Year 2019 / Volume 111 / Number 3
Original
Asparaginyl endopeptidase may promote liver sinusoidal endothelial cell angiogenesis via PI3K/Akt pathway

214-222

DOI: 10.17235/reed.2018.5709/2018

Na Li, Chu Liu, Guifen Ma, Yujen Tseng, Duyi Pan, Jie Chen, Feng Li, Xiaoqing Zeng, Tiancheng Luo, Shiyao Chen,

Abstract
Background and aims: pathological angiogenesis plays an important role in the progression of chronic liver diseases. Asparaginyl endopeptidase (AEP) participates in tumor angiogenesis and was recently shown to be associated with liver fibrosis. This study aimed to explore the effect of AEP on liver sinusoidal endothelial cell (LSECs) angiogenesis and determine the underlying mechanism. Methods: cultured LSECs were infected with lentiviruses in order to suppress AEP expression (AEP-KD1, AEP-KD2). The effect of AEP on LSECs proliferation, apoptosis and migration were subsequently determined by a CCK8 assay, flow cytometry and wound-healing and Transwell assays, respectively, in AEP knocked-down and control LSECs. The expression of the endothelial cell surface markers CD31, CD34 and von Willebrand factor (vWF) were detected by immunofluorescence assay and western blot. The angiogenic factors, vascular endothelial growth factor receptor 2 (VEGFR2) and interleukin 8 (IL 8) were detected by real-time PCR and western blot. The effect of AEP on vessel tube formation by LSECs was examined by Matrigel™ tube-formation assay. Phosphoinositide 3-kinase (PI3K)/Akt expression and phosphorylation were detected by western blot. Results: AEP was effectively knocked down by lentivirus infection in LSECs. Down-regulation of AEP expression significantly decreased proliferation and migration and increased apoptosis of LSECs. Moreover, expression levels of the endothelial cell surface markers CD31, CD34 and vWF, as well as angiogenic factors VEGFR2 and IL 8, were also reduced after AEP was knocked-down. The vessel tube formation abilities of AEP-KD1 and AEP-KD2 LSECs were significantly inhibited compared with LSECs without AEP knocked-down. Down-regulation of AEP also inhibited the phosphorylation of PI3K and Akt. Conclusion: AEP promotes LSECs angiogenesis in vitro, possibly via the PI3K/Akt pathway. AEP may therefore be a potential therapeutic target for preventing the progression of liver fibrosis.
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References
REFERENCES
1. Coulon S, Heindryckx F, Geerts A, et al. Angiogenesis in chronic liver disease and its complications. Liver Int 2011;31:146-162.
2. Zhang Z, Zhang F, Lu Y, et al. Update on implications and mechanisms of angiogenesis in liver fibrosis. Hepatol Res 2014.
3. Folkman J, Shing Y. Angiogenesis. J Biol Chem 1992;267:10931-10934.
4. Zeng XQ, Li N, Pan DY, et al. Kruppel-like factor 2 inhibit the angiogenesis of cultured human liver sinusoidal endothelial cells through the ERK1/2 signaling pathway. Biochem Biophys Res Commun 2015;464:1241-1247.
5. Sakata K, Eda S, Lee ES, et al. Neovessel formation promotes liver fibrosis via providing latent transforming growth factor-beta. Biochem Biophys Res Commun 2014;443:950-956.
6. Thabut D, Shah V. Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: new targets for the treatment of portal hypertension? J Hepatol 2010;53:976-980.
7. Chen JM, Dando PM, Rawlings ND, et al. Cloning, isolation, and characterization of mammalian legumain, an asparaginyl endopeptidase. J Biol Chem 1997;272:8090-8098.
8. Liu C, Sun C, Huang H, et al. Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy. Cancer Res 2003;63:2957-2964.
9. Wu W, Luo Y, Sun C, et al. Targeting cell-impermeable prodrug activation to tumor microenvironment eradicates multiple drug-resistant neoplasms. Cancer Res 2006;66:970-980.
10. Andrade V, Guerra M, Jardim C, et al. Nucleoplasmic calcium regulates cell proliferation through legumain. J Hepatol 2011;55:626-635.
11. Shen L, Li H, Shi Y, et al. M2 tumour-associated macrophages contribute to tumour progression via legumain remodelling the extracellular matrix in diffuse large B cell lymphoma. Sci Rep 2016;6:30347.
12. Jin J, Yuan F, Shen MQ, et al. Vascular endothelial growth factor regulates primate choroid-retinal endothelial cell proliferation and tube formation through PI3K/Akt and MEK/ERK dependent signaling. Mol Cell Biochem 2013;381:267-272.
13. Liu C, Sun C, Huang H, et al. Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy. Cancer Res 2003;63:2957-2964.
14. Zhu W, Shao Y, Yang M, et al. Asparaginyl endopeptidase promotes proliferation and invasiveness of prostate cancer cells via PI3K/AKT signaling pathway. Gene 2016;594:176-182.
15. AbdulHameed MD, Tawa GJ, Kumar K, et al. Systems level analysis and identification of pathways and networks associated with liver fibrosis. PLoS One 2014;9:e112193.
16. Zheng X, Li A, Zhao L, et al. Key role of microRNA-15a in the KLF4 suppressions of proliferation and angiogenesis in endothelial and vascular smooth muscle cells. Biochem Biophys Res Commun 2013;437:625-631.
17. Poisson J, Lemoinne S, Boulanger C, et al. Liver sinusoidal endothelial cells: physiology and role in liver diseases. J Hepatol 2016.
18. Shen M, Zhou XZ, Ye L, et al. Xanthatin inhibits corneal neovascularization by inhibiting the VEGFR2mediated STAT3/PI3K/Akt signaling pathway. Int J Mol Med 2018.
19. Tugues S, Fernandez-Varo G, Munoz-Luque J, et al. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology 2007;46:1919-1926.
20. Ehling J, Bartneck M, Wei X, G et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 2014;63:1960-1971.
21. Schuppan D, Kim YO. Evolving therapies for liver fibrosis. J Clin Invest 2013;123:1887-1901.
22. Chen JM, Dando PM, Stevens RA, et al. Cloning and expression of mouse legumain, a lysosomal endopeptidase. Biochem J 1998;335 ( Pt 1):111-117.
23. Haugen MH, Boye K, Nesland JM, et al. High expression of the cysteine proteinase legumain in colorectal cancer - implications for therapeutic targeting. Eur J Cancer 2015;51:9-17.
24. Wang L, Chen S, Zhang M, et al. Legumain: a biomarker for diagnosis and prognosis of human ovarian cancer. J Cell Biochem 2012;113:2679-2686.
25. Lewen S, Zhou H, Hu HD, et al. A Legumain-based minigene vaccine targets the tumor stroma and suppresses breast cancer growth and angiogenesis. Cancer Immunol Immunother 2008;57:507-515.
26. D'Costa ZC, Higgins C, Ong CW, et al. TBX2 represses CST6 resulting in uncontrolled legumain activity to sustain breast cancer proliferation: a novel cancer-selective target pathway with therapeutic opportunities. Oncotarget 2014;5:1609-1620.
27. Zhu W, Shao Y, Yang M, et al. Asparaginyl endopeptidase promotes proliferation and invasiveness of prostate cancer cells via PI3K/AKT signaling pathway. Gene 2016.
28. Zhang H, Wei T, Jiang X, et al. PEDF and 34-mer inhibit angiogenesis in the heart by inducing tip cells apoptosis via up-regulating PPAR-gamma to increase surface FasL. Apoptosis 2016;21:60-68.
29. Friedl P, Gilmour D. Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 2009;10:445-457.
30. Rorth P. Collective cell migration. Annu Rev Cell Dev Biol 2009;25:407-429.
31. Li N, Liu Q, Su Q, et al. Effects of legumain as a potential prognostic factor on gastric cancers. Med Oncol 2013;30:621.
32. Dill MT, Rothweiler S, Djonov V, et al. Disruption of Notch1 induces vascular remodeling, intussusceptive angiogenesis, and angiosarcomas in livers of mice. Gastroenterology 2012;142:967-977.
33. Xu B, Broome U, Uzunel M, et al. Capillarization of hepatic sinusoid by liver endothelial cell-reactive autoantibodies in patients with cirrhosis and chronic hepatitis. Am J Pathol 2003;163:1275-1289.
