A system-level approach identifies HIF-2α as a critical regulator of chondrosarcoma progression
| Autor: | Hyun Guy Kang, Yi Jun Kim, Kyoung Min Lee, Yongsik Cho, Jin-Hong Kim, Moon Jong Chang, Chong Bum Chang, Donghyeon Cheon, Hyeon Seop Kim, Hyeonkyeong Kim, Donghyun Kang, Seung Baik Kang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine animal structures Science Chondrosarcoma Regulator Mice Nude General Physics and Astronomy Bone Neoplasms Malignancy Article General Biochemistry Genetics and Molecular Biology Metastasis 03 medical and health sciences Targeted therapies 0302 clinical medicine Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Basic Helix-Loop-Helix Transcription Factors medicine Animals Humans Gene Regulatory Networks lcsh:Science Regulation of gene expression Multidisciplinary business.industry EPAS1 Gene Cancer Sarcoma General Chemistry musculoskeletal system medicine.disease Xenograft Model Antitumor Assays Isocitrate Dehydrogenase Gene Expression Regulation Neoplastic 030104 developmental biology Tumor progression 030220 oncology & carcinogenesis embryonic structures Cancer research Benzimidazoles Female lcsh:Q Cisplatin business |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Chondrosarcomas, malignant cartilaginous neoplasms, are capable of transitioning to highly aggressive, metastatic, and treatment-refractory states, resulting in significant patient mortality. Here, we aim to uncover the transcriptional program directing such tumor progression in chondrosarcomas. We conduct weighted correlation network analysis to extract a characteristic gene module underlying chondrosarcoma malignancy. Hypoxia-inducible factor-2α (HIF-2α, encoded by EPAS1) is identified as an upstream regulator that governs the malignancy gene module. HIF-2α is upregulated in high-grade chondrosarcoma biopsies and EPAS1 gene amplification is associated with poor prognosis in chondrosarcoma patients. Using tumor xenograft mouse models, we demonstrate that HIF-2α confers chondrosarcomas the capacities required for tumor growth, local invasion, and metastasis. Meanwhile, pharmacological inhibition of HIF-2α, in conjunction with the chemotherapy agents, synergistically enhances chondrosarcoma cell apoptosis and abolishes malignant signatures of chondrosarcoma in mice. We expect that our insights into the pathogenesis of chondrosarcoma will provide guidelines for the development of molecular targeted therapeutics for chondrosarcoma. Chondrosarcomas are frequently aggressive, understanding the transcriptional changes associated with progression may help in developing new treatments. Here, the authors show that HIF-2α is increased in expression on progression and pharmacological inhibition of the protein together with chemotherapy is a useful strategy for controlling tumour growth in mice. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|