Downregulation of syndecan‑1 expression induces activation of hepatic stellate cells via the TGF‑β1/Smad3 signaling pathway

Deng,Min; Xu,Longsheng; Xie,Xinsheng; Sheng,Xiong; Zou,Zhuolin; Yao,Ming

doi:10.3892/mmr.2019.10221

Downregulation of syndecan‑1 expression induces activation of hepatic stellate cells via the TGF‑β1/Smad3 signaling pathway

Authors:
- Min Deng
- Longsheng Xu
- Xinsheng Xie
- Xiong Sheng
- Zhuolin Zou
- Ming Yao
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Affiliations: Department of Infectious Diseases, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China, Department of Anesthesiology and Pain Medicine, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China, Institute of Hepatology, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
Published online on: May 9, 2019 https://doi.org/10.3892/mmr.2019.10221
Pages: 368-374

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Abstract

The activation of hepatic stellate cells (HSCs) is considered associated with liver fibrosis. However, the exact role of syndecan‑1 (SDC1), a protein that regulates the interaction between cells and the microenvironment, in the activation of HSCs resulting in liver fibrosis remains elusive. The objective of the present study was to explore the effects and mechanism of action of SDC1 in the activation of HSCs. HSCs were isolated from mouse liver and cultured to detect the expression of SDC1, transforming growth factor (TGF)‑β1, Smad3 and α‑smooth muscle actin (α‑SMA; a marker of HSC activation) by western blotting and reverse transcription‑quantitative PCR. The expression of SDC1 was found to be downregulated, while the expression of TGF‑β1, Smad3 and α‑SMA was upregulated in HSCs during cell culture. In addition, following stimulation of HSCs with recombinant SDC1, the expression of TGF‑β1, Smad3 and α‑SMA in HSCs was downregulated, whereas small interfering RNA targeting Smad3 antagonized the effects of recombinant SDC1 on α‑SMA. Taken together, these data suggest that SDC1 plays a key role in the development of liver fibrosis.