34. Miyata Y, Mitsunari K, Asai A, et al. Pathological significance and prognostic role of microvessel density, evaluated using CD31, CD34, and CD105 in prostate cancer patients after radical prostatectomy with neoadjuvant therapy. Prostate 2015;75:84-91.
35. Kobus K, Kopycinska J, Kozlowska-Wiechowska A, et al. Angiogenesis within the duodenum of patients with cirrhosis is modulated by mechanosensitive Kruppel-like factor 2 and microRNA-126. Liver Int 2012;32:1222-1232.
36. Zhang LJ, Sun MY, Ning BB, et al. Xiayuxue Decoction ([symbols; see text]) attenuates hepatic stellate cell activation and sinusoidal endothelium defenestration in CCl4-induced fibrotic liver of mice. Chin J Integr Med 2014;20:516-523.
37. Arimoto J, Ikura Y, Suekane T, et al. Expression of LYVE-1 in sinusoidal endothelium is reduced in chronically inflamed human livers. J Gastroenterol 2010;45:317-325.
38. Zhao X, Zhao Q, Luo Z, et al. Spontaneous immortalization of mouse liver sinusoidal endothelial cells. Int J Mol Med 2015;35:617-624.
39. Yokomori H, Oda M, Yoshimura K, et al. Caveolin-1 and Rac regulate endothelial capillary-like tubular formation and fenestral contraction in sinusoidal endothelial cells. Liver Int 2009;29:266-276.
40. Marrone G, Maeso-Diaz R, Garcia-Cardena G, et al. KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut 2015;64:1434-1443.
41. DeLeve LD. Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology 2015;61:1740-1746.
42. Xie G, Wang X, Wang L, et al. Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 2012;142:918-927.
43. Yan Z, Qu K, Zhang J, et al. CD147 promotes liver fibrosis progression via VEGF-A/VEGFR2 signalling-mediated cross-talk between hepatocytes and sinusoidal endothelial cells. Clin Sci (Lond) 2015;129:699-710.
44. Gong WG, Lin JL, Niu QX, et al. Paeoniflorin diminishes ConA-induced IL-8 production in primary human hepatic sinusoidal endothelial cells in the involvement of ERK1/2 and Akt phosphorylation. Int J Biochem Cell Biol 2015;62:93-100.
45. Briggs JJ, Haugen MH, Johansen HT, et al. Cystatin E/M suppresses legumain activity and invasion of human melanoma. BMC Cancer 2010;10:17.
46. Ohno Y, Nakashima J, Izumi M, et al. Association of legumain expression pattern with prostate cancer invasiveness and aggressiveness. World J Urol 2013;31:359-364.
47. Xiang R, Luo Y, Niethammer AG, et al. Oral DNA vaccines target the tumor vasculature and microenvironment and suppress tumor growth and metastasis. Immunol Rev 2008;222:117-128.
REFERENCES
1. Coulon S, Heindryckx F, Geerts A, et al. Angiogenesis in chronic liver disease and its complications. Liver Int 2011;31:146-162.
2. Zhang Z, Zhang F, Lu Y, et al. Update on implications and mechanisms of angiogenesis in liver fibrosis. Hepatol Res 2014.
3. Folkman J, Shing Y. Angiogenesis. J Biol Chem 1992;267:10931-10934.
4. Zeng XQ, Li N, Pan DY, et al. Kruppel-like factor 2 inhibit the angiogenesis of cultured human liver sinusoidal endothelial cells through the ERK1/2 signaling pathway. Biochem Biophys Res Commun 2015;464:1241-1247.
5. Sakata K, Eda S, Lee ES, et al. Neovessel formation promotes liver fibrosis via providing latent transforming growth factor-beta. Biochem Biophys Res Commun 2014;443:950-956.
6. Thabut D, Shah V. Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: new targets for the treatment of portal hypertension? J Hepatol 2010;53:976-980.
7. Chen JM, Dando PM, Rawlings ND, et al. Cloning, isolation, and characterization of mammalian legumain, an asparaginyl endopeptidase. J Biol Chem 1997;272:8090-8098.
