Division of General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Department of Surgery, University of Cincinnati, Cincinnati, OH.
Hepatology. 2021 Oct;74(4):2201-2215. doi: 10.1002/hep.31919. Epub 2021 Aug 10.
Hepatoblastoma (HBL) is a devastating pediatric liver cancer with multiple treatment options, but it ultimately requires surgery for a cure. The most malicious form of HBL is a chemo-resistant aggressive tumor that is characterized by rapid growth, metastases, and poor response to treatment. Very little is known of the mechanisms of aggressive HBL, and recent focuses have been on developing alternative treatment strategies. In this study, we examined the role of human chromosomal regions, called aggressive liver cancer domains (ALCDs), in liver cancer and evaluated the mechanisms that activate ALCDs in aggressive HBL.
We found that ALCDs are critical regions of the human genome that are located on all human chromosomes, preferentially in intronic regions of the oncogenes and other cancer-associated genes. In aggressive HBL and in patients with Hepatocellular (HCC), JNK1/2 phosphorylates p53 at Ser6, which leads to the ph-S6-p53 interacting with and delivering the poly(adenosine diphosphate ribose) polymerase 1 (PARP1)/Ku70 complexes on the oncogenes containing ALCDs. The ph-S6-p53-PARP1 complexes open chromatin around ALCDs and activate multiple oncogenic pathways. We found that the inhibition of PARP1 in patient-derived xenografts (PDXs) from aggressive HBL by the Food and Drug Administration (FDA)-approved inhibitor olaparib (Ola) significantly inhibits tumor growth. Additionally, this is associated with the reduction of the ph-S6-p53/PARP1 complexes and subsequent inhibition of ALCD-dependent oncogenes. Studies in cultured cancer cells confirmed that the Ola-mediated inhibition of the ph-S6-p53-PARP1-ALCD axis inhibits proliferation of cancer cells.
In this study, we showed that aggressive HBL is moderated by ALCDs, which are activated by the ph-S6-p53/PARP1 pathway. By using the PARP1 inhibitor Ola, we suppressed tumor growth in HBL-PDX models, which demonstrated its utility in future clinical models.
肝母细胞瘤（HBL）是一种毁灭性的小儿肝癌，有多种治疗选择，但最终需要手术治愈。HBL 最恶性的形式是一种化疗耐药的侵袭性肿瘤，其特征是生长迅速、转移和对治疗反应不佳。目前对侵袭性 HBL 的发病机制知之甚少，最近的研究重点是开发替代治疗策略。在这项研究中，我们研究了人类染色体区域（称为侵袭性肝癌域，ALCDs）在肝癌中的作用，并评估了激活侵袭性 HBL 中 ALCDs 的机制。
我们发现，ALCDs 是人类基因组的关键区域，位于所有人类染色体上，优先位于癌基因和其他癌症相关基因的内含子区域。在侵袭性 HBL 和肝细胞癌（HCC）患者中，JNK1/2 在丝氨酸 6 位磷酸化 p53，导致 ph-S6-p53 与含有 ALCD 的癌基因上的聚（腺苷二磷酸核糖）聚合酶 1（PARP1）/Ku70 复合物相互作用，并将其传递。ph-S6-p53-PARP1 复合物在 ALCD 周围打开染色质，并激活多种致癌途径。我们发现，在侵袭性 HBL 患者来源的异种移植（PDX）中，FDA 批准的抑制剂奥拉帕尼（Ola）抑制 PARP1，可显著抑制肿瘤生长。此外，这与 ph-S6-p53/PARP1 复合物的减少和随后的 ALCD 依赖性癌基因抑制有关。在培养的癌细胞中的研究证实，Ola 介导的 ph-S6-p53-PARP1-ALCD 轴抑制癌细胞的增殖。
在这项研究中，我们表明，ALCDs 介导侵袭性 HBL，其被 ph-S6-p53/PARP1 途径激活。我们使用 PARP1 抑制剂 Ola 抑制 HBL-PDX 模型中的肿瘤生长，这证明了其在未来临床模型中的应用。
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