Complement component 1, q subcomponent binding protein (C1QBP) in lipid rafts mediates hepatic metastasis of pancreatic cancer by regulating IGF-1/IGF-1R signaling
Complement component 1, q subcomponent binding protein (C1QBP) in lipid rafts mediates hepatic metastasis of pancreatic cancer by regulating IGF-1/IGF-1R signaling
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脂筏中补体成分1、q亚成分结合蛋白(C1QBP)通过调节IGF-1/IGF-1R信号介导胰腺癌肝转移
DOI：
10.1002/ijc.30831
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发表时间：
2017-10-01
影响因子：
6.4
通讯作者：
Fu, Deliang
中科院分区：
文献类型：
--
作者：
Shi, Haojun;Fang, Winston;Fu, Deliang
胰腺癌有明显的肝转移倾向。补体成分1，q亚成分结合蛋白（C1QBP）通过激活受体酪氨酸激酶介导生长因子诱导的癌细胞趋化和远处转移。巧合的是，来自肝脏和癌细胞本身的胰岛素样生长因子-1 （IGF-1）已被认为是肝转移的关键诱导剂。然而，igf -1依赖性胰腺癌肝转移的机制（C1QBP可能参与其中）仍不清楚。在这项研究中，我们证明了C1QBP表达与胰腺癌患者肝转移之间的显著关联。IGF-1诱导C1QBP从细胞质转移到脂筏，并进一步推动CD44 variant 6 (CD44v6)/C1QBP复合物在胰腺癌细胞中的形成。C1QBP在脂筏中与CD44v6相互作用，促进IGF-1R磷酸化，从而激活下游PI3K和MAPK信号通路，介导胰腺癌细胞的增殖、凋亡、侵袭、粘附和能量代谢等转移潜能。此外，C1QBP敲低可抑制裸鼠胰腺癌细胞的肝转移。因此，我们得出结论，脂筏中的C1QBP在IGF-1/ igf - 1r诱导的胰腺癌肝转移中起关键调节作用。我们关于脂筏中C1QBP的发现提供了一种阻断胰腺癌中IGF-1/IGF-1R信号的新策略，并为更有效的联合治疗提供了可靠的前提。
Pancreatic cancer shows a remarkable predilection for hepatic metastasis. Complement component 1, q subcomponent binding protein (C1QBP) can mediate growth factor-induced cancer cell chemotaxis and distant metastasis by activation of receptor tyrosine kinases. Coincidentally, insulin-like growth factor-1 (IGF-1) derived from the liver and cancer cells itself has been recognized as a critical inducer of hepatic metastasis. However, the mechanism underlying IGF-1-dependent hepatic metastasis of pancreatic cancer, in which C1QBP may be involved, remains unknown. In the study, we demonstrated a significant association between C1QBP expression and hepatic metastasis in patients with pancreatic cancer. IGF-1 induced the translocation of C1QBP from cytoplasm to lipid rafts and further drove the formation of CD44 variant 6 (CD44v6)/C1QBP complex in pancreatic cancer cells. C1QBP interacting with CD44v6 in lipid rafts promoted phosphorylation of IGF-1R and thus activated downstream PI3K and MAPK signaling pathways which mediated metastatic potential of pancreatic cancer cells including proliferation, apoptosis, invasion, adhesion and energy metabolism. Furthermore, C1QBP knockdown suppressed hepatic metastasis of pancreatic cancer cells in nude mice. We therefore conclude that C1QBP in lipid rafts serves a key regulator of IGF-1/IGF-1R-induced hepatic metastasis from pancreatic cancer. Our findings about C1QBP in lipid rafts provide a novel strategy to block IGF-1/IGF-1R signaling in pancreatic cancer and a reliable premise for more efficient combined modality therapies.