8. Liu C, Sun C, Huang H, et al. Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy. Cancer Res 2003;63:2957-2964.
9. Wu W, Luo Y, Sun C, et al. Targeting cell-impermeable prodrug activation to tumor microenvironment eradicates multiple drug-resistant neoplasms. Cancer Res 2006;66:970-980.
10. Andrade V, Guerra M, Jardim C, et al. Nucleoplasmic calcium regulates cell proliferation through legumain. J Hepatol 2011;55:626-635.
11. Shen L, Li H, Shi Y, et al. M2 tumour-associated macrophages contribute to tumour progression via legumain remodelling the extracellular matrix in diffuse large B cell lymphoma. Sci Rep 2016;6:30347.
12. Jin J, Yuan F, Shen MQ, et al. Vascular endothelial growth factor regulates primate choroid-retinal endothelial cell proliferation and tube formation through PI3K/Akt and MEK/ERK dependent signaling. Mol Cell Biochem 2013;381:267-272.
13. Liu C, Sun C, Huang H, et al. Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy. Cancer Res 2003;63:2957-2964.
14. Zhu W, Shao Y, Yang M, et al. Asparaginyl endopeptidase promotes proliferation and invasiveness of prostate cancer cells via PI3K/AKT signaling pathway. Gene 2016;594:176-182.
15. AbdulHameed MD, Tawa GJ, Kumar K, et al. Systems level analysis and identification of pathways and networks associated with liver fibrosis. PLoS One 2014;9:e112193.
16. Zheng X, Li A, Zhao L, et al. Key role of microRNA-15a in the KLF4 suppressions of proliferation and angiogenesis in endothelial and vascular smooth muscle cells. Biochem Biophys Res Commun 2013;437:625-631.
17. Poisson J, Lemoinne S, Boulanger C, et al. Liver sinusoidal endothelial cells: physiology and role in liver diseases. J Hepatol 2016.
18. Shen M, Zhou XZ, Ye L, et al. Xanthatin inhibits corneal neovascularization by inhibiting the VEGFR2mediated STAT3/PI3K/Akt signaling pathway. Int J Mol Med 2018.
19. Tugues S, Fernandez-Varo G, Munoz-Luque J, et al. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology 2007;46:1919-1926.
20. Ehling J, Bartneck M, Wei X, G et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 2014;63:1960-1971.
21. Schuppan D, Kim YO. Evolving therapies for liver fibrosis. J Clin Invest 2013;123:1887-1901.
22. Chen JM, Dando PM, Stevens RA, et al. Cloning and expression of mouse legumain, a lysosomal endopeptidase. Biochem J 1998;335 ( Pt 1):111-117.
23. Haugen MH, Boye K, Nesland JM, et al. High expression of the cysteine proteinase legumain in colorectal cancer - implications for therapeutic targeting. Eur J Cancer 2015;51:9-17.
24. Wang L, Chen S, Zhang M, et al. Legumain: a biomarker for diagnosis and prognosis of human ovarian cancer. J Cell Biochem 2012;113:2679-2686.
25. Lewen S, Zhou H, Hu HD, et al. A Legumain-based minigene vaccine targets the tumor stroma and suppresses breast cancer growth and angiogenesis. Cancer Immunol Immunother 2008;57:507-515.
26. D'Costa ZC, Higgins C, Ong CW, et al. TBX2 represses CST6 resulting in uncontrolled legumain activity to sustain breast cancer proliferation: a novel cancer-selective target pathway with therapeutic opportunities. Oncotarget 2014;5:1609-1620.
27. Zhu W, Shao Y, Yang M, et al. Asparaginyl endopeptidase promotes proliferation and invasiveness of prostate cancer cells via PI3K/AKT signaling pathway. Gene 2016.
28. Zhang H, Wei T, Jiang X, et al. PEDF and 34-mer inhibit angiogenesis in the heart by inducing tip cells apoptosis via up-regulating PPAR-gamma to increase surface FasL. Apoptosis 2016;21:60-68.
