Compound Astragalus and Salvia miltiorrhiza extract inhibits hepatocarcinogenesis via modulating TGF‑β/TβR and Imp7/8

Wu,Chao; Kan,Hongwei; Hu,Min; Liu,Xin; Boye,Alex; Jiang,Yufeng; Wu,Jiajun; Wang,Jiyu; Yang,Xiaochuan; Yang,Yan

doi:10.3892/etm.2018.6292

Compound Astragalus and Salvia miltiorrhiza extract inhibits hepatocarcinogenesis via modulating TGF‑β/TβR and Imp7/8

Authors:
- Chao Wu
- Hongwei Kan
- Min Hu
- Xin Liu
- Alex Boye
- Yufeng Jiang
- Jiajun Wu
- Jiyu Wang
- Xiaochuan Yang
- Yan Yang
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Affiliations: Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China, Department of Pathology, Anhui University of Chinese Traditional Medicine, Hefei, Anhui 230038, P.R. China, Therapeutics Research Centre, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia
Published online on: June 12, 2018 https://doi.org/10.3892/etm.2018.6292
Pages: 1052-1060
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Compound Astragalus and Salvia miltiorrhiza extract (CASE) is a Chinese herbal formula consisting of astragalosides, astragalus polysaccharide and salvianolic acids extracted from Astragalus membranaceus and Salvia miltiorhiza. Previous studies by our group have demonstrated that CASE effectively suppresses diethylinitrosamine (DEN)‑induced hepatocellular carcinoma (HCC) in rats via modulating transforming growth factor β/Mothers against decapentaplegic (TGFβ/Smad) signaling. To further elucidate the mechanism of CASE, the effects of CASE on TGF‑β1, the serine/threonine kinase receptors of TGF‑β [TGF‑β receptor type‑I (TβRΙ) and TβRII] and karyopherins [Importin 7 (Imp7) and Imp8], which are crucial for TGF‑β/Smad signaling in fibro‑hepatocarcinogenesis, were assessed in the present study using in vivo (DEN‑induced HCC in rats) and in vitro [TGF‑β1‑stimulated rat myofibroblasts (MFBs) and HepG2 cells] models of fibro‑hepatocarcinogenesis. Hematoxylin and eosin staining revealed that CASE may suppress inflammatory reactions and fibrosis in HCC as well as increasing the differentiation of HCC cells. Positive TGF‑β1 staining was increased in HCC nodule areas and in adjacent normal liver tissues in DEN‑treated rats, while TβRΙ staining was increased only in normal adjacent liver tissues. The elevated expression of TGF‑β1, TβRΙ and TβRII was suppressed by CASE. CASE treatment also reduced glutathione S‑transferase P 1 and Imp7/8 protein expression in fibro‑hepatocarcinogenesis. In vitro experiments confirmed that CASE was able to decrease the expression of TβRΙ and TβRII in TGF‑β1‑stimulated MFBs and HepG2 cells. These results indicate that the anti‑HCC effect of CASE may be achieved by mediating TGF‑β/TβR and Imp7/8 protein expression, suggesting that CASE has multiple targets in HCC treatment.

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1	Chiang JK and Kao YH: Predictors of high healthcare costs in elderly patients with liver cancer in end-of-life: A longitudinal population-based study. BMC Cancer. 17:5682017. View Article : Google Scholar : PubMed/NCBI
2	Kirstein MM and Vogel A: The pathogenesis of hepatocellular carcinoma. Dig Dis. 32:545–553. 2014. View Article : Google Scholar : PubMed/NCBI
3	Chen KW, Ou TM, Hsu CW, Horng CT, Lee CC, Tsai YY, Tsai CC, Liou YS, Yang CC, Hsueh CW and Kuo WH: Current systemic treatment of hepatocellular carcinoma: A review of the literature. World J Hepatol. 7:1412–1420. 2015. View Article : Google Scholar : PubMed/NCBI
4	Liu H, Wei W, Sun WY and Li X: Protective effects of astragaloside iv on porcine-serum-induced hepatic fibrosis in rats and in vitro effects on hepatic stellate cells. J Ethnopharmacol. 122:502–508. 2009. View Article : Google Scholar : PubMed/NCBI
5	Zhu C, Cao H, Zhou X, Dong C, Luo J, Zhang C, Liu J and Ling Y: Meta-analysis of the clinical value of danshen injection and huangqi injection in liver cirrhosis. Evid Based Complement Alternat Med. 2013:8428242013. View Article : Google Scholar : PubMed/NCBI
6	Rui W, Xie L, Liu X, He S, Wu C, Zhang X, Zhang L and Yang Y: Compound Astragalus and Salvia miltiorrhiza extract suppresses hepatocellular carcinoma progression by inhibiting fibrosis and PAI-1 mRNA transcription. J Ethnopharmacol. 151:198–209. 2014. View Article : Google Scholar : PubMed/NCBI
7	Yang Y, Yang S, Chen M and Zhang X, Zou Y and Zhang X: Compound Astragalus and Salvia miltiorrhiza extract exerts anti-fibrosis by mediating TGF-beta/smad signaling in myofibroblasts. J Ethnopharmacol. 118:264–270. 2008. View Article : Google Scholar : PubMed/NCBI
8	Zhang XX, Yang Y, Liu X, Wu C and Chen MZ: Effects of compound traditional Astragalus and Salvia miltiorrhiza extract on acute and chronic hepatic injury. TANG. 3:15.1–15.5. 2013.
9	Liu X, Yang Y, Zhang X, Xu S, He S, Huang W and Roberts MS: Compound Astragalus and Salvia miltiorrhiza extract inhibits cell invasion by modulating transforming growth factor-beta/smad in HepG2 cell. J Gastroenterol Hepatol. 25:420–426. 2010. View Article : Google Scholar : PubMed/NCBI
10	Hu X, Rui W, Wu C, He S, Jiang J, Zhang X and Yang Y: Compound Astragalus and Salvia miltiorrhiza extracts suppress hepatocarcinogenesis by modulating transforming growth factor-β/smad signaling. J Gastroenterol Hepatol. 29:1284–1291. 2014. View Article : Google Scholar : PubMed/NCBI
11	McGrath JC, Drummond GB, McLachlan EM, Kilkenny C and Wainwright CL: Guidelines for reporting experiments involving animals: The ARRIVE guidelines. Br J Pharmacol. 160:1573–1576. 2010. View Article : Google Scholar : PubMed/NCBI
12	Yoshida K, Matsuzaki K, Mori S, Tahashi Y, Yamagata H, Furukawa F, Seki T, Nishizawa M, Fujisawa J and Okazaki K: Transforming growth factor-beta and platelet-derived growth factor signal via c-jun n-terminal kinase-dependent smad2/3 phosphorylation in rat hepatic stellate cells after acute liver injury. Am J Pathol. 166:1029–1039. 2005. View Article : Google Scholar : PubMed/NCBI
13	Furukawa F, Matsuzaki K, Mori S, Tahashi Y, Yoshida K, Sugano Y, Yamagata H, Matsushita M, Seki T, Inagaki Y, et al: p38 MAPK mediates fibrogenic signal through smad3 phosphorylation in rat myofibroblasts. Hepatology. 38:879–889. 2003. View Article : Google Scholar : PubMed/NCBI
14	Wu C, Jiang J, Boye A, Jiang Y and Yang Y: Compound Astragalus and Salvia miltiorrhiza extract suppresses rabbits' hypertrophic scar by modulating the TGF-β/Smad signal. Dermatology. 229:363–368. 2014. View Article : Google Scholar : PubMed/NCBI
15	Chen G, Dai ZK, Liang RG, Xiao SJ, He SQ, Zhao HL and Xu Q: Characterization of diethylnitrosamine-induced liver carcinogenesis in syrian golden hamsters. Exp Ther Med. 3:285–292. 2012. View Article : Google Scholar : PubMed/NCBI
16	Matsuzaki K: Modulation of TGF-beta signaling during progression of chronic liver diseases. Front Biosci (Landmark Ed). 14:2923–2934. 2009. View Article : Google Scholar : PubMed/NCBI
17	Wang Q, Zhai YY, Dai JH, Li KY, Deng Q and Hen ZG: SAMD9L inactivation promotes cell proliferation via facilitating G1-S transition in hepatitis B virus-associated hepatocellular carcinoma. Int J Biol Sci. 10:807–816. 2014. View Article : Google Scholar : PubMed/NCBI
