Leucine-rich Repeats and Immunoglobulin 1 (LRIG1) Ameliorates Liver Fibrosis and Hepatic Stellate Cell Activation via Inhibiting Sphingosine Kinase 1 (SphK1)/Sphingosine-1-Phosphate (S1P) Pathway

  • Wei Zhan Department of Colorectal Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, China
  • Xin Liao Department of Imaging, Affiliated Hospital of Guizhou Medical University, Guiyang, China
  • Zhongsheng Chen Guizhou Medical University, Guiyang, China
  • Lianghe Li Guizhou Medical University, Guiyang, China
  • Tian Tian Guizhou Medical University, Guiyang, China
  • Lei Yu Department of Pathology, Guiyang Maternal and Child Health Hospital, Guiyang, China
  • Rui Li Mail Department of Traditional Chinese Medicine, Guizhou Provincial People’s Hospital, Guiyang, China
Keywords:
Carbon tetrachloride, Immunoglobulins, Leucine-rich repeats, Liver fibrosis, Sphingosine kinase, Sphingosine-1-phosphate

Abstract

To detect the leucine-rich repeats and immunoglobulin 1 (LRIG1) ameliorated liver fibrosis and hepatic stellate cell (HSC) activation via inhibiting sphingosine kinase 1 (SphK1)/Sphingosine-1-Phosphate (S1P) pathway.
C57BL/6 male mice (eight weeks old) were intraperitoneal injection with 10% carbon tetrachloride (CCl4) as an in vivo model. The LX-2 cells were induced as amodel for in vitro study by TGF-β (10 ng/mL).
The Hematoxylin-eosin (HE) staining, Masson staining, and Sirius red staining results showed that CCl4 caused serious fibrosis and injury in liver tissue, high expression of type I collagen α1 chain (Col1α1) and α-smooth muscle actin (α-SMA) in liver tissue, while the LRIG1 expression level was significantly decreased in LX-2 cell lines. The LRIG1 ameliorated CCl4-induced liver fibrosis, indicated by the fibronectin, α-SMA, LRIG1, SphK1, Col1α1, fibrin Connexin 1 (Fn1), tissue inhibitor of metalloproteinase-1 (TIMP1), sphingosine-1-phosphate (S1P), transforming growth factor-beta 1 (TGF-β1) expression level changes. Similar results were observed in TGF-β1 treated of LX-2 cells. However, the effects were attenuated by treatment with LRIG1. Moreover, SphK1 inhibitors abrogated the effect of LRIG1 on fibrosis.
These results demonstrated that LRIG1 improved liver fibrosis in vitro and in vivo via suppressing the SphK1/S1P pathway, indicating its potential use in the treatment of liver fibrosis.

