Autocrine parathyroid hormone-like hormone promotes intrahepatic cholangiocarcinoma cell proliferation via increased ERK/JNK-ATF2-cyclinD1 signaling.
Autocrine parathyroid hormone-like hormone promotes intrahepatic cholangiocarcinoma cell proliferation via increased ERK/JNK-ATF2-cyclinD1 signaling.
复制标题
自分泌甲状旁腺激素样激素通过增加 ERK/JNK-ATF2-cyclinD1 信号传导促进肝内胆管癌细胞增殖
DOI：
10.1186/s12967-017-1342-1
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发表时间：
2017-11-25
影响因子：
7.4
通讯作者：
Bai L
中科院分区：
文献类型：
--
作者：
Tang J;Liao Y;He S;Shi J;Peng L;Xu X;Xie F;Diao N;Huang J;Xie Q;Lin C;Luo X;Liao K;Ma J;Li J;Zhou D;Li Z;Xu J;Zhong C;Wang G;Bai L
背景与目的肝内胆管癌（ICC）是一种高致死率的侵袭性肿瘤。最近发现，与非肿瘤组织相比，ICC中甲状旁腺激素样激素（PTHLH）经常过表达。本研究旨在阐明PTHLH在ICC发展中的潜在机制。方法采用CCK-8法、菌落形成法、流式细胞术和异种移植模型检测PTHLH对ICC细胞增殖的影响。免疫组化（IHC）和western blot检测靶蛋白。荧光素酶报告基因、染色质免疫沉淀（ChIP）和DNA拉下实验验证了激活转录因子-2 （ATF2）的转录调控。结果与邻近组织和正常组织相比，ICC组织中spthlh表达明显上调。PTHLH表达上调提示病理分化差和肝内转移。功能研究表明，PTHLH沉默可显著抑制ICC细胞的生长，而特异性过表达PTHLH则具有相反的作用。机制上，分泌的PTHLH通过激活细胞外信号相关激酶（ERK）和c-Jun n -末端激酶（JNK）信号通路促进ICC细胞生长，进而上调ATF2和cyclinD1的表达。进一步研究发现，ATF2负向调节PTHLH启动子活性，表明存在负反馈回路。结论研究结果表明，ICC分泌的PTHLH通过激活典型的ERK/JNK-ATF2-cyclinD1信号通路，在ICC的发育过程中发挥特征性的促生长作用。我们发现了一个由ATF2和PTHLH形成的负反馈回路。在本研究中，我们探讨了ICC患者的治疗意义。
Background and aimsIntrahepatic cholangiocarcinoma (ICC) is an aggressive tumor with a high fatality rate. It was recently found that parathyroid hormone-like hormone (PTHLH) was frequently overexpressed in ICC compared with non-tumor tissue. This study aimed to elucidate the underlying mechanisms of PTHLH in ICC development.MethodsThe CCK-8 assay, colony formation assays, flow cytometry and a xenograft model were used to examine the role of PTHLH in ICC cells proliferation. Immunohistochemistry (IHC) and western blot assays were used to detect target proteins. Luciferase reporter, chromatin immunoprecipitation (ChIP) and DNA pull-down assays were used to verify the transcription regulation of activating transcription factor-2 (ATF2).ResultsPTHLH was significantly upregulated in ICC compared with adjacent and normal tissues. Upregulation of PTHLH indicated a poor pathological differentiation and intrahepatic metastasis. Functional study demonstrated that PTHLH silencing markedly suppressed ICC cells growth, while specific overexpression of PTHLH has the opposite effect. Mechanistically, secreted PTHLH could promote ICC cell growth by activating extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways, and subsequently upregulated ATF2 and cyclinD1 expression. Further study found that the promoter activity of PTHLH were negatively regulated by ATF2, indicating that a negative feedback loop exists.ConclusionsOur findings demonstrated that the ICC-secreted PTHLH plays a characteristic growth-promoting role through activating the canonical ERK/JNK-ATF2-cyclinD1 signaling pathways in ICC development. We identified a negative feedback loop formed by ATF2 and PTHLH. In this study, we explored the therapeutic implication for ICC patients.
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影响因子：
11.2
作者：
Kim W;Takyar FM;Swan K;Jeong J;VanHouten J;Sullivan C;Dann P;Yu H;Fiaschi-Taesch N;Chang W;Wysolmerski J
通讯作者：
Wysolmerski J
影响因子：
11.2
作者：
Cole AM;Myant K;Reed KR;Ridgway RA;Athineos D;Van den Brink GR;Muncan V;Clevers H;Clarke AR;Sicinski P;Sansom OJ
通讯作者：
Sansom OJ
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
8
作者：
Fortino, V;Torricelli, C;Maioli, E
通讯作者：
Maioli, E
影响因子：
3.7
作者：
NAKAMURA, T;OKUYAMA, S;ODA, K
通讯作者：
ODA, K