Sonic Hedgehog信号通路与胚胎发育和肝癌发生
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摘要
Sonichedgehog(SHH)信号通路是由SHH配体介导的信号转导途径。在哺乳动物胚胎期高度活化,调控着胚胎细胞的增殖、分化,在成体期高度保守。研究表明,成熟细胞SHH信号通路的异常激活参与了癌细胞的发生和发展,并且还发现了针对SHH通路的抑制剂。文章将回顾SHH信号通路在胚胎发育和肝癌发生中的作用,以及近几年SHH信号通路抑制剂的研究进展。从胚胎发育的角度,为寻求抗癌方法提供新的思路。
The Sonic hedgehog(SHH) signaling pathway is a signal transduction pathway mediated by SHH ligands. It is highly activated in mammalian embryonic stage, regulates the proliferation and differentiation of embryonic cells, and is basically silent during adulthood. Studies have shown that abnormal activation of the SHH signaling pathway in mature cells is involved in the development and progression of cancer cells, and inhibitors against the SHH pathway have also been discovered. This article will review the role of SHH signaling pathways in the development of embryo and liver cancer, as well as research advances in SHH signaling pathway inhibitors in recent years. From the perspective of embryo development, it provides new ideas for seeking anti-cancer methods.
The Sonic hedgehog(SHH) signaling pathway is a signal transduction pathway mediated by SHH ligands. It is highly activated in mammalian embryonic stage, regulates the proliferation and differentiation of embryonic cells, and is basically silent during adulthood. Studies have shown that abnormal activation of the SHH signaling pathway in mature cells is involved in the development and progression of cancer cells, and inhibitors against the SHH pathway have also been discovered. This article will review the role of SHH signaling pathways in the development of embryo and liver cancer, as well as research advances in SHH signaling pathway inhibitors in recent years. From the perspective of embryo development, it provides new ideas for seeking anti-cancer methods.
引文
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[3] Guo L Y,Liu P,Wen Y,et al.Sonic Hedgehog signaling pathway in primary liver cancer cells[J].Asian Pacific Journal of Tropical Medicine,2014,7(9):735-738.
[4] Luongo C,Ambrosio R,Salzano S,et al.The sonic hedgehoginduced type 3 deiodinase facilitates tumorigenesis of basal cell carcinoma by reducing Gli2 inactivation[J].Endocrinology,2014,155(6):2077-2088.
[5] Peng Y C,Levine C M,Zahid S,et al.Sonic hedgehog signals to multiple prostate stromal stem cells that replenish distinct stromal subtypes during regeneration[J].Proc Natl Acad Sci USA,2013,110(51):20611-20616.
[6] Savani M,Guo Y,Carbone D P,et al.Sonic hedgehog pathway expression in non-small cell lung cancer[J].Therapeutic Advances in Medical Oncology,2012,4(5):225-233.
[7] Ertao Z,Jianhui C,Chuangqi C,et al.Autocrine Sonic hedgehog signaling promotes gastric cancer proliferation through induction of phospholipase Cγ1 and the ERK1/2 pathway[J].Journal of Experimental&Clinical Cancer Research,2016,35(1):63.
[8] Katagiri T,Kobayashi M,Yoshimura M,et al.HIF-1 maintains a functional relationship between pancreatic cancer cells and stromal fibroblasts by upregulating expression and secretion of Sonic hedgehog[J].Oncotarget,2018,9(12):10525-10535.
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[11] Carpenter B S,Barry R L,Verhey K J,et al.The heterotrimeric kinesin-2 complex interacts with and regulates GLI protein function[J].Journal of Cell Science,2015,128(5):1034-1050.
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[13]陈婧文,汤其群.Hedgehog信号通路与脂肪细胞发育[J].中国生物化学与分子生物学报,2011,27(1):6-10.
[14] Hiroki K,Yuka S,Daigo K,et al.A novel signaling pathway mediated by the nuclear targeting of C-terminal fragments of mammalian patched 1[J].PLoS ONE,2011, 6(4):e18638.
[15] Chinchilla P,Xiao L,Kazanietz M G,et al.Hedgehog proteins activate pro-angiogenic responses in endothelial cells through non-canonical signaling pathways[J].Cell Cycle,2010,9(3):570-579.
