Jian Jiao, Zhong Nanzhe, Jiang Dongjie, Li Lei, Lou Yan, Zhou Wang, Chen Su, Xiao Jianru
Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical UniversityShanghai, China.
Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityChina.
Am J Transl Res. 2018 Mar 15;10(3):936-947. eCollection 2018.
Being a rare malignant bone tumor on the axial skeleton, chordoma is locally invasive and has a high rate of recurrence. Despite extensive studies, the mechanisms of chordoma recurrence after surgical intervention, as well as resistance to radiation and chemotherapy, remain elusive. In this study, primary chordoma cell lines PCH1 and PCH2 were established and characterized by chordoma specific markers. We found that the embryonic transcription factor Brachyury inhibits Paclitaxel induced apoptosis in different cells, including PCH1 and U2OS cells. T gene regulated genes were identified in PCH1 and U2OS using microarray. After comparing gene regulated by Brachyury in different cells and the chromatin immunoprecipitation assay, we identified carbonic anhydrase IX (CA9) as a common target gene of Brachyury. Besides, immunohistochemical staining of CA9 and Brachyury in chordoma tissues revealed that their expression levels were positively correlated. We further showed that CA9 is responsible for Paclitaxel resistance in PCH1 cell. Our data suggest that CA9 plays a role in Brachyury mediated Paclitaxel resistance and serves as a potential target for chordoma treatment.
脊索瘤是一种罕见的发生于中轴骨骼的恶性骨肿瘤，具有局部侵袭性且复发率高。尽管进行了广泛研究，但手术干预后脊索瘤复发以及对放疗和化疗耐药的机制仍不清楚。在本研究中，建立了原发性脊索瘤细胞系PCH1和PCH2，并通过脊索瘤特异性标志物进行了鉴定。我们发现胚胎转录因子Brachyury抑制紫杉醇诱导的包括PCH1和U2OS细胞在内的不同细胞凋亡。使用微阵列在PCH1和U2OS中鉴定了T基因调控的基因。在比较不同细胞中受Brachyury调控的基因并进行染色质免疫沉淀分析后，我们确定碳酸酐酶IX（CA9）是Brachyury的一个共同靶基因。此外，脊索瘤组织中CA9和Brachyury的免疫组化染色显示它们的表达水平呈正相关。我们进一步表明CA9导致PCH1细胞对紫杉醇耐药。我们的数据表明CA9在Brachyury介导的紫杉醇耐药中起作用，并作为脊索瘤治疗的潜在靶点。
