LIFR functions as a metastasis suppressor in hepatocellular carcinoma by negatively regulating phosphoinositide 3-kinase/AKT pathway
LIFR functions as a metastasis suppressor in hepatocellular carcinoma by negatively regulating phosphoinositide 3-kinase/AKT pathway
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LIFR 通过负向调节磷酸肌醇 3-激酶/AKT 通路作为肝细胞癌的转移抑制剂
DOI：
10.1093/carcin/bgv108
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发表时间：
2015-10-01
期刊：
影响因子：
4.7
通讯作者：
Qin, Wenxin
中科院分区：
文献类型：
--
作者：
Luo, Qin;Wang, Cun;Qin, Wenxin
肝细胞癌（HCC）是世界范围内癌症相关死亡的主要原因之一。肝癌患者预后差的主要原因是频繁的转移和复发。恶性肿瘤细胞中转移抑制因子的失调在肿瘤转移过程中起着关键作用。因此，迫切需要发现新的转移抑制因子，以揭示驱动HCC转移的分子机制。在本研究中，白血病抑制因子受体（LIFR）的表达在HCC中被证明是降低的，并且其表达水平在HCC转移中更低。LIFR表达下调预示肝癌患者预后不良。LIFR是其复发和生存的独立和重要的危险因素。沉默LIFR导致肝癌细胞的转移，而LIFR的异位过表达减弱了肝癌细胞在体外和体内的迁移和侵袭。此外，LIFR基因敲低可通过增强Janus激酶1（JAK 1）的磷酸化激活磷酸肌醇3激酶/V-akt鼠胸腺瘤病毒癌基因同源物（PI 3 K/AKT）信号通路，进而促进基质金属蛋白酶13（MMP 13）的表达和肝癌转移。联合应用LIFR和p-AKT或MMP 13是HCC患者预后不良的更有力的预测因子。总之，这些发现得出结论，LIFR作为一种新的转移抑制剂在肝癌中发挥作用，并可能作为肝癌患者的预后生物标志物。
Hepatocellular carcinoma (HCC) is one of the leading causes for cancer related mortality worldwide. Poor prognosis of HCC patients is mainly due to frequent metastasis and recurrence. Deregulation of metastasis suppressors in malignant cells plays critical roles during cancer metastasis. Thus, novel metastasis suppressors are urgently needed to be uncovered to shed new light on molecular mechanisms driving HCC metastasis. In the present study, decreased expression of leukemia inhibitory factor receptor (LIFR) was demonstrated in HCC, and its expression levels were even lower in HCC with metastasis. Downregulated LIFR expression predicted poor prognosis in HCC patients. LIFR was an independent and significant risk factor for their recurrence and survival. Silencing LIFR resulted in forced metastasis of HCC cells, whereas ectopic overexpression of LIFR attenuated migration and invasion of HCC cells in vitro and in vivo. Moreover, LIFR knockdown could activate phosphoinositide 3-kinase/V-akt Murine Thymoma Viral Oncogene Homolog (PI3K/AKT) signaling through enhancing phosphorylation of Janus kinase 1 (JAK1), which successively promoted matrix metalloproteinase 13 (MMP13) expression and HCC metastasis. Combination of LIFR and p-AKT or MMP13 was a more powerful predictor of poor prognosis for HCC patients. Together, these findings conclude that LIFR functions as a novel metastasis suppressor in HCC and may serve as a prognostic biomarker for HCC patients.