[16] Park T S,Zimmerlin L,Evansmoses R,et al.Chemical reversion of conventional human pluripotent stem cells to a na?ve-like state with improved multilineage differentiation potency[J].Journal of Visualized Experiments Jove,2018,10(136):1-26.
[17] Stasiulewicz M,Gray S D,Mastromina I,et al.A conserved role for Notch signaling in priming the cellular response to Shh through ciliary localisation of the key Shh transducer Smo[J].Development,2015,142(13):2291-2303.
[18] Clement V,Sanchez P,Tribolet N D,et al.HEDGEHOG-GLI1signaling regulates human glioma growth,cancer stem cell self-renewal,and tumorigenicity[J].Current Biology,2007,17(2):165-172.
[19] Podolska K,Lipiec A,Hajdukiewicz K,et al.Sonic hedgehog stimulates the recruitment of endothelial progenitor cells[J].Medycyna wieku rozwojowego,2013,17(2):151-156.
[20] Xu C,Li X,Topham M K,et al.Regulation of sonic hedgehog expression by integrin beta 1 and epidermal growth factor receptor in intestinal epithelium[J].International Union of Biochemistry and Molecular Biology Life,2014,66(10):694-703.
[21] Mclin V A,Henning S J,Jamrich M.The role of the visceral mesoderm in the development of the gastrointestinal tract[J].Gastroenterology,2009,136(7):2074-2091.
[22] Ishizuya-Oka A,Hasebe T.Sonic hedgehog and bone morphogenetic protein-4 signaling pathway involved in epithelial cell renewal along the radial axis of the intestine[J]. Digestion,2008,77(S1):42-47.
[23] Fernandessilva H,Correiapinto J,Moura R S.Canonical sonic hedgehog signaling in early lung development[J].Journal of Developmental Biology,2017,5(1):3-14.
[24] Cheryll T,Matthew T.Sonic hedgehog signaling in limb development[J].Frontiers in Cell and Developmental Biology,2017,55(28):14.
[25] Suh H N,Han H J.Sonic hedgehog increases the skin wound healing ability of mouse embryonic stem cells through micro RNA 200 family[J].Br J Pharmacol,2015,172(3):815-828.
[26] Sims J R,Lee S W,Qiu J.Sonic hedgehog regulates ischemia/hypoxia-induced neural progenitor proliferation[J].Stroke,2009,40(11):3618-3626.
[27] Falcón-Urrutia Paulina,Carrasco C M,Pablo L,et al.Shh signaling through the primary cilium modulates rat oligodendrocyte differentiation[J].PLOS ONE,2015,10(7):e0133567.
[28] Liu H,Gu D,Xie J.Clinical implications of hedgehog signaling pathway inhibitors[J].Chinese Journal of Cancer,2011,30(1):13-26.
[29]孙晓东,刘杏娥.姜黄素通过抑制Ras-ERK和Shh-GLI1信号诱导胰腺癌细胞凋亡[J].中国病理生理杂志,2012,28(6):996-1000.
[30]贺巍,范兴爱,申鹏,等.Shh信号通路在肝癌中的表达及与β-catenin的关系[J].现代消化及介入诊疗,2012,17(4):185-188.
[31]罗小军,孔宪炳,阎雄,等.Sonic Hedgehog信号通路在肝细胞癌中的表达及意义[J].中国癌症杂志,2010,20(1):12-16.
[32]胡艳红,黎七雄.原发性肝癌中SHH信号通路的研究[J].科技信息,2012,15(30):60-61.
[33] Hwang J,Kang M H,Young A Yoo,et al.The effects of sonic hedgehog signaling pathway components on non-small-cell lung cancer progression and clinical outcome[J].World Journal of Surgical Oncology,2014,12:268.
[34] Qualtrough,David,Rees,et al.The hedgehog inhibitor cyclopamine reducesβ-Catenin-Tcf transcriptional activity,induces E-cadherin expression,and reduces invasion in colorectal cancer cells[J].Cancers,2015,7(3):1885-1899.