29. Friedl P, Gilmour D. Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 2009;10:445-457.
30. Rorth P. Collective cell migration. Annu Rev Cell Dev Biol 2009;25:407-429.
31. Li N, Liu Q, Su Q, et al. Effects of legumain as a potential prognostic factor on gastric cancers. Med Oncol 2013;30:621.
32. Dill MT, Rothweiler S, Djonov V, et al. Disruption of Notch1 induces vascular remodeling, intussusceptive angiogenesis, and angiosarcomas in livers of mice. Gastroenterology 2012;142:967-977.
33. Xu B, Broome U, Uzunel M, et al. Capillarization of hepatic sinusoid by liver endothelial cell-reactive autoantibodies in patients with cirrhosis and chronic hepatitis. Am J Pathol 2003;163:1275-1289.
34. Miyata Y, Mitsunari K, Asai A, et al. Pathological significance and prognostic role of microvessel density, evaluated using CD31, CD34, and CD105 in prostate cancer patients after radical prostatectomy with neoadjuvant therapy. Prostate 2015;75:84-91.
35. Kobus K, Kopycinska J, Kozlowska-Wiechowska A, et al. Angiogenesis within the duodenum of patients with cirrhosis is modulated by mechanosensitive Kruppel-like factor 2 and microRNA-126. Liver Int 2012;32:1222-1232.
36. Zhang LJ, Sun MY, Ning BB, et al. Xiayuxue Decoction ([symbols; see text]) attenuates hepatic stellate cell activation and sinusoidal endothelium defenestration in CCl4-induced fibrotic liver of mice. Chin J Integr Med 2014;20:516-523.
37. Arimoto J, Ikura Y, Suekane T, et al. Expression of LYVE-1 in sinusoidal endothelium is reduced in chronically inflamed human livers. J Gastroenterol 2010;45:317-325.
38. Zhao X, Zhao Q, Luo Z, et al. Spontaneous immortalization of mouse liver sinusoidal endothelial cells. Int J Mol Med 2015;35:617-624.
39. Yokomori H, Oda M, Yoshimura K, et al. Caveolin-1 and Rac regulate endothelial capillary-like tubular formation and fenestral contraction in sinusoidal endothelial cells. Liver Int 2009;29:266-276.
40. Marrone G, Maeso-Diaz R, Garcia-Cardena G, et al. KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut 2015;64:1434-1443.
41. DeLeve LD. Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology 2015;61:1740-1746.
42. Xie G, Wang X, Wang L, et al. Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 2012;142:918-927.
43. Yan Z, Qu K, Zhang J, et al. CD147 promotes liver fibrosis progression via VEGF-A/VEGFR2 signalling-mediated cross-talk between hepatocytes and sinusoidal endothelial cells. Clin Sci (Lond) 2015;129:699-710.
44. Gong WG, Lin JL, Niu QX, et al. Paeoniflorin diminishes ConA-induced IL-8 production in primary human hepatic sinusoidal endothelial cells in the involvement of ERK1/2 and Akt phosphorylation. Int J Biochem Cell Biol 2015;62:93-100.
45. Briggs JJ, Haugen MH, Johansen HT, et al. Cystatin E/M suppresses legumain activity and invasion of human melanoma. BMC Cancer 2010;10:17.
46. Ohno Y, Nakashima J, Izumi M, et al. Association of legumain expression pattern with prostate cancer invasiveness and aggressiveness. World J Urol 2013;31:359-364.
47. Xiang R, Luo Y, Niethammer AG, et al. Oral DNA vaccines target the tumor vasculature and microenvironment and suppress tumor growth and metastasis. Immunol Rev 2008;222:117-128.
1. Coulon S, Heindryckx F, Geerts A, et al. Angiogenesis in chronic liver disease and its complications. Liver Int 2011;31:146-162.
2. Zhang Z, Zhang F, Lu Y, et al. Update on implications and mechanisms of angiogenesis in liver fibrosis. Hepatol Res 2014.
3. Folkman J, Shing Y. Angiogenesis. J Biol Chem 1992;267:10931-10934.
4. Zeng XQ, Li N, Pan DY, et al. Kruppel-like factor 2 inhibit the angiogenesis of cultured human liver sinusoidal endothelial cells through the ERK1/2 signaling pathway. Biochem Biophys Res Commun 2015;464:1241-1247.
