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PI3K/Akt信号通路与肝纤维化

潘澎 刘绍能

引用本文:
Citation:

PI3K/Akt信号通路与肝纤维化

基金项目: 

国家自然科学基金项目(81072803); 

详细信息
  • 中图分类号: R575.2

PI3K/Akt signaling pathway and hepatic fibrosis

Research funding: 

 

  • 摘要:

    PI3K/AKT信号通路可以通过调控基因表达,从而在细胞的存活、分化、生长、运动和凋亡等多种生理和病理过程中起到重要作用。尤其在肝纤维化的进展中,此信号通路发挥了重要的调节作用。本文将对目前有关PI3K/AKT信号通路在参与肝纤维化形成中,如何调控细胞外基质的降解、影响HSC的活化及调节肝窦毛细血管化等作用机制作一综述。这些资料不仅可以揭示相关疾病条件下,多个细胞与信号因子之间复杂的相互作用机制,而且能够突出通过阻断PI3K/AKT信号通路可以保护和治疗肝纤维化这一潜在的临床意义。

     

  • [1]Zhong W, Xie WF.New strategy for the treatment of hepatic fibrosis[J].J Clin Hepatol, 2011, 27 (3) :233-235. (in Chinese) 钟巍, 谢渭芬.肝纤维化治疗新策略[J].临床肝胆病杂志, 2011, 27 (3) :233-235.
    [2]Gressner AM, Weiskirchen R.Modern pathogenetic concepts of liver fi-brosis suggest stellate cells and TGF-beta as major players and therapeutic targets[J].J Cell Mol Med, 2006, 10 (1) :76-99.
    [3]Engelman JA.Targeting PI3K signaling in cancer:opportunities, challenges and limitations[J].Nat Rev Cancer, 2009, 9 (8) :550-562.
    [4]Franke TF.PI3K/Akt:getting it right matters[J].Oncogene, 2008, 27 (50) :6473-6488.
    [5]Whitman M, Downes CP, Keeler M, et al.Type I phosphatidyli-nositol kinase makes a novel inositol phnoshpolipid, phosphatidyli-nositol-3-phosphate[J].Nature, 1988, 332 (6165) :644-646.
    [6]Neri LM, Borgatti P, Capitani S, et al.The nuclear phosphoinosit-ide3-kinase/AKT pathway:a new second message system[J].Biochim Biophys Acta, 2002, 1584 (2-3) :73-80.
    [7]Shimamura H, Terada Y, Okado T, et al.The PI3-kinase-Akt pathway promotes mesangial cell survival and inhibits apoptosis in vitro via NF-kappa B and Bad[J].J Am Soc Nephrol, 2003, 14 (6) :1427-1434.
    [8]Djordjevic S, Driscoll PC.Structural insight into substrate specificity and regulatory mechanisms of phsophoinositide3-kinases[J].Trends Biochem Sci, 2002, 27 (8) :426-342.
    [9]Yuan TL, Cantley LC.PI3K pathway alterations in cancer:variations on a theme[J].Oncogene, 2008, 27 (41) :5497-5510.
    [10]Xu G, Zhang W, Bertram P, et al.Pharmacogenomic profiling of the PI3K/PTEN-AKT-mTOR pathway in common human tumors[J].Int J Oncol, 2004, 24 (4) :893-900.
    [11]Martelli AM, Faenza I, Billi AM, et al.Intranuclear3-phosphpi-nositide metabolism and Akt signaling:new mechanisms for tumori-genesis and protection against apoptsis[J].Cell Signal, 2006, 18 (8) :1101-1107.
    [12]Nicholson KM, Anderson NG.The protein kinase B/Akt signaling pathway in human malignancy[J].Cell Signal, 2002, 14 (5) :381-395.
    [13]Altomare DA, Testa JR.Perturbations of the AKT signaling path-ways in human cancer[J].Onconqene, 2005, 24 (50) :7455-7464.
    [14]Karn T, Holtrich U, Bruninger A, et al.Structure, expression and chromosomal mapping of C-akt:relationship to V-akt and its impli-cations[J].Oncogene, 1993, 8 (3) :745-754.
    [15]Nakatani K, Thompson DA, Barthel A, et al.UP-regulation of Akt3in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines[J].J Biol Chem, 1999, 274 (31) :21528-21532.
    [16]Coelho RP, Yuelling LM, Fuss B.Sato-Bigbee C.Neurotrophin-3targets the translational initiation machinery in oligodendrocytes[J].Glia, 2009, 57 (16) :1754-1764.
    [17]Rosen N, She QB.AKT and cancer-is it all mTOR?[J].Cancer Cell, 2006, 10 (4) :254-256.
    [18]Ward SG, Finan P.Isoform-specific phosphoinositide3-kinase inhibitors as therapeutic agents[J].Curr Opin Pharmacol, 2003, 3 (4) :426-434.