[35]陈劲松,黄炯强,詹高房,等.Sonic Hedgehog信号通路在肝癌细胞增殖中的作用[J].中国普通外科杂志,2014(9):1213-1216.
[36]刘爱梅,余功旺,黄莉霞,等.阻断Sonic Hedgehog信号对不同人肝癌细胞生长的影响[J].中国病理生理杂志,2016,32(2):208-214.
[37] Manuel H,Daniela S,Hofer T S.The binding mode of the sonic hedgehog inhibitor robotnikinin,a combined docking and QM/MM MD study[J].Frontiers in Chemistry,2017,(23):76.
[2] Zia C,Rikani A A,Maqsood C A,et al.Sonic hedgehog signalling pathway:a complex network[J].Annals of Neurosciences,2014,21(1):28-31.
[3] Guo L Y,Liu P,Wen Y,et al.Sonic Hedgehog signaling pathway in primary liver cancer cells[J].Asian Pacific Journal of Tropical Medicine,2014,7(9):735-738.
[4] Luongo C,Ambrosio R,Salzano S,et al.The sonic hedgehoginduced type 3 deiodinase facilitates tumorigenesis of basal cell carcinoma by reducing Gli2 inactivation[J].Endocrinology,2014,155(6):2077-2088.
[5] Peng Y C,Levine C M,Zahid S,et al.Sonic hedgehog signals to multiple prostate stromal stem cells that replenish distinct stromal subtypes during regeneration[J].Proc Natl Acad Sci USA,2013,110(51):20611-20616.
[6] Savani M,Guo Y,Carbone D P,et al.Sonic hedgehog pathway expression in non-small cell lung cancer[J].Therapeutic Advances in Medical Oncology,2012,4(5):225-233.
[7] Ertao Z,Jianhui C,Chuangqi C,et al.Autocrine Sonic hedgehog signaling promotes gastric cancer proliferation through induction of phospholipase Cγ1 and the ERK1/2 pathway[J].Journal of Experimental&Clinical Cancer Research,2016,35(1):63.
[8] Katagiri T,Kobayashi M,Yoshimura M,et al.HIF-1 maintains a functional relationship between pancreatic cancer cells and stromal fibroblasts by upregulating expression and secretion of Sonic hedgehog[J].Oncotarget,2018,9(12):10525-10535.
[9] Tukachinsky H,Petrov K,Watanabe M,et al.Mechanism of inhibition of the tumor suppressor Patched by Sonic Hedgehog[J].Proceedings of the National Academy of Sciences,2016,113(40):E5866-E5875.
[10] Huang S,Zhang Z,Zhang C,et al.Activation of Smurf E3ligase promoted by smoothened regulates hedgehog signaling through targeting patched turnover[J].PLoS Biology,2013,11(11):e1001721.
[11] Carpenter B S,Barry R L,Verhey K J,et al.The heterotrimeric kinesin-2 complex interacts with and regulates GLI protein function[J].Journal of Cell Science,2015,128(5):1034-1050.
[12] Cheng S Y,Yue S.Role and regulation of human tumor suppressor SUFU in hedgehog signaling[J].Advances in Cancer Research,2008,101(10):29-43.
[13]陈婧文,汤其群.Hedgehog信号通路与脂肪细胞发育[J].中国生物化学与分子生物学报,2011,27(1):6-10.
[14] Hiroki K,Yuka S,Daigo K,et al.A novel signaling pathway mediated by the nuclear targeting of C-terminal fragments of mammalian patched 1[J].PLoS ONE,2011, 6(4):e18638.
[15] Chinchilla P,Xiao L,Kazanietz M G,et al.Hedgehog proteins activate pro-angiogenic responses in endothelial cells through non-canonical signaling pathways[J].Cell Cycle,2010,9(3):570-579.
[16] Park T S,Zimmerlin L,Evansmoses R,et al.Chemical reversion of conventional human pluripotent stem cells to a na?ve-like state with improved multilineage differentiation potency[J].Journal of Visualized Experiments Jove,2018,10(136):1-26.
[17] Stasiulewicz M,Gray S D,Mastromina I,et al.A conserved role for Notch signaling in priming the cellular response to Shh through ciliary localisation of the key Shh transducer Smo[J].Development,2015,142(13):2291-2303.
