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ISL2 modulates angiogenesis through transcriptional regulation of ANGPT2 to promote cell proliferation and malignant transformation in oligodendroglioma

Oncogene volume 39, pages 5964–5978 (2020)Cite this article

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Abstract

Oligodendroglioma is an important type of lower-grade glioma (LGG), which is a slowly progressing brain tumor. Many LGGs eventually transform into a more aggressive or malignant type. Enhanced angiogenesis is a characteristic of malignantly transformed oligodendroglioma (m-oligodendroglioma). However, the pathogenesis and signaling pathways associated with angiogenesis and proliferation in m-oligodendroglioma are not well understood. In this study, we identified that Insulin Gene Enhancer Protein (ISL2) and its angiogenic capacity were inversely related to survival according to LGG patient data from an online database, and this was further confirmed with pathological LGG patient samples, including malignantly transformed samples, by detecting the expression of ISL2, the angiogenic markers vascular endothelial growth factor (VEGFA) and CD31 and the proliferation marker Ki-67. We then established novel oligodendroglioma patient tumor-derived orthotopic xenograft mouse models and cell lines to verify the role of ISL2 in regulating angiogenesis to promote oligodendroglioma growth and malignant transformation. Furthermore, ISL2 regulated ANGPT2 transcription by binding to the ANGPT2 promoter. Then, ANGPT2, a downstream gene, activated angiogenesis through VEGFA to promote oligodendroglioma malignant transformation. Finally, combining AAV-ISL2-shRNA with temozolomide suppressed oligodendroglioma progression more effectively than either monotherapy in vivo and in vitro. Thus, hypoxia-induced ISL2 regulated ANGPT2, which subsequently induced angiogenesis to promote oligodendroglioma growth and malignant transformation. Malignancy was accompanied by worsened hypoxia inside the tumor mass, creating a positive feedback loop. In conclusion, this study suggests that ISL2 is a biomarker for oligodendroglioma progression and that anti-ISL2 therapy may offer a potential clinical strategy for treating m-oligodendroglioma.

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Fig. 1: ISL2 and angiogenesis are associated with overall survival and malignant transformation in LGG patients.
Fig. 2: Establishment of oligodendroglioma PDOX models in vivo and oligodendroglioma cell lines derived from a xenograft model in vitro.
Fig. 3: ISL2 is associated with cell proliferation and the malignant transformation of oligodendroglioma in vitro and in vivo.
Fig. 4: ISL2 affects angiogenesis via ANGPT2 in oligodendroglioma in vitro and in vivo.
Fig. 5: ISL2 binds to the ANGPT2 promoter.
Fig. 6: Effects of treatments combining inhibition of ISL2 in the angiogenesis pathway with TMZ administration on oligodendroglioma in vitro and in vivo.

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Acknowledgements

This work was supported in part by the National Natural Science Foundation of China (grant nos. 81970191, 31971161, 31971224, and 81301978), the Guangdong Natural Science Foundation of China (grant nos. 2018A0303130090 and 2019A1515011332), the Youth Medical Doctors Project of Jiangsu Province of China (QNRC2016870), and the Fundamental Research Funds for the Central Universities of China (grant no. 19ykpy149).

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Authors and Affiliations

  1. Department of Pharmacology, Molecular Cancer Research Center, School of Medicine, Sun Yat-sen University, Shenzhen, China

    Lin Qi, Xin-Rong Shao, Miao Li, Shu-Na Chen, Xue-Qi Liu, Xu-Dong Zhang, Xin Li, Wenxue Zhao, Ji-An Pan, Bo Zhao & Xing-Ding Zhang

  2. Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Lin Qi

  3. Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China

    Zhong-Yong Wang

  4. Institute of Parasitology, Department of Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria

    Shi Yan

  5. Department of Interventional Radiology, Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Bo Zhang

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Qi, L., Wang, ZY., Shao, XR. et al. ISL2 modulates angiogenesis through transcriptional regulation of ANGPT2 to promote cell proliferation and malignant transformation in oligodendroglioma. Oncogene 39, 5964–5978 (2020). https://doi.org/10.1038/s41388-020-01411-y

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