A comparative integrated multi-omics analysis identifies CA2 as a novel target for chordoma
A comparative integrated multi-omics analysis identifies CA2 as a novel target for chordoma
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比较综合多组学分析将 CA2 确定为脊索瘤的新靶标
DOI：
10.1093/neuonc/noab156
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发表时间：
2021
期刊：
影响因子：
15.9
通讯作者：
Song Dianwen
中科院分区：
文献类型：
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作者：
Meng Tong;Huang Runzhi;Jin Jiali;Gao Jianxuan;Liu Fuyan;Wei Ziheng;Xu Xiaowen;Chang Zhengyan;Lin Jun;Ta Na;Huang Zongqiang;Yin Huabin;Zhou Wang;Song Dianwen
背景脉络膜炎是一种罕见的间叶性恶性肿瘤，复发率高，致瘤机制尚不清楚。遗传改变、表观遗传调节因子和染色质空间组织在脉络膜炎的发生和发展中起着至关重要的作用。在目前的研究中，我们的目标是通过使用集成的多组学analysis.MethodsThe RNA测序（RNA-seq），高通量测序（ATAC-seq），和Hi-C之间进行脉络膜和人类髓核（HNP），沿着与影像学检查和临床信息的可转座可访问的染色质进行。通过临床样本验证了所确定的目标的表达，并通过基因敲除和inhibitors.ResultsThe整合的多组学分析揭示了骨微环境在脉络膜肿瘤发生中的重要作用，通过细胞和动物实验进一步评估其功能。通过比较层次结构，CA 2（碳酸酐酶II）和THNSL 2（苏氨酸脱氢酶样2）被确定在转换的隔室，细胞特异性的边界，和环。此外，CA 2在脉络膜中高度表达，而在HNP中几乎没有发现。通过基因缺失或盐酸多佐胺药物处理抑制CA 2，可显著抑制脉络膜细胞的细胞生长和迁移。此外，盐酸多佐胺还通过阻断骨髓单核细胞的破骨细胞分化来调节骨微环境。结论本研究揭示了骨微环境在脊索瘤肿瘤发生中的作用，并确定CA 2为脊索瘤的新治疗靶点。此外，我们的研究结果表明盐酸多佐胺是一种有前途的治疗选择。
BackgroundChordoma is a rare mesenchymal malignancy, with a high recurrence rate and unclear tumorigenic mechanism. Genetic alterations, epigenetic regulators, and chromatin spatial organization play crucial roles in the initiation and progression of chordoma. In the current study, we aim to uncover the novel therapeutical targets for chordoma via using integrated multi-omics analysis.MethodsThe RNA-sequencing (RNA-seq), assay for transposable accessible chromatin by high-throughput sequencing (ATAC-seq), and Hi-C were performed between chordoma and human nucleus pulposus (HNP), along with imageological examination and clinical information. The expressions of identified targets were validated by clinical samples and their functions were further evaluated by cell and animal experiments via gene knockdown and inhibitors.ResultsThe integrated multi-omics analysis revealed the important roles of bone microenvironment in chordoma tumorigenesis. By comparing the hierarchical structures, CA2 (carbonic anhydrase II) and THNSL2 (threonine synthase-like 2) were identified in the switched compartments, cell-specific boundaries, and loops. Additionally, CA2 was highly expressed in chordoma but barely found in HNP. The cell growth and migration of chordoma cells were dramatically suppressed via inhibition of CA2 either with genetic deletion or pharmaceutical treatment with Dorzolamide HCl. Furthermore, Dorzolamide HCl also regulated the bone microenvironment by blocking the osteoclast differentiation of bone marrow monocytes.ConclusionThis study uncovers the roles of bone microenvironment in the chordoma tumorigenesis and identifies CA2 as a novel therapeutic target for chordoma. Besides, our findings suggest Dorzolamide HCl as a promising therapeutic option for chordoma.