SPOCK1 Overexpression Induced by Platelet-derived Growth Factor-BB Promotes Hepatic Stellate Cell Activation and Liver Fibrosis Through the Integrin α5β1/PI3K/Akt Signaling Pathway

Overview

Journal Lab Invest

Specialty Pathology

Date 2020 Apr 16

PMID 32291390

Citations 23

Authors

Zhipeng Du

Zhuoying Lin

Zhihui Wang

Danfei Liu

Dean Tian

Limin Xia

Affiliations

Soon will be listed here.

Abstract

Sparc/osteonectin, cwcv, and kazal-like domain proteoglycan 1 (SPOCK1) is a matricellular protein which regulates cell proliferation, invasion, and survival but the function of SPOCK1 in liver fibrosis is obscure. In this study, we found that SPOCK1 expression increased significantly in fibrotic liver tissues and activated primary rat hepatic stellate cells (R-HSCs). SPOCK1 co-localized with α-smooth muscle actin (α-SMA) in the cytoplasm. Mechanistically, we found platelet-derived growth factor-BB (PDGF-BB) induced SPOCK1 expression by activating the PI3K/Akt/forkhead box M1 (FoxM1) signaling pathway. Intracellular SPOCK1 downregulation decreased the HSC activation, proliferation, and migration induced by PDGF-BB. Furthermore, intracellular SPOCK1 overexpression or recombinant SPOCK1 treatment promoted HSC activation, proliferation, and migration by activating the PI3K/Akt signaling pathway. Co-immunoprecipitation, double immunofluorescence staining indicated that SPOCK1 interacted with integrin α5β1, and neutralization of integrin α5β1 significantly reduced the role of recombinant SPOCK1 in HSCs. In vivo HSC-specific SPOCK1 knockdown following lentivirus administration dramatically ameliorated thioacetamide (TAA)-induced collagen deposition in rat livers. Collectively, our study indicates that SPOCK1 is crucial for hepatic fibrosis and it might be a promising therapeutic target.

Citing Articles

SLC41A1 overexpression correlates with immune cell infiltration in HCC and promotes its malignant progression.

Chen G, Du Z, Rao C Int J Med Sci. 2024; 21(15):3069-3082.

PMID: 39628683 PMC: 11610328. DOI: 10.7150/ijms.100155.

SPOCK: Master regulator of malignant tumors (Review).

Xiao M, Xue J, Jin E Mol Med Rep. 2024; 30(6).

PMID: 39392048 PMC: 11487499. DOI: 10.3892/mmr.2024.13355.

The possible pathogenesis of liver fibrosis: therapeutic potential of natural polyphenols.

Niu C, Zhang J, Okolo P Pharmacol Rep. 2024; 76(5):944-961.

PMID: 39162986 DOI: 10.1007/s43440-024-00638-w.

From NAFLD to NASH: Understanding the spectrum of non-alcoholic liver diseases and their consequences.

Samy A, Kandeil M, Sabry D, Abdel-Ghany A, Mahmoud M Heliyon. 2024; 10(9):e30387.

PMID: 38737288 PMC: 11088336. DOI: 10.1016/j.heliyon.2024.e30387.

Hypoxia-driven TNS4 fosters HNSCC tumorigenesis by stabilizing integrin α5β1 complex and triggering FAK-mediated Akt and TGFβ signaling pathways.

Zhao X, Mai Z, Liu L, Lu Y, Cui L, Yu J Int J Biol Sci. 2024; 20(1):231-248.

PMID: 38164166 PMC: 10750279. DOI: 10.7150/ijbs.86317.

References

Bataller R, Brenner D . Liver fibrosis. J Clin Invest. 2005; 115(2):209-18. PMC: 546435. DOI: 10.1172/JCI24282. View

Asrani S, Devarbhavi H, Eaton J, Kamath P . Burden of liver diseases in the world. J Hepatol. 2018; 70(1):151-171. DOI: 10.1016/j.jhep.2018.09.014. View

Schuppan D, Kim Y . Evolving therapies for liver fibrosis. J Clin Invest. 2013; 123(5):1887-901. PMC: 3635731. DOI: 10.1172/JCI66028. View

Mederacke I, Hsu C, Troeger J, Huebener P, Mu X, Dapito D . Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun. 2013; 4:2823. PMC: 4059406. DOI: 10.1038/ncomms3823. View

Tsuchida T, Friedman S . Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017; 14(7):397-411. DOI: 10.1038/nrgastro.2017.38. View

