An Akt/Hypoxia-Inducible Factor-1α/Platelet-Derived Growth Factor-BB Autocrine Loop Mediates Hypoxia-Induced Chemoresistance in Liver Cancer Cells and Tumorigenic Hepatic Progenitor Cells
An Akt/Hypoxia-Inducible Factor-1α/Platelet-Derived Growth Factor-BB Autocrine Loop Mediates Hypoxia-Induced Chemoresistance in Liver Cancer Cells and Tumorigenic Hepatic Progenitor Cells
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DOI：
10.1158/1078-0432.ccr-08-2127
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发表时间：
2009-05-15
影响因子：
11.5
通讯作者：
Fan, Sheung Tat
中科院分区：
文献类型：
--
作者：
Lau, Chi Keung;Yang, Zhen Fan;Fan, Sheung Tat
目的：本研究旨在探讨肝癌细胞和致瘤性肝祖细胞（卵圆细胞）中缺氧介导的化疗耐药机制，并确定阻断Akt/缺氧诱导因子 -1α（HIF -1α）/血小板衍生生长因子（PDGF）-BB自分泌环是否能提高缺氧环境下的化疗效果。
实验设计：在常氧和缺氧条件下，用顺铂对5种肝细胞癌（HCC）细胞系和2种肝祖细胞系进行体外处理。为在体内使肿瘤细胞产生缺血性缺氧，对原位肝癌模型进行肝动脉结扎。分别通过门静脉注射顺铂和瘤内注射HIF -1α抑制剂YC1。
结果：缺氧条件下细胞活力高于常氧条件。缺氧条件下HIF -1α和Akt上调，与PDGF -BB形成自分泌信号环。Akt/HIF -1α/PDGF -BB信号通路调节Akt，使肝癌细胞系在体外对顺铂产生耐药性。在缺氧条件下，这种自分泌信号环也导致致瘤性肝祖细胞系PIL2产生化疗耐药，但在非致瘤性细胞系PIL4中则没有。在原位肝癌模型中，阻断HIF -1α活性与缺血性缺氧相结合显著提高了化疗效果，抑制了肿瘤生长并延长了动物生存期。
结论：阻断Akt/HIF -1α/PDGF -BB自分泌信号可提高缺氧条件下肝癌细胞和致瘤性肝祖细胞的化疗敏感性，从而为肝癌提供一种有效的治疗策略。
Purpose: The goals of the present study were to investigate the mechanism of hypoxia-mediated chemoresistance in liver cancer cells and tumorigenic hepatic progenitor (oval) cells and to determine whether disrupting an Akt/hypoxia-inducible factor-1 alpha (HIF-1 alpha)/platelet-derived growth factor (PDGF)-BB autocrine loop can enhance chemotherapeutic efficacy in hypoxia.Experimental Design: Five hepatocellular carcinoma (HCC) cell lines and two hepatic progenitor cell lines were treated in vitro with cisplatin under both normoxic and hypoxic conditions. To generate ischemic hypoxia for tumor cells in vivo, hepatic artery ligation was applied to an orthotopic HCC model. Cisplatin and YC1, which is a HIF-1 alpha inhibitor, were administered by portal vein and intratumoral injections, respectively.Results: Cell viability was higher under hypoxic than normoxic conditions. HIF-1 alpha and Akt were up-regulated under hypoxic conditions, forming an autocrine signaling loop with PDGF-BB. Akt/HIF-1 alpha/PDGF-BB signaling regulated Akt to confer cisplatin resistance to HCC cell lines in vitro. This autocrine signaling loop also contributed to chemoresistance in the tumorigenic hepatic progenitor cell line PIL2 under hypoxic conditions but not in the nontumorigenic cell line PIL4. In an orthotopic HCC model, combining blockade of HIF-1 alpha activity with ischemic hypoxia significantly enhanced the efficacy of chemotherapy, leading to suppression of tumor growth and prolongation of animal survival.Conclusion: Blockade of Akt/HIF-1 alpha/PDGF-BB autocrine signaling could enhance the chemosensitivity of liver cancer cells and tumorigenic hepatic progenitor cells under hypoxic conditions and thus provide an effective therapeutic strategy for HCC.