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RSF1 requires CEBP/β and hSNF2H to promote IL-1β-mediated angiogenesis: the clinical and therapeutic relevance of RSF1 overexpression and amplification in myxofibrosarcomas

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Abstract

Myxofibrosarcoma is genetically complex and lacks effective nonsurgical treatment strategies; thus, elucidation of novel molecular drivers is urgently needed. Reanalyzing public myxofibrosarcoma datasets, we identified mRNA upregulation and recurrent gain of RSF1 and characterized this chromatin remodeling gene. Myxofibrosarcoma cell lines were employed to elucidate the oncogenic mechanisms of RSF1 by genetic manipulation and two IL-1β-neutralizing antibodies (RD24, P2D7KK), highlighting the regulatory basis and targetability of downstream IL-1β-mediated angiogenesis. Tumor samples were assessed for RSF1, IL-1β, and microvascular density (MVD) by immunohistochemistry and for RSF1 gene status by FISH. In vivo, RSF1-silenced and P2D7KK-treated xenografts were analyzed for tumor-promoting effects and the IL-1β-linked therapeutic relevance of RSF1, respectively. In vitro, RSF1 overexpression promoted invasive and angiogenic phenotypes with a stronger proangiogenic effect. RT-PCR profiling identified IL1B as a top-ranking candidate upregulated by RSF1. RSF1 required hSNF2H and CEBP/β to cotransactivate the IL1B promoter, which increased the IL1B mRNA level, IL-1β secretion and angiogenic capacity. Angiogenesis induced by RSF1-upregulated IL-1β was counteracted by IL1B knockdown and both IL-1β-neutralizing antibodies. Clinically, RSF1 overexpression was highly associated with RSF1 amplification, IL-1β overexpression, increased MVD and higher grades (all P ≤ 0.01) and independently predicted shorter disease-specific survival (P = 0.019, hazard ratio: 4.556). In vivo, both RSF1 knockdown and anti-IL-1β P2D7KK (200 μg twice weekly) enabled significant growth inhibition and devascularization in xenografts. In conclusion, RSF1 overexpression, partly attributable to RSF1 amplification, contributes a novel proangiogenic function by partnering with CEBP/β to cotransactivate IL1B, highlighting its prognostic, pathogenetic, and therapeutic relevance in myxofibrosarcomas.

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Acknowledgements

The authors thank Kaohsiung Chang Gung genomic (CLRPG8G0593) and tissue bank (CLRPG810032) core laboratories for technical assistance. The authors also thank Bioresource Collection and Research Center, Food Industry Research and Development Institute for the authentication of myxofibrosarcoma cell lines.

Funding

This work was sponsored by Taiwan National Ministry of Science and Technology (108-2320-B-182A-017-MY3 to HY Huang), Chang Gung Hospital (CMRPG8G0881, CMRPG8G0882 to HY Huang) and Ministry of Health and Welfare (MOHW104-TDU-M-212-133004 and 101-2320-B-384-001-MY3 to CF Li).

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Authors and Affiliations

  1. Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan

    Chien-Feng Li & Ti-Chen Chan

  2. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan

    Chien-Feng Li & Ti-Chen Chan

  3. Institute of Precision Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan

    Chien-Feng Li

  4. Singapore Immunology Network; Agency for Science, Technology and Research (A*STAR), Singapore, Singapore

    Cheng-I. Wang

  5. Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Fu-Min Fang

  6. Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Po-Chun Lin

  7. Department of Anatomic Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123, Ta-Pei Rd., Niao-Sung District, Kaohsiung, Taiwan

    Shih-Chen Yu & Hsuan-Ying Huang

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  1. Chien-Feng Li
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Contributions

Conception and design: CFL, HYH. Development of methodology: CFL, TCC, CIW, HYH. Acquisition, interpretation and analysis of the data: CFL, TCC, CIW, FMF, PCL, SCY, HYH. Writing, review, and/or revision of the manuscript: CFL, CIW, HYH. Study supervision: CFL, HYH. All authors had final approval of the submitted manuscript.

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Correspondence to Hsuan-Ying Huang.

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H.Y. Huang reports receiving other research support from Bayer. No conflicts of interest are declared by other authors.

Ethical approval

The Chang Gung institutional review board approved the use of formalin-fixed tumor tissues under anonymous processing with a waiver of informed consent for this study (201701067B0).

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Li, CF., Chan, TC., Wang, CI. et al. RSF1 requires CEBP/β and hSNF2H to promote IL-1β-mediated angiogenesis: the clinical and therapeutic relevance of RSF1 overexpression and amplification in myxofibrosarcomas. Angiogenesis 24, 533–548 (2021). https://doi.org/10.1007/s10456-020-09764-4

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