Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation.
Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation.
复制标题
白血病抑制因子可以通过PI3K/AKT依赖性MCL-1激活来保护胆管癌细胞免受药物诱导的凋亡。
DOI：
10.18632/oncotarget.4482
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发表时间：
2015-09-22
期刊：
影响因子：
--
通讯作者：
Strazzabosco M
中科院分区：
文献类型：
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作者：
Morton SD;Cadamuro M;Brivio S;Vismara M;Stecca T;Massani M;Bassi N;Furlanetto A;Joplin RE;Floreani A;Fabris L;Strazzabosco M
胆管癌是一种侵袭性强、化疗耐药的肝脏恶性肿瘤。白血病抑制因子（LIF）是一种IL-6家族细胞因子，可促进多种肿瘤的进展。为了研究LIF在胆管癌中的作用，我们评估了人样本中LIF及其受体（LIFR）的表达。在建立的和原代人胆管癌细胞系中评估LIF分泌和LIFR表达。在胆管癌细胞中，我们测试了LIF对增殖、侵袭、干细胞样表型、化疗诱导的凋亡（吉西他滨+顺铂）、促凋亡（Bax）和抗凋亡（Mcl-1）蛋白的表达水平（有/无PI 3 K抑制）以及pSTAT 3、pERK 1/2、pAKT的影响。在LIFR沉默和Mcl-1失活后评价LIF对化疗诱导的细胞凋亡的作用。结果表明，LIF和LIFR的表达高于在肿瘤的胆管细胞比在对照组; LIF也表达的肿瘤间质细胞。LIF对胆管癌细胞增殖、侵袭和干性特征没有影响，但它能抵消药物诱导的细胞凋亡。LIF刺激后，细胞凋亡减少与Mcl-1和pAKT上调相关，并被PI 3 K抑制所消除。LIFR沉默和Mcl-1阻断恢复了药物诱导的细胞凋亡。总之，自分泌和旁分泌LIF信号通过一种新的STAT 3和MAPK非依赖性、PI 3 K/AKT依赖性途径上调Mcl-1，促进胆管癌的化疗耐药性。靶向LIF信号传导可以增加CCA对化疗的反应性。
Cholangiocarcinoma is an aggressive, strongly chemoresistant liver malignancy. Leukemia inhibitory factor (LIF), an IL-6 family cytokine, promotes progression of various carcinomas. To investigate the role of LIF in cholangiocarcinoma, we evaluated the expression of LIF and its receptor (LIFR) in human samples. LIF secretion and LIFR expression were assessed in established and primary human cholangiocarcinoma cell lines. In cholangiocarcinoma cells, we tested LIF effects on proliferation, invasion, stem cell-like phenotype, chemotherapy-induced apoptosis (gemcitabine+cisplatin), expression levels of pro-apoptotic (Bax) and anti-apoptotic (Mcl-1) proteins, with/without PI3K inhibition, and of pSTAT3, pERK1/2, pAKT. LIF effect on chemotherapy-induced apoptosis was evaluated after LIFR silencing and Mcl-1 inactivation. Results show that LIF and LIFR expression were higher in neoplastic than in control cholangiocytes; LIF was also expressed by tumor stromal cells. LIF had no effects on cholangiocarcinoma cell proliferation, invasion, and stemness signatures, whilst it counteracted drug-induced apoptosis. Upon LIF stimulation, decreased apoptosis was associated with Mcl-1 and pAKT up-regulation and abolished by PI3K inhibition. LIFR silencing and Mcl-1 blockade restored drug-induced apoptosis. In conclusion, autocrine and paracrine LIF signaling promote chemoresistance in cholangiocarcinoma by up-regulating Mcl-1 via a novel STAT3- and MAPK-independent, PI3K/AKT-dependent pathway. Targeting LIF signaling may increase CCA responsiveness to chemotherapy.