Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Dis Markers. 2022 Feb 14;2022:7729968. doi: 10.1155/2022/7729968. eCollection 2022.
Chondrosarcoma is a group of primary bone cancers that arise from transformed cells of chondrocytic lineage. Tumor recurrence and metastasis are devastating for patients with chondrosarcoma since there are no effective treatment options. IDH mutations occur in over 50% of tumors from patients with conventional or dedifferentiated chondrosarcomas and represent an attractive target for therapy. However, their role in the pathogenesis of chondrosarcoma remains largely unknown. In this study, we sought to determine the association of IDH mutation and HIF-1 in chondrosarcoma. We used the chondrosarcoma JJ012 cell line and its derived CRISPR/Cas9 mutant IDH1 (IDH1) knockout (KO) cells. RNA-Seq data analysis revealed downregulation of several HIF-1 target genes upon loss of IDH1. This was associated with reduced HIF-1 levels in the IDH1 KO cells and tumors. Loss of IDH1 also attenuated the expression of angiogenic markers in tumor tissues and abrogated the angiogenic capacity of JJ012 cells. Moreover, we observed that exogenous expression of HIF-1 significantly promoted anchorage-independent colony-formation by IDH1 KO cells. These results suggest IDH1 mutation confers angiogenic and tumorigenic properties of JJ012 cells by inducing HIF-1. Thus, the HIF pathway represents a promising candidate for combinatorial regimens to target IDH1 mutated chondrosarcomas.
软骨肉瘤是一组源自软骨细胞系转化细胞的原发性骨癌。肿瘤复发和转移对软骨肉瘤患者来说是毁灭性的，因为目前没有有效的治疗选择。IDH 突变发生在超过 50%的传统或去分化软骨肉瘤患者的肿瘤中，代表了治疗的一个有吸引力的靶点。然而，它们在软骨肉瘤发病机制中的作用在很大程度上仍然未知。在这项研究中，我们试图确定 IDH 突变与软骨肉瘤中的 HIF-1 的关联。我们使用了软骨肉瘤 JJ012 细胞系及其衍生的 CRISPR/Cas9 突变 IDH1（IDH1）敲除（KO）细胞。RNA-Seq 数据分析显示，IDH1 缺失时，几个 HIF-1 靶基因的表达下调。这与 IDH1 KO 细胞和肿瘤中 HIF-1 水平降低有关。IDH1 的缺失还减弱了肿瘤组织中血管生成标记物的表达，并取消了 JJ012 细胞的血管生成能力。此外，我们观察到外源性表达 HIF-1 显著促进了 IDH1 KO 细胞的非锚定依赖性集落形成。这些结果表明，IDH1 突变通过诱导 HIF-1 赋予 JJ012 细胞血管生成和肿瘤形成特性。因此，HIF 通路代表了针对 IDH1 突变型软骨肉瘤的联合治疗方案的有前途的候选方案。
