| 270 | 9 | 45 |
| 下载次数 | 被引频次 | 阅读次数 |
高危型人乳头瘤病毒（HPV）感染是宫颈癌发病的明确危险因素，但相关的分子机制尚不清楚。YAP1是Hippo/YAP通路的关键分子，通过激活Wnt/β-catenin通路促进胃癌细胞、肝癌细胞增殖。为了阐明YAP1与Wnt/β-catenin信号通路在高危型HPV感染导致宫颈癌发病中的作用，本研究分析了高危型HPV阳性宫颈癌细胞中YAP1与Wnt/β-catenin信号通路的关系及生物学意义。首先检测高危型HPV阳性与阴性宫颈癌组织、高危型HPV阳性及阴性宫颈癌细胞与正常宫颈上皮细胞中YAP1、Wnt1、Wnt3a及β-catenin的表达，分析高危型HPV阳性宫颈癌组织中YAP1与Wnt1、Wnt3a、β-catenin的相关性；然后培养HPV16阳性的SiHa细胞及HPV18阳性的HeLa细胞，转染阴性对照（NC）或YAP1 siRNA、给予溶剂DMSO或Wnt/β-catenin激动剂SKL2001进行干预，检测细胞增殖活力A490及Wnt1、Wnt3a、β-catenin的表达水平。结果显示，高危型HPV阳性宫颈癌组织中YAP1、Wnt1、Wnt3a、β-catenin的表达水平高于高危型HPV阴性宫颈癌组织（P<0.05）且YAP1与Wnt1、Wnt3a、β-catenin呈正相关；转染YAP1 siRNA后，si-YAP1组SiHa细胞及HeLa细胞的A490水平及YAP1、Wnt1、Wnt3a、β-catenin表达水平均低于si-NC组（P<0.05）；转染YAP1 siRNA的同时使用SKL2001,si-YAP1+SKL2001组A490水平、β-catenin表达水平均高于si-YAP1+DMSO组（P<0.05）。以上结果表明高危型HPV阳性的宫颈癌细胞中YAP1表达增加通过Wnt/β-catenin通路调控细胞增殖。
Abstract：High-risk human papillomavirus(HPV)infection is a risk factor for cervical cancer,but the related molecular mechanism is not clear. YAP1 is a key molecule of the Hippo/YAP pathway. YAP1 promotes the proliferation of gastric cancer cells and liver cancer cells by activating the wingless type(Wnt)/β-catenin pathway. We wished to clarify the role of the YAP1 and Wnt/β-catenin signaling pathway in the pathogenesis of cervical cancer caused by high-risk HPV infection. We analyzed the relationship and biological importance of YAP1 and the Wnt/β-catenin pathway in high-risk HPV-positive cervical cancer cells. First,expression of YAP1,Wnt1,and Wnt3a β-catenin in high-risk HPV-positive and-negative cervical cancer tissues,high-risk HPV-positive and-negative cervical cancer cells,and normal cervical epithelial cells was measured. Then,HPV16-positive SiHa cells and HPV18-positive HeLa cells were cultured and transfected with negative control(NC) or YAP1 siRNA,or given the solvent dimethyl sulfoxide(DMSO) or an agonist of Wnt/β-catenin(SKL2001). The cell-proliferation activity at 490 nm(A490)and expression of Wnt1 and Wnt3a β-catenin were measured. Expression of YAP1,Wnt1,and Wnt3a β-catenin in high-risk HPV-positive cervical cancer was higher than that in high-risk HPV-negative cervical cancer(P < 0.05)and YAP1 was positively correlated with expression of Wnt1 and Wnt3a β-catenin. After transfection with YAP1 siRNA,we discovered that A490and expression of YAP1,Wnt1,and Wnt3a β-catenin in SiHa cells and HeLa cells of the si-YAP1 group were lower than those of the si-NC group(P < 0.05). SKL2001 was used while transfecting YAP1 siRNA,and A490and expression of β-catenin in SiHa cells and HeLa cells of the si-YAP1+SKL2001 group were higher than those in the si-YAP1+DMSO group(P < 0.05). Overall,our results showed that high expression of YAP1 in high-risk HPV-positive cervical cancer cells regulated cell proliferation through the Wnt/β-catenin pathway.
[1]李想，刘灿，周维. 2005~2015年中国宫颈癌发病与死亡趋势分析[J].华中科技大学学报（医学版），2021,50(3):325-330,346.
[2]刘萍.中国大陆13年宫颈癌临床流行病学大数据评价[J].中国实用妇科与产科杂志，2018,34(1):41-45.