    [19] Cantley LC.The phosphoinositide3-kinase pathway[J].Science, 2002, 296 (5573) :1655-1657.
    [20]Suire S, Condliffe AM, Ferguson GL, et al.Gbetagammas and the Ras binding domain of p110gamma are both important regulators of PI3Kgamma signaling in neutrophils[J].Nat Cell Biol, 2006, 8 (11) :1303-1309.
    [21]Blume-Jensen P, Hunter T.Oncogenic kinase signalling[J].Na-ture, 2001, 411 (6835) :355-365.
    [22]Solit DB, Basso AD, Olshen AB, et al.Inhibition of heat shock protein 90function down-regulates Akt kinase and sensitizes tumors to Taxol[J].Cancer Res, 2003, 63 (9) :2139-2144.
    [23]Brazil DP, Hemmings BA.Ten years of protein kinase B signalling:a hard Akt to follow[J].Trends Biochem Sci, 2001, 26 (11) :657-664.
    [24]Hao LS, Zhang XL, Zhou ZH.Relationship of PTEN expression with apoptosis of hepatic stellate cells in liver tissues of rats with he-patic fibrosis induced by bile stagnation[J].Med J Chin People’s Liberation Army, 2010, 35 (7) :836-838. (in Chinese) 郝礼森, 张晓岚, 周智宏, 等.胆汁淤积性肝纤维化大鼠肝组织中PTEN表达与肝星状细胞凋亡的关系研究[J].解放军医学杂志, 2010, 35 (7) :836-838.
    [25]Guan HG, Xu YF, Lan J.PDGF is dependent on PI3K/AKT path-way to induce proliferation of Hsc and synthesis of typeⅠcollagen[J].Chin J Exp Surg, 2007, 24 (11) :1332-1334. (in Chi-nese) 管洪庚, 徐永峰, 兰晶.血小板源生长因子通过PI3K/AKT途径促肝星状细胞增殖与Ⅰ型胶原合成[J].中华实验外科杂志, 2007, 24 (11) :1332-1334.
    [26]Niu LW, Yang Z, Wu JL, et al.Leptin protein expression and its effect on liver fibrosis of mice with schistosomiasis ja-ponica[J].Acta Acad Med Jiangxi, 2007, 47 (4) :12-15. (in Chinese) 牛丽文, 杨镇, 邬剑利, 等.瘦素蛋白在小鼠日本血吸虫病肝纤维化组织中的表达及意义[J].江西医学院学报, 2007, 47 (4) :12-15.
    [27]Zhang Y, Zhang J.Effect of activated PI3-K on epithelial-mesenchymal trans-differentiation of HK cells induced by TGF-β1in vitro[J].Med J Chin People’s Liberation Army, 2006, 31 (6) :553-555. (in Chinese) 张勇, 张璟.PI3-K的激活在TGF-β1诱导肾小管上皮细胞间质转分化过程中的作用[J].解放军医学杂志, 2006, 31 (6) :553-555.
    [28]Allison RD, Katsounas A.Association of interleukin-15-in-duced peripheral immune activation with hepatic stellate cell activation in persons coinfected with hepatitis C virus and HIV[J].J Infect Dis, 2009, 200 (4) :619-623.
    [29]Parola M, Pinzani M.Hepatic wound repair[J].Fibrogenesis Tissue Repair, 2009, 2 (1) :4.
    [30] Hao LS, Zhang XL, Zhou ZH, et al.Relationship of PTEN ex-pression with apoptosis of hepatic stellate cells in liver tis-sues of rats with hepatic fibrosis induced by bile stagnation[J].Med J Chin People’s Liberation Army, 2010, 35 (7) :836-838. (in Chinese) 郝礼森, 张晓岚, 周智宏, 等.胆汁淤积性肝纤维化大鼠肝组织中PTEN表达与肝星状细胞凋亡的关系研究[J].解放军医学杂志, 2010, 35 (7) :836-838.
    [31]Xu YF, Guan HG, Xue WJ, et al.Effects of pi3k signal transduc-tion on rat hepatic stellate cell proliferation and type i collagen ex-pression stimulated by platelet derived growth factor[J].Suzhou Univ J Med Sci, 2006, 26 (3) :389-391, 411. (in Chinese) 徐永锋, 管洪庚, 薛万江, 等.磷脂酰肌醇3 (PI3K) 激酶信号途径对血小板源生长因子促肝星状细胞增殖与I型胶原表达的影响[J].苏州大学学报 (医学版) , 2006, 26 (3) :389-391, 411.
    [32]Guo LL, Dai LL, Tang J.Salvianic acid A (Danshensu) inhibits proliferation and activation in rat hepatic stellate cells induced by platelet derived growth factor-BB[J].Acta Acad Med Militaris Tertiae, 2011, 33 (15) :1610-1614. (in Chinese) 呙琳琳, 戴立里, 唐静.丹参素对PDGF-BB刺激下肝星状细胞的抑制作用[J].第三军医大学学报, 2011, 33 (15) :1610-1614.
