BKCa participates in E2 inducing endometrial adenocarcinoma by activating MEK/ERK pathway.
BKCa participates in E2 inducing endometrial adenocarcinoma by activating MEK/ERK pathway.
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BKCa通过激活MEK/ERK通路参与E2诱导子宫内膜腺癌。
DOI：
10.1186/s12885-018-5027-9
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发表时间：
2018-11-16
期刊：
影响因子：
3.8
通讯作者：
Li B
中科院分区：
文献类型：
--
作者：
Wang F;Chen Q;Huang G;Guo X;Li N;Li Y;Li B
大电导、电压门控、钙(Ca(2+))激活的钾通道(BKCa)在调节Ca(2+)信号和细胞生理功能中起着重要作用，并在某些类型的肿瘤中异常表达。本研究旨在探讨BKCa在子宫内膜腺癌中的致癌作用及其临床意义，并探讨17-雌二醇(17β-estadiol，E_2)通过BKCa诱导MEK1/2和ERK1/2异常激活的机制。应用免疫组织化学方法检测263例子宫内膜癌组织中BKCa、ERK1/2和p-ERK1/2的表达，其中包括185例I型子宫内膜癌组织、38例子宫内膜不典型增生组织和40例正常子宫内膜组织。用siRNA-BKCa和/或E2分别检测Ishikawa细胞的生长、周期、凋亡率、迁移和侵袭能力，并用Western印迹分析这些感兴趣蛋白的表达。我们发现BKCa在185例I型子宫内膜腺癌组织中的表达显著高于正常子宫内膜和非典型子宫内膜增生症组织。此外，体外实验还发现，BKca基因的表达下调通过促进细胞凋亡和阻断G1/S的转变来抑制细胞生长，抑制Ishakiwa细胞的迁移和侵袭，并降低p-mek1/2和p-erk1/2的表达。此外，RNAi介导的bkca基因表达下调减弱了E2刺激诱导的细胞生长和侵袭的增加，以及p-mek1/2和p-erk1/2蛋白表达的上调。更重要的是，BKCa和p-ERK1/2的异常表达与I型子宫内膜癌的不良预后因素密切相关，p-ERK1/2的表达上调与子宫内膜癌患者的无病生存期(DFS)和总生存期(OS)显著相关，是I型子宫内膜癌患者独立的预后因素。我们的结果表明，BKCa及其下游的关键效应因子p-ERK1/2可能参与了子宫内膜腺癌的发生发展过程中的重要信号通路，为子宫内膜腺癌的治疗提供了一条新的途径。本文的在线版本(10.1186/s12885-0185027-9)包含补充材料，可供授权用户使用。
The large-conductance, voltage-gated, calcium (Ca (2+))-activated potassium channel (BKCa) plays an important role in regulating Ca (2+) signaling and cell physiological function, and is aberrantly expressed in some types of cancers. The present study focuses on identifying the oncogenic potential and clinical significance of BKCa in endometrial adenocarcinoma, as well as exploring the mechanistic relevance by 17β -estradiol (E2) inducing aberrant activation of MEK1/2 and ERK1/2 via BKCa. The expression of BKCa, ERK1/2 and p-ERK1/2 were examined by immunohistochemical staining in 263 cases, including 185 primary types I endometrial cancer tissues, 38 atypical endometrial hyperplasia tissues and 40 normal endometrium tissues. Cell growth, cycle, apoptosis rate, migration and invasion was separately tested in Ishikawa cells using siRNA-BKCa and/or E2 treatment, as well as the expression of these interested proteins by western blot analysis. We showed that expression of BKCa is significantly elevated in 185 types I endometrial adenocarcinoma tissues compared to those of the normal endometrium and atypical endometrial hyperplasia tissues. Furthermore, in vitro observations revealed that down-regulation of BKCa expression inhibited cell growth by both enhancing apoptosis and blocking G1/S transition, suppressed cell migration and invasion in Ishakiwa cells, and decreased the expression of p-MEK1/2 and p-ERK1/2. Additionally, RNAi-mediated knockdown of BKCa attenuated the increased cellular growth and invasion, as well as the elevated expression of p-MEK1/2 and p-ERK1/2 proteins, induced by E2 stimulation. More importantly, the aberrant expression of BKCa and p-ERK1/2 were closely related with poor prognostic factors in type I endometrial cancer, and up-regulated expression of p-ERK1/2 was significantly associated with shorter disease-free survival (DFS) and overall survival (OS) and was an independent prognostic factor in type I endometrial cancer patients. Our results demonstrated that BKCa and the key downstream effectors p-ERK1/2 could be involved in important signaling pathways in initiation and development of endometrial adenocarcinoma and may provide a new therapeutic approach for women with endometrial cancer. The online version of this article (10.1186/s12885-018-5027-9) contains supplementary material, which is available to authorized users.
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影响因子：
3.8
作者：
Khaitan D;Sankpal UT;Weksler B;Meister EA;Romero IA;Couraud PO;Ningaraj NS
通讯作者：
Ningaraj NS
KCNMA1与PTK2协同作用是胃癌的新型抑癌基因，与疾病结局相关
影响因子：
37.3
作者：
Ma, Gaoxiang;Liu, Hanting;Chu, Haiyan
通讯作者：
Chu, Haiyan
影响因子：
3.7
作者：
Oeggerli M;Tian Y;Ruiz C;Wijker B;Sauter G;Obermann E;Güth U;Zlobec I;Sausbier M;Kunzelmann K;Bubendorf L
通讯作者：
Bubendorf L
DOI：
10.1186/1477-7827-7-27
发表时间：
2009-04-05
期刊：
Reproductive biology and endocrinology : RB&E
影响因子：
--
作者：
Gao L;Cong B;Zhang L;Ni X
通讯作者：
Ni X
影响因子：
4
作者：
Lorca RA;Prabagaran M;England SK
通讯作者：
England SK