Numb基因在肝纤维化进展中的应用价值

胥文; 许燕楠; 刘平; 慕永平

doi:10.3969/j.issn.1001-5256.2019.08.044

Numb基因在肝纤维化进展中的应用价值

DOI: 10.3969/j.issn.1001-5256.2019.08.044

上海中医药大学附属曙光医院肝病研究所

基金项目:

国家自然科学基金面上项目(81573948,81874390)；

详细信息

中图分类号: R575.2
计量
- 文章访问数: 904
- HTML全文浏览量: 39
- PDF下载量: 216
- 被引次数: 0
出版历程
- 收稿日期: 2019-01-29
- 出版日期: 2019-08-20

Role of the Numb gene in the progression of liver fibrosis

Institute of Hepatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine

Research funding:

摘要

摘要: 肝纤维化是机体对创伤修复的应答反应,是各种慢性肝病走向肝硬化的必经之路,目前尚无阻断或逆转肝纤维化的化学或生物药品上市。肝纤维化的发病机制十分复杂,涉及TGFβ/Smad、Notch、Wnt、Hedgehog等多种信号通路,但如何执简驭繁仍然是治疗领域面临的关键问题。Numb,一个非常关键的细胞命运决定因子,参与Notch、Wnt、Hedgehog等信号通路的调控,但其在抗肝纤维化中的作用尚未得到充分重视,综述了Numb在抗肝纤维化中的潜在应用价值。
- 肝硬化 /
- Numb /
- 信号传导
Abstract: Liver fibrosis is the response of the body to wound repair, and it is the only way for various chronic liver diseases to develop into liver cirrhosis. At present, there is still no chemical or biological drugs for blocking or reversing liver fibrosis. Liver fibrosis has a complex pathogenesis, which involves the TGF-β/Smad, Notch, Wnt, and Hedgehog signaling pathways. However, how to use simple methods to solve this complex issue remains a key scientific problem in the treatment field. As a critical determinant for cell fate, Numb is involved in the regulation of various signaling pathways such as Notch, Wnt, and Hedgehog, but its role in anti-fibrosis has not been taken seriously.This article reviews the potential value of Numb in anti-fibrosis.
- liver cirrhosis /
- Numb /
- signal transduction

HTML全文

参考文献(51)

[1] PELLICORO A, RAMACHANDRAN P, IREDALE JP, et al. Liver fibrosis and repair:Immune regulation of wound healing in a solid organ[J]. Nat Rev Immunol, 2014, 14 (3) :181-194.

[2] MOREIRA RK. Hepatic stellate cells and liver fibrosis[J].Compr Physiol, 2013, 3 (4) :1473-1492.

[3] TACKE F, TRAUTWEIN C. Mechanisms of liver fibrosis resolution[J]. J Hepatol, 2015, 63 (4) :1038-1039.

[4] UEMURA T, SHEPHERD S, ACKERMAN L, et al. Numb, a gene required in determination of cell fate during sensory organ formation in Drosophila embryos[J]. Cell, 1989, 58 (2) :349-360.

[5] KOCH U, RADTKE F. Notch signaling in solid tumors[J]. Curr Top Dev Biol, 2010, 92 (6) :411-455.

[6] MARCOTULLIO LD, FERRETTI E, GRECO A, et al. Numb is a suppressor of Hedgehog signaling and targets Gli1 for Itchdependent ubiquitination[J]. Nat Cell Biol, 2006, 8 (12) :1415-1423.

[7] CAYOUETTE M, RAFF M. Asymmetric segregation of Numb:A mechanism for neural specification from Drosophila to mammals[J]. Nat Neurosci, 2002, 5 (12) :1265-1269.

[8] ZHAO C, GUO H, LI J, et al. Numb family proteins are essential for cardiac morphogenesis and progenitor differentiation[J]. Development, 2014, 141 (2) :281-295.

[9] YANG Y, CHEN L, TIAN Y, et al. Numb modulates the paracellular permeability of intestinal epithelial cells through regulating apical junctional complex assembly and myosin light chain phosphorylation[J]. Exp Cell Res, 2013, 319 (20) :3214-3225.

[10] GULINO A, DI ML, SCREPANTI I. The multiple functions of Numb[J]. Expe Cell Res, 2010, 316 (6) :900-906.

[11] KARACZYN A, BANI-YAGHOUB M, TREMBLAY R, et al. Two novel human NUMB isoforms provide a potential link between development and cancer[J]. Neural Dev, 2010, 5 (1) :31-31.