18	Datta S, Ghosh A, Dasgupta D, Ghosh A, Roychoudhury S, Roy G, Das S, Das K, Gupta S, Basu K, et al: Novel point and combo-mutations in the genome of hepatitis B virus-genotype D: Characterization and impact on liver disease progression to hepatocellular carcinoma. PloS One. 9:e1100122014. View Article : Google Scholar : PubMed/NCBI
19	Ren W, Qi X, Yang Z, Han G and Fan D: Prevalence and risk factors of hepatocellular carcinoma in budd-chiari syndrome: A systematic review. Eur J Gastroenterol Hepatol. 25:830–841. 2013. View Article : Google Scholar : PubMed/NCBI
20	Ando N, Shimizu M, Okuno M, Matsushima-Nishiwaki R, Tsurumi H, Tanaka T and Moriwaki H: Expression of retinoid X receptor alpha is decreased in 3′-methyl-4-dimethylaminoazobenzene-induced hepatocellular carcinoma in rats. Oncol Rep. 18:879–884. 2007.PubMed/NCBI
21	De Mattia E, Cecchin E, Polesel J, Bignucolo A, Roncato R, Lupo F, Crovatto M, Buonadonna A, Tiribelli C and Toffoli G: Genetic biomarkers for hepatocellular cancer risk in a caucasian population. World J Gastroenterol. 23:6674–6684. 2017. View Article : Google Scholar : PubMed/NCBI
22	Yu W, Huang C, Wang Q, Huang T, Ding Y, Ma C, Ma H and Chen W: MEF2 transcription factors promotes EMT and invasiveness of hepatocellular carcinoma through TGF-β1 autoregulation circuitry. Tumour Biol. 35:10943–10951. 2014. View Article : Google Scholar : PubMed/NCBI
23	Meindl-Beinker NM, Matsuzaki K and Dooley S: TGF-β signaling in onset and progression of hepatocellular carcinoma. Dig Dis. 30:514–523. 2012. View Article : Google Scholar : PubMed/NCBI
24	Hidaka H, Nakazawa T, Shibuya A, Minamino T, Takada J, Tanaka Y, Okuwaki Y, Watanabe M and Koizumi W: Effects of 1-year administration of olmesartan on portal pressure and TGF-beta1 in selected patients with cirrhosis: A randomized controlled trial. J Gastroenterol. 46:1316–1323. 2011. View Article : Google Scholar : PubMed/NCBI
25	Lee D, Chung YH, Kim JA and Lee YS, Lee D, Jang MK, Kim KM, Lim YS, Lee HC and Lee YS: Transforming growth factor beta 1 overexpression is closely related to invasiveness of hepatocellular carcinoma. Oncology. 82:11–18. 2012. View Article : Google Scholar : PubMed/NCBI
26	Tan Y, Xu Q, Li Y, Mao X and Zhang K: Crosstalk between the p38 and TGF-β signaling pathways through TβRI, TβRII and Smad3 expression in plancental choriocarcinoma JEG-3 cells. Oncol Lett. 8:1307–1311. 2014. View Article : Google Scholar : PubMed/NCBI
27	Liu C, Xu P, Lamouille S, Xu J and Derynck R: TACE-mediated ectodomain shedding of the type I TGF-beta receptor downregulates TGF-beta signaling. Mol Cell. 35:26–36. 2009. View Article : Google Scholar : PubMed/NCBI
28	Gramling MW and Church FC: Plasminogen activator inhibitor-1 is an aggregate response factor with pleiotropic effects on cell signaling in vascular disease and the tumor microenvironment. Thromb Res. 125:377–381. 2010. View Article : Google Scholar : PubMed/NCBI
29	Shi Y and Massague J: Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 113:685–700. 2003. View Article : Google Scholar : PubMed/NCBI
30	Yao X, Chen X, Cottonham C and Xu L: Preferential utilization of Imp7/8 in nuclear import of smads. J Biol Chem. 283:22867–22874. 2008. View Article : Google Scholar : PubMed/NCBI
31	Dong XM, Yin RH, Yang Y, Feng ZW, Ning HM, Dong L, Zheng WW, Tang LJ, Wang J, Jia YX, et al: GATA-2 inhibits transforming growth factor-β signaling pathway through interaction with Smad4. Cell signal. 26:1089–1097. 2014. View Article : Google Scholar : PubMed/NCBI
32	Puche JE, Saiman Y and Friedman SL: Hepatic stellate cells and liver fibrosis. Compr Physiol. 3:1473–1492. 2013. View Article : Google Scholar : PubMed/NCBI
33	Lee UE and Friedman SL: Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol. 25:195–206. 2011. View Article : Google Scholar : PubMed/NCBI
34	Mikula M, Proell V, Fischer AN and Mikulits W: Activated hepatic stellate cells induce tumor progression of neoplastic hepatocytes in a TGF-beta dependent fashion. J Cell Physiol. 209:560–567. 2006. View Article : Google Scholar : PubMed/NCBI
35	Qiu GH, Xie X, Xu F, Shi X, Wang Y and Deng L: Distinctive pharmacological differences between liver cancer cell lines HepG2 and Hep3B. Cytotechnology. 67:1–12. 2015. View Article : Google Scholar : PubMed/NCBI