PDF下载 ( 1991 KB)
PI3K/Akt signaling pathway and hepatic fibrosis
-
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。
Abstract:The phosphatidylinositol 3-kinase (PI3K) /Akt intracellular signaling pathway plays important roles in both normal physiological and pathogenic processes by regulating the expression of genes involved in cell survival, differentiation, growth, movement, and apoptosis.In particular, the PI3K/Akt signaling pathway has been implicated in the development and progression of haptic fibrosis.In this review, we summarize the current knowledge of the mechanisms by which PI3K/Akt signal transduction regulates extracellular matrix degradation, hepatic stellate cell activation, and sinusoidal capillarization, all of which play important roles in the formation of hepatic fibrosis.This information not only reveals the complex interplay of mulitple cellular processes and signaling factors underlying the disease condition, but also highlights the potential therapeutic benefit of inhibiting the PI3K/AKT pathway to prevent and treat liver fibrosis.
-
Key words:
- PI3K/Akt /
- signaling pathways /
- liver cirrhosis
-
[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, Bruninger 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. -
本文二维码
计量
- 文章访问数: 4359
- HTML全文浏览量: 68
- PDF下载量: 1151
- 被引次数: 0
下载:
