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首页> 外文OA文献 >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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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

机译：akt /缺氧诱导因子-1α/血小板衍生生长因子-BB自分泌环介导缺氧诱导的肝癌细胞和致瘤肝祖细胞的化学抗性

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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-1α (HIF-1α)/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-1α inhibitor, were administered by portal vein and intratumoral injections, respectively. Results: Cell viability was higher under hypoxic than normoxic conditions. HIF-1α and Akt were up-regulated under hypoxic conditions, forming an autocrine signaling loop with PDGF-BB. Akt/HIF-1α/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-1α 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-1α/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. © 2009 American Association for Cancer Research.
机译：目的：本研究的目的是研究缺氧介导的肝癌细胞和致瘤性肝祖细胞（卵形）细胞中化学抗药性的机制，并确定是否破坏Akt /低氧诱导因子-1α（HIF-1α）/血小板衍生生长因子（PDGF）-BB自分泌环可增强缺氧的化疗效果。实验设计：在常氧和低氧条件下，用顺铂体外处理了五个肝细胞癌（HCC）细胞系和两个肝祖细胞系。为了在体内为肿瘤细胞产生缺血性缺氧，将肝动脉结扎应用于原位HCC模型。顺铂和HIF-1α抑制剂YC1分别通过门静脉和瘤内注射给药。结果：低氧条件下的细胞活力高于常氧条件。在缺氧条件下，HIF-1α和Akt上调，与PDGF-BB形成自分泌信号回路。 Akt /HIF-1α/ PDGF-BB信号传导调节Akt，使其在体外对HCC细胞系产生顺铂耐药性。在缺氧条件下，这种自分泌信号回路还有助于致癌性肝祖细胞PIL2的化学抗性，而非致癌性细胞系PIL4的抗化学性。在原位肝癌模型中，将HIF-1α活性的阻断与缺血性缺氧相结合，可显着增强化疗的功效，从而抑制肿瘤的生长并延长动物的生存期。结论：在低氧条件下，阻断Akt /HIF-1α/ PDGF-BB自分泌信号传导可以增强肝癌细胞和致癌肝祖细胞的化学敏感性，从而为HCC提供有效的治疗策略。 ©2009美国癌症研究协会。

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