References

1. Wallace K, Burt AD, Wright MC. Liver fibrosis. Biochem J. 2008;411(1):1-18.
2. Hernandez-Gea V, Friedman SL. Pathogenesis of Liver Fibrosis. Annu Rev Pathol 2011;6(1):425-56.
3. Nyström H, Naredi P, Hafström L, Sund M. Type IV collagen as a tumour marker for colorectal liver metastases. Eur J Surg Oncol. 2011;37(7):611-7.
4. Zhang DY, Friedman SL. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology. 2012;56(2):769-75.
5. Beuge MMV, Prakash J, Lacombe M, Post E, Reker-Smit C, Beljaars L, et al. Increased Liver Uptake and Reduced Hepatic Stellate Cell Activation with a Cell-Specific Conjugate of the Rho-kinase Inhibitor Y27632. Pharm Res. 2011;28(8):2045-54.
6. Chaponnier C, Goethals M, Janmey PA, Gabbiani F, Gabbiani G, Vandekerckhove J. The specific NH2-terminal sequence Ac-EEED of alpha-smooth muscle actin plays a role in polymerization in vitro and in vivo. J Cell Biol. 1995;130(4):887-95.
7. Hinz B, Celetta G, Tomasek JJ, Gabbiani G, Chaponnier C. Alpha-Smooth Muscle Actin Expression Upregulates Fibroblast Contractile Activity. Mol Biol Cell. 2001;12(9):2730-41.
8. Jr RKS, Jr HFY. Stellate Cell Contraction: Role, Regulation, and Potential Therapeutic Target. Clin Liver Dis. 2008;12(4):791-803.
9. Pinzani M, Rosselli M, Zuckermann M. Liver cirrhosis. Lancet. 2008;371(9615):838-51.
10. Laederich MB, Melanie FD, Lily Y, Ellen I, Xiuli W, Carraway KL, et al. The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. J Biol Chem. 2004;279(45):47050-6.
11. Gal G, Chanan R, Menachem K, Ido A, Ami C, Jonas N, et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. Embo Journal. 2014;23(16):3270-81.
12. Zhou L, Li X, Zhou F, Jin ZA, Chen D, Wang P, et al. Down‐regulation of LRIG1 by microRNA‐20a modulates gastric cancer multidrug resistance. Cancer Science. 2018;109(4):1044-54.
13. Yang NY, Zhou Y, Zhao HY, Liu XY, Sun Z, Shang JJ. Increased interleukin 1α and interleukin 1β expression is involved in the progression of periapical lesions in primary teeth. Bmc Oral Health. 2018;18(1):124-30.
14. Lindquist D, Alsina FC, Herdenberg C, Larsson C, Höppener J, Wang N, et al. LRIG1 negatively regulates RET mutants and is downregulated in thyroid cancer. International Journal of Oncology. 2018;52(4):1189-97.
15. Thomasson M, Hedman H, Guo D, Ljungberg B, Henriksson R. LRIG1 and epidermal growth factor receptor in renal cell carcinoma: a quantitative RT--PCR and immunohistochemical analysis. Br J Cancer. 2003;89(7):1285-9.
16. Miller JK, Shattuck DL, Ingalla EQ, Lily Y, Borowsky AD, Young LJT, et al. Suppression of the negative regulator LRIG1 contributes to ErbB2 overexpression in breast cancer. Cancer Res. 2008;68(20):8286-94.
17. Stutz M, Shattuck DM, Sweeney C. LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII. Oncogene. 2008;27(43):5741-52.
18. Ljuslinder I, Golovleva I, Henriksson R, Grankvist K, Malmer B, Hedman H. Co-incidental increase in gene copy number of ERBB2 and LRIG1 in breast cancer. Breast Cancer Res. 2009;11(3):403-5.
19. LindstrÖM AK, Ekman K, Stendahl U, Tot T, Henriksson R, Hedman H, et al. LRIG1 and squamous epithelial uterine cervical cancer: correlation to prognosis, other tumor markers, sex steroid hormones, and smoking. Int J Gynecol Cancer. 2010;18(2):312-7.
20. J J-C S, C-C L, C-H H, C-I L, M-T L, S-C L, et al. LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK-SPHK1 signaling and extracellular matrix remodeling. Oncogene. 2014;33(11):1375-84.
21. Sarah S, Sheldon M. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol. 2003;4(5):397-407.
22. Long DA, Price KL. Sphingosine kinase-1: a potential mediator of renal fibrosis. Kidney Int. 2009;76(8):815-7.
23. Nicole GL, Swaney JS, Moreno KM, Sabbadini RA. Sphingosine-1-phosphate and sphingosine kinase are critical for transforming growth factor-beta-stimulated collagen production by cardiac fibroblasts. Cardiovasc Res. 2009;82(2):303-12.
24. Long Shuang H, Evgeny B, Biji M, Panfeng F, Gorshkova IA, Donghong H, et al. Targeting sphingosine kinase 1 attenuates bleomycin-induced pulmonary fibrosis. FASEB J. 2013;27(4):1749-60.
25. Schwalm S, Pfeilschifter J, Huwiler A. Sphingosine-1-phosphate: a Janus-faced mediator of fibrotic diseases. Biochim Biophys Acta. 2013;1831(1):239-50.
26. Shizhong B, Yoshihide A, Andreea B, Kristin H, Faye H, Maria T. Dihydrosphingosine 1-phosphate has a potent antifibrotic effect in scleroderma fibroblasts via normalization of phosphatase and tensin homolog levels. Arthritis Rheum. 2014;62(7):2117-26.
27. Gonzã l-FnB, Sà nchez DI, Gonzã l-GJ, Tuã±Ã³N MJ. Sphingosine 1-Phosphate Signaling as a Target in Hepatic Fibrosis Therapy. Front Pharmacol. 2017;8:579-94.
28. Rohrbach T, Maceyka M, Spiegel S. Sphingosine kinase and sphingosine-1-phosphate in liver pathobiology. Crit Rev Biochem Mol Biol. 2017;52(5):543-53.