[12] FLORES AN, MCDERMOTT N, MEUNIER A, et al. NUMB inhibition of NOTCH signaling as a therapeutic target in prostate cancer[J]. Nat Rev Urol, 2014, 11 (9) :499-507.

[13] SMITH CA, DHO SE, DONALDSON J, et al. The cell fate determinant numb interacts with EHD/Rme-1 family proteins and has a role in endocytic recycling[J]. Mol Biol Cell, 2004, 15 (8) :3698-3708.

[14] REICHARDT I, KNOBLICH JA. Cell biology:Notch recycling is numbed[J]. Curr Biol, 2013, 23 (7) :270-272.

[15] GREER RL, STALEY BK, LIOU A, et al. Numb regulates acinar cell dedifferentiation and survival during pancreatic damage and acinar to ductal metaplasia[J]. Gastroenterology, 2013, 145 (5) :1088-1097.

[16] LIU D, CUI L, WANG Y, et al. HBV e antigen and its precursors promote the progress of HCC by interacting with NUMB and decreasing p53 activity[J]. Hepatology, 2016, 64 (2) :390-404.

[17] SHENG W, DONG M, CHEN C, et al. Musashi 2 promotes the development and progression of pancreatic cancer by downregulating Numb protein[J]. Oncotarget, 2016, 8 (9) :14359-14373.

[18] ZHU F, LIU W, LI T, et al. Numb contributes to renal fibrosis by promoting tubular epithelial cell cycle arrest at G2/M[J].Oncotarget, 2016, 7 (18) :25604-25619.

[19] ZHANG Z, QU J, ZHENG C, et al. Nrf2 antioxidant pathway suppresses Numb-mediated epithelial–mesenchymal transition during pulmonary fibrosis[J]. Cell Death Dis, 2018, 9 (2) :83.

[20] NI MM, WANG YR, WU WW, et al. Novel insights on Notch signaling pathways in liver fibrosis[J]. Eur J Pharmacol, 2018, 826:66-74.

[21] CHEN E, CEN Y, LU D, et al. IL-22 inactivates hepatic stellate cells via downregulation of the TGF-β1/Notch signaling pathway[J]. Mol Med Rep, 2018, 17 (4) :5449-5453.

[22] WANG Y, SHEN RW, HAN B, et al. Notch signaling mediated by TGF-β/Smad pathway in concanavalin A-induced liver fibrosis in rats[J]. World J Gastroenterol, 2017, 23 (13) :2330-2336.

[23] ZHANG X, DU G, XU Y, et al. Inhibition of notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes[J]. Lab Invest, 2016, 96 (3) :350-360.

[24] BARTH JM, KOHLER K. How to take autophagy and endocytosis up a notch[J]. Biomed Res Int, 2014, 2014:960803.

[25] QIU L, JOAZEIRO C, FANG N, et al. Recognition and ubiquitination of Notch by Itch, a hect-type E3 ubiquitin ligase[J]. J Biol Chem, 2000, 275 (46) :35734-35737.

[26] PAUL J, SINGH AK, KATHANIA M, et al. IL-17-driven intestinal fibrosis is inhibited by Itch-mediated ubiquitination of HIC-5[J]. Mucosal Immunol, 2017, 11 (2) :427-436.

[27] ZHANG X, LIU P, MU YP. Relationship between the Notch signaling pathway and the development and progression of liver fibrosis[J]. J Clin Hepatol, 2018, 34 (1) :181-183. (in Chinese) 张旭, 刘平, 慕永平. Notch信号通路与肝纤维化发生发展的关系[J].临床肝胆病杂志, 2018, 34 (1) :181-183.

[28] BERDNIK D, TRK T, GONZLEZ-GAITN M, et al. The endocytic protein alpha-Adaptin is required for numb-mediated asymmetric cell division in Drosophila[J]. Dev Cell, 2002, 3 (2) :221-231.

[29] COUTURIER L, TRYLINSKI M, MAZOUNI K, et al. A fluorescent tagging approach in Drosophila reveals late endosomal trafficking of Notch and Sanpodo[J]. J Cell Biol, 2014, 207 (3) :351-363.

[30] BOULTER L, GOVAERE O, BIRD TG, et al. Macrophage derived Wnt signalling opposes Notch signalling in a Numb mediated manner to specify HPC fate in chronic liver disease in human and mouse[J]. Nat Med, 2012, 18 (4) :572-579.

[31] CHEN J, TSCHUDYSENEY B, MA X, et al. Salvianolic acid B enhances hepatic differentiation of human embryonic stem cells via upregulation of WNT pathway and inhibition of Notch pathway[J]. Stem Cells Dev, 2017, 27 (4) :252-261.