Borkham-Kamphorst E, Weiskirchen R . The PDGF system and its antagonists in liver fibrosis. Cytokine Growth Factor Rev. 2015; 28:53-61. DOI: 10.1016/j.cytogfr.2015.10.002. View

Murphy-Ullrich J, Sage E . Revisiting the matricellular concept. Matrix Biol. 2014; 37:1-14. PMC: 4379989. DOI: 10.1016/j.matbio.2014.07.005. View

Wu T, Ouyang G . Matricellular proteins: multifaceted extracellular regulators in tumor dormancy. Protein Cell. 2014; 5(4):249-52. PMC: 3978162. DOI: 10.1007/s13238-014-0023-6. View

Bradshaw A . Diverse biological functions of the SPARC family of proteins. Int J Biochem Cell Biol. 2012; 44(3):480-8. PMC: 3312742. DOI: 10.1016/j.biocel.2011.12.021. View

10.

Edgell C, Basalamah M, Marr H . Testican-1: a differentially expressed proteoglycan with protease inhibiting activities. Int Rev Cytol. 2004; 236:101-22. DOI: 10.1016/S0074-7696(04)36003-1. View

11.

Bocock J, Edgell C, Marr H, Erickson A . Human proteoglycan testican-1 inhibits the lysosomal cysteine protease cathepsin L. Eur J Biochem. 2003; 270(19):4008-15. DOI: 10.1046/j.1432-1033.2003.03789.x. View

12.

Chen L, Chan T, Liu M, Kong K, Qiu J, Li Y . SPOCK1 is regulated by CHD1L and blocks apoptosis and promotes HCC cell invasiveness and metastasis in mice. Gastroenterology. 2012; 144(1):179-191.e4. DOI: 10.1053/j.gastro.2012.09.042. View

13.

Song X, Han P, Liu J, Wang Y, Li D, He J . Up-regulation of SPOCK1 induces epithelial-mesenchymal transition and promotes migration and invasion in esophageal squamous cell carcinoma. J Mol Histol. 2015; 46(4-5):347-56. DOI: 10.1007/s10735-015-9627-2. View

14.

Zhao P, Guan H, Dai Z, Ma Y, Liu X, Wang X . Knockdown of SPOCK1 Inhibits the Proliferation and Invasion in Colorectal Cancer Cells by Suppressing the PI3K/Akt Pathway. Oncol Res. 2017; 24(6):437-445. PMC: 7838686. DOI: 10.3727/096504016X14685034103554. View

15.

Shu Y, Weng H, Ye Y, Hu Y, Bao R, Cao Y . SPOCK1 as a potential cancer prognostic marker promotes the proliferation and metastasis of gallbladder cancer cells by activating the PI3K/AKT pathway. Mol Cancer. 2015; 14:12. PMC: 4320842. DOI: 10.1186/s12943-014-0276-y. View

16.

Fan L, Jeng Y, Lu Y, Lien H . SPOCK1 Is a Novel Transforming Growth Factor-β-Induced Myoepithelial Marker That Enhances Invasion and Correlates with Poor Prognosis in Breast Cancer. PLoS One. 2016; 11(9):e0162933. PMC: 5023187. DOI: 10.1371/journal.pone.0162933. View

17.

Miao L, Wang Y, Xia H, Yao C, Cai H, Song Y . SPOCK1 is a novel transforming growth factor-β target gene that regulates lung cancer cell epithelial-mesenchymal transition. Biochem Biophys Res Commun. 2013; 440(4):792-7. DOI: 10.1016/j.bbrc.2013.10.024. View

18.

Atorrasagasti C, Aquino J, Hofman L, Alaniz L, Malvicini M, Garcia M . SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGF. Am J Physiol Gastrointest Liver Physiol. 2011; 300(5):G739-48. PMC: 3094149. DOI: 10.1152/ajpgi.00316.2010. View

19.

Atorrasagasti C, Peixoto E, Aquino J, Kippes N, Malvicini M, Alaniz L . Lack of the matricellular protein SPARC (secreted protein, acidic and rich in cysteine) attenuates liver fibrogenesis in mice. PLoS One. 2013; 8(2):e54962. PMC: 3569438. DOI: 10.1371/journal.pone.0054962. View

20.

Koo J, Lee H, Kim W, Kim S . Endoplasmic Reticulum Stress in Hepatic Stellate Cells Promotes Liver Fibrosis via PERK-Mediated Degradation of HNRNPA1 and Up-regulation of SMAD2. Gastroenterology. 2015; 150(1):181-193.e8. DOI: 10.1053/j.gastro.2015.09.039. View