29. Wang E, He X, Zeng M. The Role of S1P and the Related Signaling Pathway in the Development of Tissue Fibrosis. Front Pharmacol. 2019;9:1504-18.
30. Changyong L, Xiangming J, Lin Y, Xihong L, Shi Y, Liying L. Involvement of sphingosine 1-phosphate (SIP)/S1P3 signaling in cholestasis-induced liver fibrosis. Am J Pathol. 2009;175(4):1464-72.
31. Li C, Zheng S, You H, Liu X, Lin M, Yang L, et al. Sphingosine 1-phosphate (S1P)/S1P receptors are involved in human liver fibrosis by action on hepatic myofibroblasts motility. J Hepatol. 2011;54(6):1205-13.
32. Yang L, Yue S, Yang L, Liu X, Han Z, Zhang Y, et al. Sphingosine kinase/sphingosine 1-phosphate (S1P)/S1P receptor axis is involved in liver fibrosis-associated angiogenesis. J Hepatol. 2013;59(1):114-23.
33. Xiu L, Chang N, Yang L, Liu X, Yang L, Ge J, et al. Intracellular sphingosine 1-phosphate contributes to collagen expression of hepatic myofibroblasts in human liver fibrosis independent of its receptors. Am J Pathol. 2015;185(2):387-98.
34. Yang L, Chang N, Liu X, Han Z, Zhu T, Li C, et al. Bone Marrow-Derived Mesenchymal Stem Cells Differentiate to Hepatic Myofibroblasts by Transforming Growth Factor-β1 via Sphingosine Kinase/Sphingosine 1-Phosphate (S1P)/S1P Receptor Axis. Am J Pathol. 2012;181(1):85-97.
35. Lan T, Li C, Yang G, Sun Y, Zhuang L, Ou Y, et al. Sphingosine kinase 1 promotes liver fibrosis by preventing miR-19b-3p-mediated inhibition of CCR2. Hepatology. 2018;68(3):1070-86.
36. González-Fernández B, Sánchez DI, Crespo I, San-Miguel B, Álvarez M, Tuñón MJ, et al. Inhibition of the SphK1/S1P signaling pathway by melatonin in mice with liver fibrosis and human hepatic stellate cells. Biofactors. 2016;43(2):272-82.
37. Yang Y, Uhlig S. The role of sphingolipids in respiratory disease. Ther Adv Respir Dis. 2011;5(5):325-44.
38. Huang LS, Berdyshev EV, Tran JT, Xie L, Chen J, Ebenezer DL, et al. Sphingosine-1-phosphate lyase is an endogenous suppressor of pulmonary fibrosis: role of S1P signalling and autophagy. Thorax. 2015;70(12):1138-48.
39. Takuwa Y, Ikeda H, Okamoto Y, Takuwa N, Yoshioka K. Sphingosine-1-phosphate as a mediator involved in development of fibrotic diseases. Biochim Biophys Acta. 2013;1831(1):185-92.
40. Succony L, Gowers K, Hynds RE, Thakrar R, Giangreco A, Davies D, et al. S9 The role of LRIG1-dependent EGFR signalling in airway homoeostasis and squamous cell lung cancer development. Thorax. 2016;71(3):3-8.
41. H H, Jonas N, Dongsheng G, Roger H. Is LRIG1 a tumour suppressor gene at chromosome 3p14.3? Acta Oncol. 2002;41(4):352-4.
42. Sheu JJ, Lee Chko JY. Chromosome 3p12.3-p14.2 and 3q26.2-q26.32 are genomic markers for prognosis of advanced nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev. 2009;18(10):2709-16.
43. Yuesheng J, Charlotte J, Mei L, Sai-Wah T, Jingke Z, Johan W, et al. Karyotypic evolution and tumor progression in head and neck squamous cell carcinomas. Cancer Genet Cytogenet. 2005;156(1):1-7.
44. Abhold EL, Kiang A, Rahimy E, Kuo SZ, Wangrodriguez J, Lopez JP, et al. EGFR Kinase Promotes Acquisition of Stem Cell-Like Properties: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma Stem Cells. Plos One. 2012;7(2):32459-67.
45. Burtness B. The role of cetuximab in the treatment of squamous cell cancer of the head and neck. Expert Opin Biol Ther. 2005;5(8):1085-93.
46. Pyne NJ, Susan P. Sphingosine 1-phosphate and cancer. Nat Rev Cancer. 2010;10(7):489-503.
47. Selvam SP, Ogretmen B. Sphingosine kinase/sphingosine 1-phosphate signaling in cancer therapeutics and drug resistance. Handb Exp Pharmacol. 2013;216(216):3-27.
48. Susan P, Robert B, Pyne NJ. Sphingosine kinase inhibitors and cancer: seeking the golden sword of Hercules. Cancer Res. 2011;71(21):6576-82.
49. Fukuda, Yu, Kihara, Akio, Igarashi, Yasuyuki. Distribution of sphingosine kinase activity in mouse tissues: contribution of SPHK1. Biochem Biophys Res Commun. 2003;309(1):155-60.
50. Powell A, Wang Y, Li Y, Poulin E, Means A, Washington M, et al. The Pan-ErbB Negative Regulator Lrig1 Is an Intestinal Stem Cell Marker that Functions as a Tumor Suppressor. Cell. 2012;149(1):146-58.
51. Chen, Wu, Fu, Feng. Expression of MMP-2 and TIMP-1 in cerebrospinal fluid and the correlation with dynamic changes of serum PCT in neonatal purulent meningitis. Exp Ther Med. 2018;15(2):1285-8.
Published
2020-08-25
How to Cite
1.
Zhan W, Liao X, Chen Z, Li L, Tian T, Yu L, Li R. Leucine-rich Repeats and Immunoglobulin 1 (LRIG1) Ameliorates Liver Fibrosis and Hepatic Stellate Cell Activation via Inhibiting Sphingosine Kinase 1 (SphK1)/Sphingosine-1-Phosphate (S1P) Pathway. Iran J Allergy Asthma Immunol. 19(4):395-406.
Section
Original Article(s)