白藜芦醇通过调节Hippo信号通路抑制胰腺星状细胞活化
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摘要
目的探讨白藜芦醇对胰腺星状细胞活化的影响及Hippo信号通路的作用。方法组织块胰酶消化法提取原代胰腺星状细胞,给予白藜芦醇干预胰腺星状细胞,Western blot、免疫荧光染色检测胰腺星状细胞活化的指标,Transwell侵袭实验及Western blot检测间接共培养条件下胰腺癌细胞Panc-1侵袭能力及EMT指标E-cadherin,Vimentin的变化。结果白藜芦醇能够抑制胰腺星状细胞的活化,抑制α-SMA及YAP、CTGF及CYR61的表达;白藜芦醇干预后的胰腺星状细胞上清与胰腺癌细胞共培养后,Panc-1细胞侵袭能力降低(P<0.05),E-cadherin表达升高,Vimentin表达降低(P<0.05)。结论白藜芦醇能够抑制胰腺星状细胞活化,并降低共培养条件下胰腺癌细胞Panc-1的侵袭能力和EMT转化。
Objective To investigate the inhibitory effect of resveratrol on the activation of pancreatic stellate cells and to explore the role of the Hippo signaling pathway in it. Methods Pancreatic stellate cells(PSCs) were isolated by trypsin digestion and then treated with resveratrol. Western blot and immunofluorescence staining were used to detect the activation of the cells. Transwell invasion assay and Western blot were used to detect the invasive ability of Panc-1 and the expressions of E-cadherin and Vimentin in pancreatic cancer cells(PCs)-PSCs indirect co-culture conditions. Results Resveratrol could inhibit the activation of PSCs and inhibit YAP, CTGF and CYR61 expressions. After co-culture with PSCs condition medium pre-treated with resveratrol, the invasive ability of Panc-1 cells was significant reduced(P<0.05). E-cadherin expression was increased while Vimentin expression was decreased(P<0.05). Conclusion Resveratrol can inhibit the activation of pancreatic stellate cells via inhibiting YAP expression and can also inhibit the invasion and EMT transformation of Panc-1 cells under co-culture conditions.
Objective To investigate the inhibitory effect of resveratrol on the activation of pancreatic stellate cells and to explore the role of the Hippo signaling pathway in it. Methods Pancreatic stellate cells(PSCs) were isolated by trypsin digestion and then treated with resveratrol. Western blot and immunofluorescence staining were used to detect the activation of the cells. Transwell invasion assay and Western blot were used to detect the invasive ability of Panc-1 and the expressions of E-cadherin and Vimentin in pancreatic cancer cells(PCs)-PSCs indirect co-culture conditions. Results Resveratrol could inhibit the activation of PSCs and inhibit YAP, CTGF and CYR61 expressions. After co-culture with PSCs condition medium pre-treated with resveratrol, the invasive ability of Panc-1 cells was significant reduced(P<0.05). E-cadherin expression was increased while Vimentin expression was decreased(P<0.05). Conclusion Resveratrol can inhibit the activation of pancreatic stellate cells via inhibiting YAP expression and can also inhibit the invasion and EMT transformation of Panc-1 cells under co-culture conditions.
引文
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[2] LI X,MA Q,XU Q,et al.Targeting the cancer-stroma interaction:A potential approach for pancreatic cancer treatment[J].Curr Pharm Des,2012,18(17):2404-2415.
[3] ROWE RG,WEISS SJ.Navigating ECM barriers at the invasive front:The cancer cell-stroma interface[J].Annu Rev Cell Dev Biol,2009,25:567-595.
[4] PARK JH,SHIN JE,PARK HW.The role of hippo pathway in cancer stem cell biology[J].Mol Cells,2018,41(2):83-92.
[5] CHATTERJEE K,ALSHARIF D,MAZZA C,et al.Resveratrol and pterostilbene exhibit anticancer properties involving the downregulation of HPV oncoprotein E6 in cervical cancer cells[J].Nutrients,2018,10(2):36-40.
[6] SINGH CK,NDIAYE MA,AHMAD N.Resveratrol and cancer:Challenges for clinical translation[J].Biochim Biophys Acta,2015,1852(6):1178-1185.
[7] 秦勇,马清涌,党晓燕,等.白藜芦醇对胰腺癌Miapaca-2细胞侵袭转移能力影响的体外观察[J].西安交通大学学报(医学版),2014,35(1):64-68.
[8] 李佳辉,段万星,王铮,等.胰腺癌上皮与间质:环境选择与肿瘤演化[J].临床与病理杂志,2015,35(3):16-19.
[9] LEE J,CONDELLO S,YAKUBOV B,et al.Tissue transglutaminase mediated tumor-stroma interaction promotes pancreatic cancer progression[J].Clin Cancer Res,2015,21(19):4482-4493.
[10] NEESSE A,ALGüL H,TUVESON DA,et al.Stromal biology and therapy in pancreatic cancer:A changing paradigm[J].Gut,2015,64(9):1476-1484.
[11] ERKAN M,ADLER G,APTE MV,et al.StellaTUM:Current consensus and discussion on pancreatic stellate cell research[J].Gut,2012,61(2):172-178.
[12] TANG D,WANG D,YUAN Z,et al.Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma[J].Int J Cancer,2013,132(5):993-1003.
[13] XU Q,WANG Z,CHEN X,et al.Stromal-derived factor-1α/CXCL12-CXCR4 chemotactic pathway promotes perineural invasion in pancreatic cancer[J].Oncotarget,2015,6(7):4717-4732.
[14] LI X,WANG Z,MA Q,et al.Sonic hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer[J].Clin Cancer Res,2014,20(16):4326-4338.
[15] ZHANG Y,ZHOU M,WEI H,et al.Furin promotes epithelial-mesenchymal transition in pancreatic cancer cells via Hippo-YAP pathway[J].Int J Oncol,2017,50(4):1352-1362.
[16] JOHNSON R,HALDER G.The two faces of Hippo:Targeting the Hippo pathway for regenerative medicine and cancer treatment[J].Nat Rev Drug Discov,2014,13(1):63-79.
[17] JIANG Z,CHEN X,CHEN K,et al.YAP inhibition by resveratrol via activation of AMPK enhances the sensitivity of pancreatic cancer cells to gemcitabine[J].Nutrients,2016,8(10):22-28.
[18] XU Q,ZONG L,CHEN X,et al.Resveratrol in the treatment of pancreatic cancer[J].Ann N Y Acad Sci,2015,1348(1):10-19.
[19] JIANG Z,CHEN K,CHENG L,et al.Resveratrol and cancer treatment:Updates[J].Ann N Y Acad Sci,2017,1403(1):59-69.