NCBI
10	Wang L, Ling Y, Chen Y, et al: Flavonoid baicalein suppresses adhesion, migration and invasion of MDA-MB-231 human breast cancer cells. Cancer Lett. 297:42–48. 2010. View Article : Google Scholar : PubMed/NCBI
11	Wu B, Li J, Huang D, et al: Baicalein mediates inhibition of migration and invasiveness of skin carcinoma through Ezrin in A431 cells. BMC Cancer. 11:5272011. View Article : Google Scholar : PubMed/NCBI
12	Wu JY, Tsai KW, Li YZ, et al: Anti-bladder-tumor effect of baicalein from Scutellaria baicalensis Georgi and its application in vivo. Evid Based Complement Alternat Med. 2013:5797512013.PubMed/NCBI
13	Chiu YW, Lin TH, Huang WS, et al: Baicalein inhibits the migration and invasive properties of human hepatoma cells. Toxicol Appl Pharmacol. 255:316–326. 2011. View Article : Google Scholar : PubMed/NCBI
14	Zhang Y, Song L, Cai L, Wei R, Hu H and Jin W: Effects of baicalein on apoptosis, cell cycle arrest, migration and invasion of osteosarcoma cells. Food Chem Toxicol. 53:325–333. 2013. View Article : Google Scholar : PubMed/NCBI
15	Picon A, Gold LI, Wang J, Cohen A and Friedman E: A subset of metastatic human colon cancers expresses elevated levels of transforming growth factor beta1. Cancer Epidemiol Biomarkers Prev. 7:497–504. 1998.
16	Fransvea E, Angelotti U, Antonaci S and Giannelli G: Blocking transforming growth factor-beta up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells. Hepatology. 47:1557–1566. 2008. View Article : Google Scholar : PubMed/NCBI
17	Takano S, Kanai F, Jazag A, et al: Smad4 is essential for down-regulation of E-cadherin induced by TGF-beta in pancreatic cancer cell line PANC-1. J Biochem. 141:345–351. 2007. View Article : Google Scholar : PubMed/NCBI
18	Wiercinska E, Naber HP, Pardali E, van der Pluijm G, van Dam H and ten Dijke P: The TGF-β/Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system. Breast Cancer Res Treat. 128:657–666. 2011.
19	Deckers M, van Dinther M, Buijs J, et al: The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res. 66:2202–2209. 2006. View Article : Google Scholar
20	Shiou SR, Datta PK, Dhawan P, et al: Smad4-dependent regulation of urokinase plasminogen activator secretion and RNA stability associated with invasiveness by autocrine and paracrine transforming growth factor-beta. J Biol Chem. 281:33971–33981. 2006. View Article : Google Scholar
21	Araki K, Shimura T, Suzuki H, et al: 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.PubMed/NCBI
22	Cheng JC, Auersperg N and Leung PC: TGF-beta induces serous borderline ovarian tumor cell invasion by activating EMT but triggers apoptosis in low-grade serous ovarian carcinoma cells. PLoS One. 7:e424362012. View Article : Google Scholar
23	Dai M, Al-Odaini AA, Fils-Aimé N, et al: Cyclin D1 cooperates with p21 to regulate TGFβ-mediated breast cancer cell migration and tumor local invasion. Breast Cancer Res. 15:R492013.PubMed/NCBI
24	Derycke LD and Bracke ME: N-cadherin in the spotlight of cell-cell adhesion, differentiation, embryogenesis, invasion and signalling. Int J Dev Biol. 48:463–476. 2004. View Article : Google Scholar : PubMed/NCBI
25	Satelli A and Li S: vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol Life Sci. 68:3033–3046. 2011. View Article : Google Scholar : PubMed/NCBI
26	Jia B, Liu H, Kong Q and Li B: Overexpression of ZEB1 associated with metastasis and invasion in patients with gastric carcinoma. Mol Cell Biochem. 366:223–229. 2012. View Article : Google Scholar : PubMed/NCBI
27	Okugawa Y, Toiyama Y, Tanaka K, et al: Clinical significance of Zinc finger E-box Binding homeobox 1 (ZEB1) in human gastric cancer. J Surg Oncol. 106:280–285. 2012. View Article : Google Scholar : PubMed/NCBI
28	Dai YH, Tang YP, Zhu HY, et al: ZEB2 promotes the metastasis of gastric cancer and modulates epithelial mesenchymal transition of gastric cancer cells. Dig Dis Sci. 57:1253–1260. 2012. View Article : Google Scholar