    [33]Xu J, Zhu J, Pan L, et al.Expression of leptin in hepatic fibrosis and its relation with hepatic stellate cell activation[J].World Chin J Dig, 2009, 17 (21) :2127-2130. (in Chinese) 许晶, 朱净, 潘亮, 等.瘦素在肝纤维化组织中的表达及其与肝星状细胞活化的关系[J].世界华人消化杂志, 2009, 17 (21) :2127-2130.
    [34]Yang L, Zhao ZX, Hou JL, et al.Hepatic expression of CB1 in rats with fibrosis and the relationship with FAK[J].J Clin Hepatol, 2011, 27 (8) :824-826, 836. (in Chinese) 杨莉, 赵召霞, 侯军良, 等.大麻素受体1、FAKmRNA在小鼠肝纤维化形成过程中肝组织中的表达及相互关系[J].临床肝胆病杂志, 2011, 27 (8) :824-826, 836.
    [35]Guo L, Bi S, Wang ZX, et al.PTEN inhibits trans-differentiation of hypertrophic scar fibroblasts in vitro[J].Acta Acad Med Mili-taris Tertiae, 2011, 33 (2) :160-163. (in Chinese) 郭亮, 毕胜, 王珍祥, 等.PTEN抑制增生性瘢痕成纤维细胞转分化作用及其机制[J].第三军医大学学报, 2011, 33 (2) :160-163.
    [36]Gao JC, Wang Y, Jiang HQ.Inhibitory effect of sorafenib on collagen synthesis in human hepatic stellate cells[J].Chin J Pathophysiol, 2012, 28 (1) :85-89. (in Chinese) 高俊茶, 王妍, 姜慧卿.索拉非尼抑制人肝星状细胞胶原合成[J].中国病理生理杂志, 2012, 28 (1) :85-89.
    [37]Corpechot C, Barbu V, Wendum D.Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis[J].Hepatology, 2002, 35 (5) :1010-1021.
    [38]Ferrara N, Kerbel RS.Angiogenesis as a therapeutic target[J].Nature, 2005, 438 (7070) :967-974.
    [39]Jiang BH, Zheng JZ, Aoki M, et al.Phosphatidylinositol3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells[J].P Natl Acad Sci USA, 2000, 97 (4) :1749-1753.
    [40]Abid MR, Guo S, Minami T, et al.Vascular endothelial growth factor activates PI3K/Akt/Forkhead signaling in endothelial cells[J].Arterioscler Thromb Vasc Biol, 2004, 24 (2) :294-300.
    [41]Cantley LC.The phosphoinositide3-kinase pathway[J].Science, 2002, 296 (5573) :1655-1657.
    [42]Huang J, Kontos CD.PTEN modulates vascular endothelial growth factor-mediated signaling and angiogenic effects[J].J Biol Chem, 2002, 277 (13) :10760-10766.
    [43]Fang J, Ding M, Yang L, et al.PI3K/PTEN/AKT signaling regu-lates prostate tumor angiogenesis[J].Cell Signal, 2007, 19 (12) :2487-2497.
    [44]Cai J, Ahmad S, Jiang WG, et al.Activation of vascular endotheli-al growth factor receptor-1sustains angiogenesis and Bcl-2ex-pression via the phosphatidylinositol3-kinase pathway in endothe-lial cells[J].Diabetes, 2003, 52 (12) :2959-2968.
    [45]Zundel W, Schindler C, Haas-Kogan D.Loss of PTEN facilitates HIF-1-mediated gene expression[J].Genes Dev, 2000, 14 (4) :391-396.
    [46]Zhu L, Loo WT, Louis WC.PTEN and VEGF:possible predictors for sentinel lymph node micro-metastasis in breast cancer[J].Biomed Pharmacother, 2007, 61 (9) :558-561.
    [47]Hamada K, Sasaki T, Koni PA, et al.The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis[J].GenesDev, 2005, 19 (17) :2054-2065.
    [48]Pore N, Liu S, Haas-Kogan DA.PTEN mutation and epidermal growth factor receptor activation regulatevascular endothelial growth factor (VEGF) mRNA expression in human glioblastoma cells by transactivating the proximal VEGF promoter[J].CancerRes, 2003, 63 (1) :236-241.
    [49]Skinner HD, Zheng JZ, Fang J, et al.Vascular endothelial growth factor transcriptional activation is mediated by hypoxia-inducible factor1α, HDM2, and p70S6K1in response to phosphatidyli-nositol3-kinase/AKT signaling[J].J Biol Chem, 2004, 279 (44) :45643-45651.
    [50]Jiang BH, Liu LZ.AKT signaling in regulating angiogenesis[J].Curr Cancer Drug Targets, 2008, 8 (1) :19-26.
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