[32] IRVINE KM, CLOUSTONl AD, GADD VL, et al. Deletion of Wntless in myeloid cells exacerbates liver fibrosis and the ductular reaction in chronic liver injury[J]. Fibrogenesis Tissue Repair, 2015, 8 (1) :19.

[33] WANG S, SONG K, SRIVASTAVA R, et al. Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a[J]. FASEB J, 2015, 29 (8) :3436-3445.

[34] QU C, HE D, LU X, et al. SIK1 silencing promotes HCC progression and WNT/β-catenin activation[J]. J Hepatology, 2016, 64 (5) :1076-1089.

[35] LADA AG, MONGA SPS. Beta-catenin signaling in hepatic development and progenitors:Which way does the WNT blow?[J]. Dev Dyn, 2015, 240 (3) :486-500.

[36] GE WS, WANG YJ, WU JX, et al. beta-catenin is overexpressed in hepatic fibrosis and blockage of Wnt/beta-catenin signaling inhibits hepatic stellate cell activation[J]. Mol Med Rep, 2014, 9 (6) :2145-2151.

[37] BURKE ZD, REED KR, PHESSE TJ, et al. Liver zonation occurs through a beta-catenin-dependent, c-Myc-independent mechanism[J]. Gastroenterology, 2009, 136 (7) :2316-2324.

[38] MCGILL MA, MCGLADE CJ. Mammalian numb proteins promote Notch1 receptor ubiquitination and degradation of the Notch1 intracellular domain[J]. J Biol Chem, 2003, 278 (25) :23196-23203.

[39] STRAZZABOSCO M, FABRIS L. The balance between Notch/Wnt signaling regulates progenitor cells’commitment during liver repair:Mystery solved?[J]. J Hepatol, 2013, 58 (1) :181-183.

[40] CARPINO G, NOBILI V, RENZI A, et al. Macrophage activation in pediatric nonalcoholic fatty liver disease (NAFLD) correlates with hepatic progenitor cell response via Wnt3a pathway[J]. PLo S One, 2016, 11 (6) :e0157246.

[41] FENG Y, REN J, GUI Y, et al. Wnt/β-Catenin–promoted macrophage alternative activation contributes to kidney fibrosis[J]. J Am Soc Nephrol, 2017, 29 (1) :182-193.

[42] SICA A, INVERNIZZI P, MANTOVANI A. Macrophage plasticity and polarization in liver homeostasis and pathology[J].Hepatology, 2014, 59 (5) :2034-2042.

[43] ZHOU XG, LIU HG. Hedgehog signaling pathway in liver diseases[J/CD]. Chin J Liver Dis:Electronic Edition, 2017, 9 (3) :30-35. (in Chinese) 周新刚, 刘红刚. Hedgehog信号通路在肝脏疾病中的研究进展[J/CD].中国肝脏病杂志:电子版, 2017, 9 (3) :30-35.

[44] VARJOSALO M, TAIPALE J. Hedgehog:Functions and mechanisms[J]. Genes Dev, 2008, 22 (18) :2454-2472.

[45] CHUNG SI, MOON H, JU HL, et al. Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model[J]. J Hepatol, 2016, 64 (3) :618-627.

[46] CHEN Y, CHOI SS, MICHELOTTI GA, et al. Hedgehog controls hepatic stellate cell fate by regulating metabolism[J].Gastroenterology, 2012, 143 (5) :1319-1329.

[47] ZHANG F, HAO M, JIN H, et al. Canonical hedgehog signaling regulates hepatic stellate cell-mediated angiogenesis in liver fibrosis[J]. Brit J Pharmacol, 2017, 174 (5) :409-423.

[48] KWON H, SONG K, HAN C, et al. Inhibition of hedgehog signaling ameliorates hepatic inflammation in mice with nonalcoholic fatty liver disease[J]. Hepatology, 2016, 63 (4) :1155-1169.

[49] OMENETTI A, DIEHL AM. Hedgehog signaling in cholangiocytes[J]. Curr Opin Gastroen, 2011, 27 (3) :268-275.

[50] GAO WQ, GUO Y, ZHANG K, et al. Numb (-/low) enriches a castration resistant prostate cancer cell subpopulation associated with enhanced Notch and Hedgehog signaling[J]. Clin Cancer Res, 2017, 23 (21) :6744-6756.

[51] PARK J, ZHANG JJ, MORO A, et al. Regulation of Sox9 by Sonic Hedgehog (Shh) is essential for patterning and formation of tracheal cartilage[J]. Dev Dyn, 2010, 239 (2) :514-526.

施引文献

资源附件(0)

访问统计