Claudin-4 activity in ovarian tumor cell apoptosis resistance and migration.
Claudin-4 activity in ovarian tumor cell apoptosis resistance and migration.
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DOI：
10.1186/s12885-016-2799-7
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发表时间：
2016-10-11
期刊：
影响因子：
3.8
通讯作者：
Baumgartner HK
中科院分区：
文献类型：
--
作者：
Hicks DA;Galimanis CE;Webb PG;Spillman MA;Behbakht K;Neville MC;Baumgartner HK
Claudin-4是一种跨膜蛋白，在大多数上皮性卵巢肿瘤中高水平表达，与亚型无关，并且与化疗耐药和高度移动的肿瘤细胞相关。本研究的目的是确定紧密连接蛋白-4在细胞凋亡抗性和迁移中发挥的功能作用，以及用小模拟肽靶向紧密连接蛋白-4活性的治疗效用。我们使用体外半胱天冬酶和划痕测定以及卵巢癌的体内小鼠模型来检查人卵巢肿瘤细胞系（SKOV 3、OVCAR 3、PEO 4）中的密蛋白-4活性。通过用模拟紧密连接蛋白-4的第二胞外环中的DFYNP序列的小肽处理细胞来破坏紧密连接蛋白-4活性。Claudin-4的表达也改变了使用shRNA介导的基因沉默。claudin-4活性的破坏和claudin-4表达的丧失均显著增加了响应于凋亡诱导剂星形孢菌素的肿瘤细胞半胱天冬酶-3活化（分别为4至10倍），并使肿瘤细胞迁移减少了50%。模拟肽对缺乏紧密连接蛋白-4表达的细胞没有影响。与对照肽处理的小鼠相比，每48小时腹膜内注射4 mg/kg模拟肽处理三周后，由于细胞凋亡增加，携带ZsGreen-PEO 4卵巢肿瘤的雌性无胸腺裸鼠显示卵巢肿瘤负荷显著降低。紧密连接蛋白-4在功能上有助于卵巢肿瘤细胞凋亡抗性和迁移，并且紧密连接蛋白-4的靶向细胞外环相互作用可能对降低卵巢肿瘤负荷具有治疗意义。
Claudin-4 is a transmembrane protein expressed at high levels in the majority of epithelial ovarian tumors, irrespective of subtype, and has been associated with tumor cells that are both chemoresistant and highly mobile. The objective of this study was to determine the functional role that claudin-4 plays in apoptosis resistance and migration as well as the therapeutic utility of targeting claudin-4 activity with a small mimic peptide. We examined claudin-4 activity in human ovarian tumor cell lines (SKOV3, OVCAR3, PEO4) using in vitro caspase and scratch assays as well as an in vivo mouse model of ovarian cancer. Claudin-4 activity was disrupted by treating cells with a small peptide that mimics the DFYNP sequence in the second extracellular loop of claudin-4. Claudin-4 expression was also altered using shRNA-mediated gene silencing. Both the disruption of claudin-4 activity and the loss of claudin-4 expression significantly increased tumor cell caspase-3 activation (4 to 10-fold, respectively) in response to the apoptotic inducer staurosporine and reduced tumor cell migration by 50 %. The mimic peptide had no effect on cells that lacked claudin-4 expression. Female athymic nude mice bearing ZsGreen-PEO4 ovarian tumors showed a significant decrease in ovarian tumor burden, due to increased apoptosis, after treatment with intraperitoneal injections of 4 mg/kg mimic peptide every 48 h for three weeks, compared to control peptide treated mice. Claudin-4 functionally contributes to both ovarian tumor cell apoptosis resistance and migration and targeting extracellular loop interactions of claudin-4 may have therapeutic implications for reducing ovarian tumor burden.
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DOI：
10.1038/modpathol.2012.187
发表时间：
2013-04
期刊：
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.1
作者：
Tan, Tuan Zea;Miow, Qing Hao;Huang, Ruby Yun-Ju;Wong, Meng Kang;Ye, Jieru;Lau, Jieying Amelia;Wu, Meng Chu;Hadi, Luqman Hakim Bin Abdul;Soong, Richie;Choolani, Mahesh;Davidson, Ben;Nesland, Jahn M.;Wang, Ling-Zhi;Matsumura, Noriomi;Mandai, Masaki;Konishi, Ikuo;Goh, Boon-Cher;Chang, Jeffrey T.;Thiery, Jean Paul;Mori, Seiichi
通讯作者：
Mori, Seiichi
影响因子：
6.4
作者：
Lanigan, Fiona;McKiernan, Eadaoin;Gallagher, William M.
通讯作者：
Gallagher, William M.
影响因子：
4.8
作者：
Shang, Xiying;Lin, Xinjian;Howell, Stephen B.
通讯作者：
Howell, Stephen B.
影响因子：
11.2
作者：
Spillman MA;Manning NG;Dye WW;Sartorius CA;Post MD;Harrell JC;Jacobsen BM;Horwitz KB
通讯作者：
Horwitz KB