[18] Clement V,Sanchez P,Tribolet N D,et al.HEDGEHOG-GLI1signaling regulates human glioma growth,cancer stem cell self-renewal,and tumorigenicity[J].Current Biology,2007,17(2):165-172.
[19] Podolska K,Lipiec A,Hajdukiewicz K,et al.Sonic hedgehog stimulates the recruitment of endothelial progenitor cells[J].Medycyna wieku rozwojowego,2013,17(2):151-156.
[20] Xu C,Li X,Topham M K,et al.Regulation of sonic hedgehog expression by integrin beta 1 and epidermal growth factor receptor in intestinal epithelium[J].International Union of Biochemistry and Molecular Biology Life,2014,66(10):694-703.
[21] Mclin V A,Henning S J,Jamrich M.The role of the visceral mesoderm in the development of the gastrointestinal tract[J].Gastroenterology,2009,136(7):2074-2091.
[22] Ishizuya-Oka A,Hasebe T.Sonic hedgehog and bone morphogenetic protein-4 signaling pathway involved in epithelial cell renewal along the radial axis of the intestine[J]. Digestion,2008,77(S1):42-47.
[23] Fernandessilva H,Correiapinto J,Moura R S.Canonical sonic hedgehog signaling in early lung development[J].Journal of Developmental Biology,2017,5(1):3-14.
[24] Cheryll T,Matthew T.Sonic hedgehog signaling in limb development[J].Frontiers in Cell and Developmental Biology,2017,55(28):14.
[25] Suh H N,Han H J.Sonic hedgehog increases the skin wound healing ability of mouse embryonic stem cells through micro RNA 200 family[J].Br J Pharmacol,2015,172(3):815-828.
[26] Sims J R,Lee S W,Qiu J.Sonic hedgehog regulates ischemia/hypoxia-induced neural progenitor proliferation[J].Stroke,2009,40(11):3618-3626.
[27] Falcón-Urrutia Paulina,Carrasco C M,Pablo L,et al.Shh signaling through the primary cilium modulates rat oligodendrocyte differentiation[J].PLOS ONE,2015,10(7):e0133567.
[28] Liu H,Gu D,Xie J.Clinical implications of hedgehog signaling pathway inhibitors[J].Chinese Journal of Cancer,2011,30(1):13-26.
[29]孙晓东,刘杏娥.姜黄素通过抑制Ras-ERK和Shh-GLI1信号诱导胰腺癌细胞凋亡[J].中国病理生理杂志,2012,28(6):996-1000.
[30]贺巍,范兴爱,申鹏,等.Shh信号通路在肝癌中的表达及与β-catenin的关系[J].现代消化及介入诊疗,2012,17(4):185-188.
[31]罗小军,孔宪炳,阎雄,等.Sonic Hedgehog信号通路在肝细胞癌中的表达及意义[J].中国癌症杂志,2010,20(1):12-16.
[32]胡艳红,黎七雄.原发性肝癌中SHH信号通路的研究[J].科技信息,2012,15(30):60-61.
[33] Hwang J,Kang M H,Young A Yoo,et al.The effects of sonic hedgehog signaling pathway components on non-small-cell lung cancer progression and clinical outcome[J].World Journal of Surgical Oncology,2014,12:268.
[34] Qualtrough,David,Rees,et al.The hedgehog inhibitor cyclopamine reducesβ-Catenin-Tcf transcriptional activity,induces E-cadherin expression,and reduces invasion in colorectal cancer cells[J].Cancers,2015,7(3):1885-1899.
[35]陈劲松,黄炯强,詹高房,等.Sonic Hedgehog信号通路在肝癌细胞增殖中的作用[J].中国普通外科杂志,2014(9):1213-1216.
[36]刘爱梅,余功旺,黄莉霞,等.阻断Sonic Hedgehog信号对不同人肝癌细胞生长的影响[J].中国病理生理杂志,2016,32(2):208-214.
[37] Manuel H,Daniela S,Hofer T S.The binding mode of the sonic hedgehog inhibitor robotnikinin,a combined docking and QM/MM MD study[J].Frontiers in Chemistry,2017,(23):76.