[3] Gupta SM,Mania-PramanikJ. Molecular mechanisms in progression of HPV-associated cervical carcinogenesis[J].J Biomed Sci,2019,26(1):28.
[4] Ali MAM,Bedair RN,Abd El Atti RM. Cervical highrisk human papillomavirus infection among women residing in the Gulf Cooperation Council countries:Prevalence,type-specific distribution,and correlation with cervical cytology[J]. Cancer Cytopathol,2019,127(9):567-577.
[5]李利玲，王少帅，汪向红，徐铮铮，王芳，肖祎芳，李寒君. HPV感染宫颈癌患者Hippo-YAP通路改变及其与临床特征的关系[J].中华医院感染学杂志，2021,31(9):1415-1418.
[6]张伟，李保中，王子铭，张志忠，李守淼，刘志强，张艳.沉默YAP通过Wnt/β-catenin信号通路影响胃癌BGC823细胞的凋亡[J].肿瘤防治研究，2018,45(11):864-869.
[7] Wang S,Zhou L,Ling L,Meng X,Chu F,Zhang S,Zhou F. The Crosstalk between hippo-yap pathway and innate immunity[J]. Front Immunol, 2020, 27(11):323.
[8] Wang C, Davis JS. At the center of cervical carcinogenesis:synergism between high-risk HPV and the hyperactivated YAP1[J]. Mol Cell Oncol,2019,6(5):e1612677.
[9] Sulaiman A,McGarry S,Li L,Jia D,Ooi S,Addison C,Dimitroulakos J,Arnaout A,Nessim C,Yao Z,Ji G,Song H,Gadde S,Li X,Wang L. Dual inhibition of Wnt and Yes-associated protein signaling retards the growth of triple-negative breast cancer in both mesenchymal and epithelial states[J]. Mol Oncol,2018,12(4):423-440.
[10]Gao J,Han W,He Y,Zhou J,Miao J,Zhang G. Livin promotes tumor progression through YAP activation in ovarian cancer[J]. Am J Cancer Res,2020,10(10):3179-3193.
[11]Findik S,Findik S,Abuo?lu S,Cihan FG,Ilter H,Iyisoy MS. Human papillomavirus(HPV)subtypes and their relationships with cervical smear results in cervical cancer screening:a community-based study from the central Anatolia region of Turkey[J]. Int J Clin Exp Pathol,2019,12(4):1391-1398.
[12]Jiang L, Li J, Zhang C, Shang Y, Lin J.YAP-mediated crosstalk between the Wnt and Hippo signaling pathways(Review)[J]. Mol Med Rep,2020,22(5):4101-4106.
[13]Tang X, Sun Y, Wan G, Sun J, Sun J, Pan C.Knockdown of YAP inhibits growth in Hep-2 laryngeal cancer cells via epithelial-mesenchymal transition and the Wnt/beta-catenin pathway[J]. BMC Cancer,2019,19(1):654.
[14]Min Q,Molina L,Li J,Adebayo Michael AO,Russell JO,Preziosi ME,Singh S,Poddar M,Matz-Soja M,Ranganathan S,Bell AW,Gebhardt R,Gaunitz F,Yu J,Tao J,Monga SP. beta-Catenin and Yes-Associated Protein 1 Cooperate in Hepatoblastoma Pathogenesis[J]. Am J Pathol,2019,189(5):1091-1104.
[15]Wang B, Li X, Liu L, Wang M. beta-Catenin:oncogenic role and therapeutic target in cervical cancer[J]. Biol Res,2020,53(1):33.
[16]Drews CM,Case S,Vande Pol SB. E6 proteins from high-risk HPV, low-risk HPV, and animal papillomaviruses activate the Wnt/beta-catenin pathway through E6AP-dependent degradation of NHERF1[J/OL]. PLoS Pathog,2019,15(4):e1007575.
[17]Ayala-Calvillo E, Mojica-Vázquez LH, GarcíaCarrancáA, González-Maya L. Wnt/beta-catenin pathway activation and silencing of the APC gene in HPV-positive human cervical cancer-derived cells[J].Mol Med Rep,2018,17(1):200-208.
基本信息:
DOI：10.13242/j.cnki.bingduxuebao.004158
中图分类号:R737.33
引用信息:
[1]姜英,周红.高危型HPV阳性宫颈癌细胞中YAP1与Wnt/β-catenin信号通路的关系及生物学意义[J].病毒学报,2022,38(04):889-895.DOI:10.13242/j.cnki.bingduxuebao.004158.
2021-10-13
2021
2021-12-24
2022-06-30
2022
1
2022-07-04
2022-07-04
2022-07-04