5. Sakata K, Eda S, Lee ES, et al. Neovessel formation promotes liver fibrosis via providing latent transforming growth factor-beta. Biochem Biophys Res Commun 2014;443:950-956.
6. Thabut D, Shah V. Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: new targets for the treatment of portal hypertension? J Hepatol 2010;53:976-980.
7. Chen JM, Dando PM, Rawlings ND, et al. Cloning, isolation, and characterization of mammalian legumain, an asparaginyl endopeptidase. J Biol Chem 1997;272:8090-8098.
8. Liu C, Sun C, Huang H, et al. Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy. Cancer Res 2003;63:2957-2964.
9. Wu W, Luo Y, Sun C, et al. Targeting cell-impermeable prodrug activation to tumor microenvironment eradicates multiple drug-resistant neoplasms. Cancer Res 2006;66:970-980.
10. Andrade V, Guerra M, Jardim C, et al. Nucleoplasmic calcium regulates cell proliferation through legumain. J Hepatol 2011;55:626-635.
11. Shen L, Li H, Shi Y, et al. M2 tumour-associated macrophages contribute to tumour progression via legumain remodelling the extracellular matrix in diffuse large B cell lymphoma. Sci Rep 2016;6:30347.
12. Jin J, Yuan F, Shen MQ, et al. Vascular endothelial growth factor regulates primate choroid-retinal endothelial cell proliferation and tube formation through PI3K/Akt and MEK/ERK dependent signaling. Mol Cell Biochem 2013;381:267-272.
13. Liu C, Sun C, Huang H, et al. Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy. Cancer Res 2003;63:2957-2964.
14. Zhu W, Shao Y, Yang M, et al. Asparaginyl endopeptidase promotes proliferation and invasiveness of prostate cancer cells via PI3K/AKT signaling pathway. Gene 2016;594:176-182.
15. AbdulHameed MD, Tawa GJ, Kumar K, et al. Systems level analysis and identification of pathways and networks associated with liver fibrosis. PLoS One 2014;9:e112193.
16. Zheng X, Li A, Zhao L, et al. Key role of microRNA-15a in the KLF4 suppressions of proliferation and angiogenesis in endothelial and vascular smooth muscle cells. Biochem Biophys Res Commun 2013;437:625-631.
17. Poisson J, Lemoinne S, Boulanger C, et al. Liver sinusoidal endothelial cells: physiology and role in liver diseases. J Hepatol 2016.
18. Shen M, Zhou XZ, Ye L, et al. Xanthatin inhibits corneal neovascularization by inhibiting the VEGFR2mediated STAT3/PI3K/Akt signaling pathway. Int J Mol Med 2018.
19. Tugues S, Fernandez-Varo G, Munoz-Luque J, et al. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology 2007;46:1919-1926.
20. Ehling J, Bartneck M, Wei X, G et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 2014;63:1960-1971.
21. Schuppan D, Kim YO. Evolving therapies for liver fibrosis. J Clin Invest 2013;123:1887-1901.
22. Chen JM, Dando PM, Stevens RA, et al. Cloning and expression of mouse legumain, a lysosomal endopeptidase. Biochem J 1998;335 ( Pt 1):111-117.
23. Haugen MH, Boye K, Nesland JM, et al. High expression of the cysteine proteinase legumain in colorectal cancer - implications for therapeutic targeting. Eur J Cancer 2015;51:9-17.
24. Wang L, Chen S, Zhang M, et al. Legumain: a biomarker for diagnosis and prognosis of human ovarian cancer. J Cell Biochem 2012;113:2679-2686.
25. Lewen S, Zhou H, Hu HD, et al. A Legumain-based minigene vaccine targets the tumor stroma and suppresses breast cancer growth and angiogenesis. Cancer Immunol Immunother 2008;57:507-515.
26. D'Costa ZC, Higgins C, Ong CW, et al. TBX2 represses CST6 resulting in uncontrolled legumain activity to sustain breast cancer proliferation: a novel cancer-selective target pathway with therapeutic opportunities. Oncotarget 2014;5:1609-1620.
