丹参酮ⅡA通过EP2调控β-arrestin/β-catenin信号通路抑制大肠癌侵袭转移机制
|
摘要
目的:探讨丹参酮ⅡA对大肠癌细胞转移能力的影响及可能的作用机制。方法:利用CCK-8检测不同浓度丹参酮ⅡA对人结肠癌LoVo细胞增殖的影响;采用transwell、划痕实验研究丹参酮ⅡA对人结肠癌LoVo细胞侵袭转移能力的影响;利用Western Blot研究丹参酮ⅡA对EP2介导的β-arrestin/β-catenin信号传递轴的影响。结果:丹参酮ⅡA能够以剂量和时间依赖性方式抑制人结肠癌LoVo细胞的增殖;EP2能够促进LoVo细胞的侵袭转移能力(P<0.01),上调β-arretin的表达,进一步促进β-catenin的核转移(P<0.01);与空白对照组比较,丹参酮ⅡA能够明显抑制LoVo细胞的侵袭转移能力且呈剂量依赖性(P<0.01);同时,丹参酮ⅡA能够直接下调EP2受体的表达,抑制β-arretin的激活,进一步抑制β-catenin的核转移(P<0.01)。结论:丹参酮ⅡA能够抑制EP2/β-arrestin信号通路的激活,从而阻断β-catenin信号通路,发挥抗大肠癌侵袭转移的作用。
Objective: To investigate the effect of tanshinone ⅡA on the metastatic ability of colorectal cancer cells and its possible mechanism. Methods: The effects of different concentrations of tanshinone ⅡA on the proliferation of human colon cancer LoVo cells were detected by CCK-8. The effects of tanshinone ⅡA on the invasion and metastasis of human colon cancer LoVo cells were studied by transwell and scratch test. Western Blot were used to investigate the effect of tanshinone ⅡA on EP2-mediated β-arrestin/β-catenin signaling axis. Results: Tanshinone ⅡA inhibited the proliferation of human colon cancer LoVo cells in a dose-and time-dependent manner. EP2 promoted the invasion and metastasis of LoVo cells(P<0.01), up-regulated the expression of β-arretin, and further promoted the nuclear transfer of β-catenin(P<0.01); compared with the blank control group,tanshinone ⅡA could significantly inhibit the invasion and metastasis of LoVo cells in a dose-dependent manner(P<0.01).Meanwhile, tanshinone ⅡA could directly down-regulate the expression of EP2 receptor and inhibit activation of β-arretin so as to further inhibited nuclear transfer of β-catenin(P<0.01). Conclusion: Tanshinone ⅡA can inhibit the activation of EP2/β-arrestin signaling pathway, thereby blocking the β-catenin signaling pathway and exerting its role in the invasion and metastasis of colorectal cancer.
Objective: To investigate the effect of tanshinone ⅡA on the metastatic ability of colorectal cancer cells and its possible mechanism. Methods: The effects of different concentrations of tanshinone ⅡA on the proliferation of human colon cancer LoVo cells were detected by CCK-8. The effects of tanshinone ⅡA on the invasion and metastasis of human colon cancer LoVo cells were studied by transwell and scratch test. Western Blot were used to investigate the effect of tanshinone ⅡA on EP2-mediated β-arrestin/β-catenin signaling axis. Results: Tanshinone ⅡA inhibited the proliferation of human colon cancer LoVo cells in a dose-and time-dependent manner. EP2 promoted the invasion and metastasis of LoVo cells(P<0.01), up-regulated the expression of β-arretin, and further promoted the nuclear transfer of β-catenin(P<0.01); compared with the blank control group,tanshinone ⅡA could significantly inhibit the invasion and metastasis of LoVo cells in a dose-dependent manner(P<0.01).Meanwhile, tanshinone ⅡA could directly down-regulate the expression of EP2 receptor and inhibit activation of β-arretin so as to further inhibited nuclear transfer of β-catenin(P<0.01). Conclusion: Tanshinone ⅡA can inhibit the activation of EP2/β-arrestin signaling pathway, thereby blocking the β-catenin signaling pathway and exerting its role in the invasion and metastasis of colorectal cancer.
