ASIC1 and ASIC3 contribute to acidity-induced EMT of pancreatic cancer through activating Ca(2+)/RhoA pathway.
ASIC1 and ASIC3 contribute to acidity-induced EMT of pancreatic cancer through activating Ca(2+)/RhoA pathway.
复制标题
ASIC1和ASIC3通过激活Ca2/RhoA途径促进酸性诱导的胰腺癌EMT
DOI：
10.1038/cddis.2017.189
复制
发表时间：
2017-05-18
影响因子：
9
通讯作者：
Zhao G
中科院分区：
文献类型：
--
作者：
Zhu S;Zhou HY;Deng SC;Deng SJ;He C;Li X;Chen JY;Jin Y;Hu ZL;Wang F;Wang CY;Zhao G
胞外酸对癌细胞有重要作用。酸敏离子通道(ASICs)是细胞外酸性pH的关键受体，在不同疾病中表达不同，参与了多种疾病的发病机制。本研究报告ASIC1和ASIC3主要表达于胰腺癌细胞的细胞膜上，在胰腺癌组织中表达上调。ASIC1和ASIC3负责酸性诱导的内向电流，这是提高细胞内钙浓度([Ca2+]i)所必需的。用siRNA或药物抑制剂抑制ASIC1和ASIC3可显著降低酸性条件下的[Ca2+]i及其下游RhoA，从而抑制酸性诱导的胰腺癌细胞上皮-间充质转化(EMT)。同时，用钙络合剂BAPTA-AM下调[Ca2+]i或用siRNA敲除RhoA也能显著抑制酸性诱导的胰腺癌细胞EMT。在异种移植模型中，ASIC1和ASIC3基因的敲除虽然对胰腺癌细胞的增殖没有明显的影响，但显著地抑制了移植瘤的肝和肺转移。此外，胰腺癌细胞中ASIC1、ASIC3与间质标志物Vimentin的表达呈正相关，与上皮性标志物E-cadherin的表达呈负相关。综上所述，本研究表明ASICs是酸性诱导EMT的主要调节因子。此外，数据还证实了ASICs与[Ca2+]I/RhoA通路之间的功能联系，该通路参与了酸性诱导的EMT。
Extracellular acid can have important effects on cancer cells. Acid-sensing ion channels (ASICs), which emerged as key receptors for extracellular acidic pH, are differently expressed during various diseases and have been implicated in underlying pathogenesis. This study reports that ASIC1 and ASIC3 are mainly expressed on membrane of pancreatic cancer cells and upregulated in pancreatic cancer tissues. ASIC1 and ASIC3 are responsible for an acidity-induced inward current, which is required for elevation of intracellular Ca 2+ concentration ([Ca 2+] i). Inhibition of ASIC1 and ASIC3 with siRNA or pharmacological inhibitor significantly decreased [Ca 2+] i and its downstream RhoA during acidity and, thus, suppressed acidity-induced epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. Meanwhile, downregulating [Ca 2+] i with calcium chelating agent BAPTA-AM or knockdown of RhoA with siRNA also significantly repressed acidity-induced EMT of pancreatic cancer cells. Significantly, although without obvious effect on proliferation, knockdown of ASIC1 and ASIC3 in pancreatic cancer cells significantly suppresses liver and lung metastasis in xenograft model. In addition, ASIC1 and ASIC3 are positively correlated with expression of mesenchymal marker vimentin, but inversely correlated with epithelial marker E-cadherin in pancreatic cancer cells. In conclusion, this study indicates that ASICs are master regulator of acidity-induced EMT. In addition, the data demonstrate a functional link between ASICs and [Ca 2+] i/RhoA pathway, which contributes to the acidity-induced EMT.
登录
查看更多内容
影响因子：
4.9
作者：
Gong W;Kolker SJ;Usachev Y;Walder RY;Boyle DL;Firestein GS;Sluka KA
通讯作者：
Sluka KA
癌症中的microRNA生物发生途径。
DOI：
10.1038/nrc3932
发表时间：
2015-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Lin S;Gregory RI
通讯作者：
Gregory RI
影响因子：
8
作者：
Gupta SC;Singh R;Asters M;Liu J;Zhang X;Pabbidi MR;Watabe K;Mo YY
通讯作者：
Mo YY
影响因子：
--
作者：
GILLIES, RJ;LIU, Z;BHUJWALLA, Z
通讯作者：
BHUJWALLA, Z
影响因子：
11.2
作者：
Monet, Michael;Lehen'kyi, V'yacheslav;Prevarskaya, Natalia
通讯作者：
Prevarskaya, Natalia