27. Zhu W, Shao Y, Yang M, et al. Asparaginyl endopeptidase promotes proliferation and invasiveness of prostate cancer cells via PI3K/AKT signaling pathway. Gene 2016.
28. Zhang H, Wei T, Jiang X, et al. PEDF and 34-mer inhibit angiogenesis in the heart by inducing tip cells apoptosis via up-regulating PPAR-gamma to increase surface FasL. Apoptosis 2016;21:60-68.
29. Friedl P, Gilmour D. Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 2009;10:445-457.
30. Rorth P. Collective cell migration. Annu Rev Cell Dev Biol 2009;25:407-429.
31. Li N, Liu Q, Su Q, et al. Effects of legumain as a potential prognostic factor on gastric cancers. Med Oncol 2013;30:621.
32. Dill MT, Rothweiler S, Djonov V, et al. Disruption of Notch1 induces vascular remodeling, intussusceptive angiogenesis, and angiosarcomas in livers of mice. Gastroenterology 2012;142:967-977.
33. Xu B, Broome U, Uzunel M, et al. Capillarization of hepatic sinusoid by liver endothelial cell-reactive autoantibodies in patients with cirrhosis and chronic hepatitis. Am J Pathol 2003;163:1275-1289.
34. Miyata Y, Mitsunari K, Asai A, et al. Pathological significance and prognostic role of microvessel density, evaluated using CD31, CD34, and CD105 in prostate cancer patients after radical prostatectomy with neoadjuvant therapy. Prostate 2015;75:84-91.
35. Kobus K, Kopycinska J, Kozlowska-Wiechowska A, et al. Angiogenesis within the duodenum of patients with cirrhosis is modulated by mechanosensitive Kruppel-like factor 2 and microRNA-126. Liver Int 2012;32:1222-1232.
36. Zhang LJ, Sun MY, Ning BB, et al. Xiayuxue Decoction ([symbols; see text]) attenuates hepatic stellate cell activation and sinusoidal endothelium defenestration in CCl4-induced fibrotic liver of mice. Chin J Integr Med 2014;20:516-523.
37. Arimoto J, Ikura Y, Suekane T, et al. Expression of LYVE-1 in sinusoidal endothelium is reduced in chronically inflamed human livers. J Gastroenterol 2010;45:317-325.
38. Zhao X, Zhao Q, Luo Z, et al. Spontaneous immortalization of mouse liver sinusoidal endothelial cells. Int J Mol Med 2015;35:617-624.
39. Yokomori H, Oda M, Yoshimura K, et al. Caveolin-1 and Rac regulate endothelial capillary-like tubular formation and fenestral contraction in sinusoidal endothelial cells. Liver Int 2009;29:266-276.
40. Marrone G, Maeso-Diaz R, Garcia-Cardena G, et al. KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut 2015;64:1434-1443.
41. DeLeve LD. Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology 2015;61:1740-1746.
42. Xie G, Wang X, Wang L, et al. Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 2012;142:918-927.
43. Yan Z, Qu K, Zhang J, et al. CD147 promotes liver fibrosis progression via VEGF-A/VEGFR2 signalling-mediated cross-talk between hepatocytes and sinusoidal endothelial cells. Clin Sci (Lond) 2015;129:699-710.
44. Gong WG, Lin JL, Niu QX, et al. Paeoniflorin diminishes ConA-induced IL-8 production in primary human hepatic sinusoidal endothelial cells in the involvement of ERK1/2 and Akt phosphorylation. Int J Biochem Cell Biol 2015;62:93-100.
45. Briggs JJ, Haugen MH, Johansen HT, et al. Cystatin E/M suppresses legumain activity and invasion of human melanoma. BMC Cancer 2010;10:17.
46. Ohno Y, Nakashima J, Izumi M, et al. Association of legumain expression pattern with prostate cancer invasiveness and aggressiveness. World J Urol 2013;31:359-364.
47. Xiang R, Luo Y, Niethammer AG, et al. Oral DNA vaccines target the tumor vasculature and microenvironment and suppress tumor growth and metastasis. Immunol Rev 2008;222:117-128.
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Received: 08/05/2018

Accepted: 12/10/2018

Online First: 03/12/2018

Published: 04/03/2019

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