引文
[1]Benson A B 3rd,Arnoletti J P,Bekaii-Saab T,et al.National Comprehensive Cancer Network:Colon Cancer.J Natl Compr Canc Netw,2011,9(11):1238-90
[2]Yamaguchi Y,Hotta K,Imai K,et al.Recurrence after curative surgical resection of T1 rectal cancer:a report of two cases.Dig Endosc,2013,12:26-30
[3]季青,李琦.长链非编码RNA在肿瘤发生、发展中的作用研究现状.中国癌症杂志,2011,21(3):232-235
[4]Ji Q,Zhang L,Fu X,et al.Long non-coding RNA MALAT1 promotes tumour growth and metastasis in colorectal cancer through binding to SFPQ and releasing oncogene PTBP2 from SFPQ/PTBP2complex.Br J Cancer,2014,111(4):736-749
[5]Ji Q,Liu X,Fu X,et al.Resveratrol inhibits invasion and metastasis of colorectal cancer cells via MALAT1 mediated Wnt/β-Catenin signal pathway.PLoS One,2013,8(11):e78700
[6]刘宣,王炎,殷佩浩,等.Wnt/β-catenin信号通路对人肠癌细胞VEGF表达的调控作用.中国癌症杂志,2012,22(12):881-885
[7]季青,周宁,刘宣,等.MALAT1、COX-2、β-catenin、MMP-3、MMP-9等基因在结直肠癌发生发展中的意义.国际肿瘤学杂志,2012,39(6):477-480
[8]刘宣,李丹光,周利红,等.PGE2/COX-2激活Wnt/β-catenin信号通路调控人肠癌细胞VEGF表达.第二军医大学学报,2012,33(11):1178-1181
[9]Yun S P,Ryu J M,Jang M W,et al.Interaction of profilin-1 and F-actin via aβ-arrestin-1/JNK signaling pathway involved in prostaglandin E(2)-induced human mesenchymal stem cells migration and proliferation.J Cell Physiol,2011,226(2):559-571
[10]Chun K S,Lao H C,Trempus C S,et al.The prostaglandin receptor EP2 activates multiple signaling pathways and beta-arrestin1complex formation during mouse skin papilloma development.Carcinogenesis,2009,30(9):1620-1627
[11]Zhang L,Ji Q,Liu X,et al.Norcantharidin inhibits tumor angiogenesis via blocking VEGFR2/MEK/ERK signaling pathways.Cancer Sci,2013,104(5):604-610
[12]Xu C,Yang M,Tian J,et al.MALAT-1:A long non-coding RNA and its important 3’end functional motif in colorectal cancer metastasis.Int J Oncol,2011,39(1):169-175
[2]Yamaguchi Y,Hotta K,Imai K,et al.Recurrence after curative surgical resection of T1 rectal cancer:a report of two cases.Dig Endosc,2013,12:26-30
[3]季青,李琦.长链非编码RNA在肿瘤发生、发展中的作用研究现状.中国癌症杂志,2011,21(3):232-235
[4]Ji Q,Zhang L,Fu X,et al.Long non-coding RNA MALAT1 promotes tumour growth and metastasis in colorectal cancer through binding to SFPQ and releasing oncogene PTBP2 from SFPQ/PTBP2complex.Br J Cancer,2014,111(4):736-749
[5]Ji Q,Liu X,Fu X,et al.Resveratrol inhibits invasion and metastasis of colorectal cancer cells via MALAT1 mediated Wnt/β-Catenin signal pathway.PLoS One,2013,8(11):e78700
[6]刘宣,王炎,殷佩浩,等.Wnt/β-catenin信号通路对人肠癌细胞VEGF表达的调控作用.中国癌症杂志,2012,22(12):881-885
[7]季青,周宁,刘宣,等.MALAT1、COX-2、β-catenin、MMP-3、MMP-9等基因在结直肠癌发生发展中的意义.国际肿瘤学杂志,2012,39(6):477-480
[8]刘宣,李丹光,周利红,等.PGE2/COX-2激活Wnt/β-catenin信号通路调控人肠癌细胞VEGF表达.第二军医大学学报,2012,33(11):1178-1181
[9]Yun S P,Ryu J M,Jang M W,et al.Interaction of profilin-1 and F-actin via aβ-arrestin-1/JNK signaling pathway involved in prostaglandin E(2)-induced human mesenchymal stem cells migration and proliferation.J Cell Physiol,2011,226(2):559-571
[10]Chun K S,Lao H C,Trempus C S,et al.The prostaglandin receptor EP2 activates multiple signaling pathways and beta-arrestin1complex formation during mouse skin papilloma development.Carcinogenesis,2009,30(9):1620-1627
[11]Zhang L,Ji Q,Liu X,et al.Norcantharidin inhibits tumor angiogenesis via blocking VEGFR2/MEK/ERK signaling pathways.Cancer Sci,2013,104(5):604-610
[12]Xu C,Yang M,Tian J,et al.MALAT-1:A long non-coding RNA and its important 3’end functional motif in colorectal cancer metastasis.Int J Oncol,2011,39(1):169-175