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1	Han X, Hong Y and Zhang K: TUG1 is involved in liver fibrosis and activation of HSCs by regulating miR-29b. Biochem Biophys Res Commun. 503:1394–1400. 2018. View Article : Google Scholar : PubMed/NCBI
2	Friedman SL: Hepatic stellate cells: Protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 88:125–172. 2008. View Article : Google Scholar : PubMed/NCBI
3	Ding H, Ma JJ, Wang WP, Zeng WJ, Jiang T, Huang BJ and Chen SY: Assessment of liver fibrosis: The relationship between point shear wave elastography and quantitative histological analysis. J Gastroenterol Hepatol. 30:553–558. 2015. View Article : Google Scholar : PubMed/NCBI
4	Manon-Jensen T, Multhaupt HA and Couchman JR: Mapping of matrix metalloproteinase cleavage sites on syndecan-1 and syndecan-4 ectodomains. FEBS J. 280:2320–2331. 2013. View Article : Google Scholar : PubMed/NCBI
5	Pasqualon T, Lue H, Groening S, Pruessmeyer J, Jahr H, Denecke B, Bernhagen J and Ludwig A: Cell surface syndecan-1 contributes to binding and function of macrophage migration inhibitory factor (MIF) on epithelial tumor cells. Biochim Biophys Acta. 1863:717–726. 2016. View Article : Google Scholar : PubMed/NCBI
6	Masola V, Gambaro G, Tibaldi E, Brunati AM, Gastaldello A, D'Angelo A, Onisto M and Lupo A; Heparanase and syndecan-1 interplay orchestrates fibroblast growth factor-2-induced epithelial-mesenchymal transition in renal tubular cells, : J Biol Chem. 287:1478–1488. 2012. View Article : Google Scholar : PubMed/NCBI
7	Yu Y, Duan J, Li Y, Li Y, Jing L, Yang M, Wang J and Sun Z: Silica nanoparticles induce liver fibrosis via TGF-beta1/Smad3 pathway in ICR mice. Int J Nanomedicine. 12:6045–6057. 2017. View Article : Google Scholar : PubMed/NCBI
8	Lee JH, Jang EJ, Seo HL, Ku SK, Lee JR, Shin SS, Park SD, Kim SC and Kim YW: Sauchinone attenuates liver fibrosis and hepatic stellate cell activation through TGF-beta/Smad signaling pathway. Chem Biol Interact. 224:58–67. 2014. View Article : Google Scholar : PubMed/NCBI
9	Hara T, Yoshida E, Shinkai Y, Yamamoto C, Fujiwara Y, Kumagai Y and Kaji T: Biglycan intensifies ALK5-Smad2/3 signaling by TGF-beta1 and downregulates syndecan-4 in cultured vascular endothelial cells. J Cell Biochem. 118:1087–1096. 2017. View Article : Google Scholar : PubMed/NCBI
10	Zhao H, Zhang LE, Guo S, Yuan T, Xia B, Zhang L and Zhang Y: Overexpression of DNA methyltransferase 1 as a negative independent prognostic factor in primary gastrointestinal diffuse large B-cell lymphoma treated with CHOP-like regimen and rituximab. Oncology Letters. 9:2307–2312. 2015. View Article : Google Scholar : PubMed/NCBI
11	Schuppan D and Afdhal NH: Liver cirrhosis. Lancet. 371:838–851. 2008. View Article : Google Scholar : PubMed/NCBI
12	Schafer DF and Jones EA: Potential neural mechanisms in the pathogenesis of hepatic encephalopathy. Prog Liver Dis. 7:615–627. 1982.PubMed/NCBI
13	Takegami Y, Ohkawara B, Ito M, Masuda A, Nakashima H, Ishiguro N and Ohno K: R-spondin 2 facilitates differentiation of proliferating chondrocytes into hypertrophic chondrocytes by enhancing Wnt/beta-catenin signaling in endochondral ossification. Biochem Biophys Res Commun. 473:255–264. 2016. View Article : Google Scholar : PubMed/NCBI
14	Yang JJ, Tao H, Huang C and Li J: Nuclear erythroid 2-related factor 2: A novel potential therapeutic target for liver fibrosis. Food Chem Toxicol. 59:421–427. 2013. View Article : Google Scholar : PubMed/NCBI
15	Yang CQ, Yang L, Yang WZ, Zhang Z, Zhang H, Chang YZ, Yuan M and Chen XM: Mechanism of hepatic stellate cell migration during liver fibrosis. Zhonghua Yi Xue Za Zhi. 88:119–122. 2008.(In Chinese). PubMed/NCBI
16	Park SM, Deering RP, Lu Y, Tivnan P, Lianoglou S, Al-Shahrour F, Ebert BL, Hacohen N, Leslie C, Daley GQ, et al: Musashi-2 controls cell fate, lineage bias, and TGF-β signaling in HSC. J Exp Med. 211:71–87. 2014. View Article : Google Scholar : PubMed/NCBI
17	Yu F, Fan X, Chen B, Dong P and Zheng J: Activation of hepatic stellate cells is inhibited by microRNA-378a-3p via wnt10a. Cell Physiol Biochem. 39:2409–2420. 2016. View Article : Google Scholar : PubMed/NCBI
18	Kim KA, Kakitani M, Zhao J, Oshima T, Tang T, Binnerts M, Liu Y, Boyle B, Park E, Emtage P, et al: Mitogenic influence of human R-spondin1 on the intestinal epithelium. Science. 309:1256–1259. 2005. View Article : Google Scholar : PubMed/NCBI
19	Beauvais DM, Jung O, Yang Y, Sanderson RD and Rapraeger AC: Syndecan-1 (CD138) suppresses apoptosis in multiple myeloma by activating IGF1 receptor: Prevention by synstatinIGF1R inhibits tumor growth. Cancer Res. 76:4981–4993. 2016. View Article : Google Scholar : PubMed/NCBI
20	Goto K: CD138 expression is observed in the urothelial epithelium and in various urothelial carcinomas, and cannot be evidence for plasmacytoid urothelial carcinoma. Int J Surg Pathol. 24:614–619. 2016. View Article : Google Scholar : PubMed/NCBI
21	Xu D, Hu J, Xu S, De Bruyne E, Menu E, Van Camp B, Vanderkerken K and Van Valckenborgh E: Dll1/Notch activation accelerates multiple myeloma disease development by promoting CD138+ MM-cell proliferation. Leukemia. 26:1402–1405. 2012. View Article : Google Scholar : PubMed/NCBI
22	Baghy K, Tátrai P, Regős E and Kovalszky I: Proteoglycans in liver cancer. World J Gastroenterol. 22:379–393. 2016. View Article : Google Scholar : PubMed/NCBI
23	Regős E, Abdelfattah HH, Reszegi A, Szilák L, Werling K, Szabó G, Kiss A, Schaff Z, Kovalszky I and Baghy K: Syndecan-1 inhibits early stages of liver fibrogenesis by interfering with TGFβ1 action and upregulating MMP14. Matrix Biol. 68-69:474–489. 2018. View Article : Google Scholar : PubMed/NCBI