Twist通过EMT促使结直肠癌SW480细胞获得干性及化疗抵抗能力的作用及机制研究
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摘要
目的研究Twist对结直肠癌SW480细胞的上皮-间质转化(EMT)、肿瘤干细胞表型及化疗抵抗能力的影响。方法收集2012年1～12月武汉大学人民医院结直肠癌患者临床样本共30例,分析Twist在结直肠癌组织及其癌旁组织中的表达差异;通过过表达手段,检测Twist对SW480细胞的EMT表型转换调控情况;分析Twist对SW480细胞的成球能力、干细胞标志物表达、化疗抵抗的影响。结果 Twist在结直肠癌组织中的表达显著高于癌旁组织(P <0.05)。体外实验证实Twist可促使SW480细胞EMT表型转换,表现为Twist促使SW480细胞形态变化及上调间质相关的N-钙黏蛋白表达,而显著抑制上皮相关的E-钙黏蛋白表达(P <0.05)。Twist上调SW480细胞的成球能力及肿瘤干细胞标志物Bmi-1、Nanog、CD44的表达(P <0.05);Twist可通过ABCB1/P-gp途径使SW480细胞获得化疗药物抵抗能力。结论 Twist可促使结直肠癌SW480细胞发生EMT、获得干细胞特性及耐药能力,Twist可作为潜在的结直肠癌化疗抵抗治疗靶点。
Objective To study the effect of Twist on epithelial-mesenchymal transition(EMT), cancer stem cell phenotype and chemotherapy resistance of SW480 cells. Methods From January to December 2012, 30 colorectal cancer samples were collected in Renmin Hospital, Wuhan University. And the expression of Twist in colon cancer tissues and adjacent tissues were analyzed; the effect of Twist on SW480 cells EMT phenotype switching was detected through the over expression assay. The role of Twist in SW480 cells mammospheres number, cancer stem cell markers expression and chemotherapy resistance were investigated. Results The expression of Twist in colon cancer tissues was significantly higher than that in adjacent tissues(P < 0.05). Twist could promote EMT phenotype switching, evidenced by the changes in cell morphology, the up-regulation of interstitial-associated N-cadherin expression, and the significant inhibition of epithelial-associated E-cadherin expression(P < 0.05). Twist increased mammospheres number and the expression of cancer stem cell markers SW480 cells, such as Bmi-1, Nanog, CD44 in(P < 0.05). Twist could promote SW480 cells to obtain chemotherapy resistance ability through ABCB1/P-gp pathway. Conclusion Twist could promote SW480 cells EMT phenotype switching, stem cell characteristics and chemotherapy resistance ability obtaining, indicating that Twist could serve as a potential target for chemotherapy resistance of colorectal cancer.
Objective To study the effect of Twist on epithelial-mesenchymal transition(EMT), cancer stem cell phenotype and chemotherapy resistance of SW480 cells. Methods From January to December 2012, 30 colorectal cancer samples were collected in Renmin Hospital, Wuhan University. And the expression of Twist in colon cancer tissues and adjacent tissues were analyzed; the effect of Twist on SW480 cells EMT phenotype switching was detected through the over expression assay. The role of Twist in SW480 cells mammospheres number, cancer stem cell markers expression and chemotherapy resistance were investigated. Results The expression of Twist in colon cancer tissues was significantly higher than that in adjacent tissues(P < 0.05). Twist could promote EMT phenotype switching, evidenced by the changes in cell morphology, the up-regulation of interstitial-associated N-cadherin expression, and the significant inhibition of epithelial-associated E-cadherin expression(P < 0.05). Twist increased mammospheres number and the expression of cancer stem cell markers SW480 cells, such as Bmi-1, Nanog, CD44 in(P < 0.05). Twist could promote SW480 cells to obtain chemotherapy resistance ability through ABCB1/P-gp pathway. Conclusion Twist could promote SW480 cells EMT phenotype switching, stem cell characteristics and chemotherapy resistance ability obtaining, indicating that Twist could serve as a potential target for chemotherapy resistance of colorectal cancer.
引文
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[5] Campbell K. Contribution of epithelial-mesenchymal transitions to organogenesis and cancer metastasis[J]. Curr Opin Cell Biol,2018,55:30-35.
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[7] Liu B,Miyake H,Nishikawa M,et al. Expression profile of epithelial-mesenchymal transition markers in non-muscle-invasive urothelial carcinoma of the bladder:correlation with intravesical recurrence following transurethral resection[J]. Urol Oncol,2015,33(3):110.
[8] Sui H,Zhu L,Deng W,et al. Epithelial-mesenchymal transition and drug resistance:role,molecular mechanisms,and therapeutic strategies[J]. Oncol Res Treat,2014,37(10):584-589.
[9] Huang J,Li H,Ren G. Epithelial-mesenchymal transition and drug resistance in breast cancer(Review)[J]. Int J Oncol,2015,47(3):840-848.
[10] Dong CY,Liu XY,Wang N,et al. Twist-1,a novel regulator of hematopoietic stem cell self-renewal and myeloid lineage development[J]. Stem Cells,2014,32(12):3173-3182.
[11] Pirinen E,Soini Y. A survey of zeb1,twist and claudin 1and 4 expression during placental development and disease[J]. APMIS,2014,122(6):530-538.
[12] Brenner H,Kloor M,Pox CP. Colorectal cancer[J]. Lancet,2014,383:1490-502.
[13] Siegel R,DeSantis C,Virgo K,et al. Cancer treatment and survivorship statistics[J]. CA Cancer J Clin,2012,62(4):220-241.
[14] Center MM,Jemal A,Smith RA,et al. Worldwide variations in colorectal cancer[J]. CA Cancer J Clin,2009,59(6):366-378.
[15] Roncucci L,Mariani F. Prevention of colorectal cancer:How many tools do we have in our basket?[J]. Eur J Intern Med,2015,26(10):752-756.
[16] Goodwin Jinesh G,Willis DL,Kamat AM. Bladder cancer stem cells:biological and therapeutic perspectives[J].Curr Stem Cell Res Ther,2014,9(2):89-101.
[17] Islam F,Gopalan V,Wahab R,et al. Cancer stem cells in oesophageal squamous cell carcinoma:Identification,prognostic and treatment perspectives[J]. Crit Rev Oncol Hematol,2015,6(1):9-19.
[18] Friedmann-Morvinski D,Verma IM. Dedifferentiation and reprogrammin g:origins of cancer stem cells[J]. EMBO Rep,2014,15(3):244-253.
[19] Mladinich M,Ruan D,Chan CH. Tackling cancer stem cells via inhibition of EMT transcription factors[J]. Stem Cells Int,2016,2016:5285892.
[20] Nuti SV,Mor G,Li PR,et al. TWIST and ovarian cancer stem cells:implications for chemoresistance and metastasis[J]. Oncotarget,2014,5(17):7260-7271.
[21] Hano M,Tomá?ováL,?ere?M,et al. Interplay between P-Glycoprotein Expression and Resistance to Endoplasmic Reticulum Stressors[J]. Molecules,2018,23(2).pii:E337. doi:10.3390/molecules23020337.
[22] Joshi P,Vishwakarma RA,Bharate SB. Natural alkaloids as P-gp inhibitors for multidrug resistance reversal in cancer[J]. Eur J Med Chem,2017,138:273-292.