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Caspase-3 in glioma indicates an unfavorable prognosis by involving surrounding angiogenesis and tumor cell repopulation

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Abstract

Aim

Effective biomarkers for estimating glioma prognosis are deficient. Canonically, caspase-3 acts as an “apoptosis executioner”. However, its prognostic role in glioma and mechanistic effects on prognosis remain unclear.

Methods

With glioma tissue microarrays, the prognostic roles of cleaved caspase-3 and its association with angiogenesis were explored. Next, by analyzing the mRNA microarray data from the CGGA, the prognostic role of CASP3 expression and correlations between CASP3 and markers of glioma angiogenesis and proliferation were investigated. To biologically interpret the prognostic role of caspase-3 in glioma, the influence of caspase-3 on surrounding angiogenesis and glioma cell repopulation was investigated with an in vitro cell co-culture model, which comprises irradiated U87 cells and un-irradiated firefly luciferase (Fluc)-labeled HUVEC (HUVEC-Fluc) or U87 (U87-Fluc) cells. The over-expressed dominant-negative caspase-3 was used to suppress normal caspase-3 activity.

Results

High levels of cleaved caspase-3 expression were associated with poor survival outcomes in glioma patients. Higher microvessel density was observed in patients with high levels of cleaved caspase-3 expression. By mining the microarray data in CGGA, it was revealed that higher CASP3 expression was found in glioma patients with lower Karnofsky Performance score, higher WHO grade, malignant histological subtype, wild-type IDH. Higher CASP3 expression indicated a worse survival rate in glioma patients. Patients with high CASP3 expression and negative IDH mutation showed the worst survival rate. Positive correlations were found between CASP3 and markers of tumor angiogenesis and proliferation. Subsequent data based on an in vitro cell co-culture model revealed that caspase-3 in irradiated glioma cells mediated pro-angiogenic and repopulation-promoting effects via regulating COX-2 signaling. With glioma tissue microarrays, high levels of COX-2 expression showed inferior survival outcomes in glioma patients. Glioma patients with high levels of cleaved caspase-3 and COX-2 expression showed the worst survival outcomes.

Conclusion

This study innovatively identified an unfavorable prognostic role of caspase-3 in glioma. The pro-angiogenic and repopulation-prompting effects of caspase-3/COX-2 signaling may explain its unfavorable prognostic role and offer novel insights into therapy sensitization and curative effect prediction of glioma.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

The study was funded by the National Natural Science Foundation of China (No. 81803048 to X.F., No. 81972887 to J.C.), the Natural Science Foundation of Shanghai (No. 21ZR1451100 to J.C.), the Shanghai Pujiang Program (No. 2021PJD056 to J.C.), and the Shanghai "Rising Stars of Medical Talents" Youth Development Program (No. SHWRS (2021)_099 to J.C.).

Author information

Author notes

  1. Xiao Feng, Feng Zhu and Lihua Dai contributed equally to this work.

Authors and Affiliations

  1. Cancer Center, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Jinshui District, 7 Weiwu Road, Zhengzhou, Henan, 450003, People’s Republic of China

    Xiao Feng & Shundong Cang

  2. Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, People’s Republic of China

    Feng Zhu & Lihua Dai

  3. School of Life Sciences, Fudan University, Shanghai, 200438, People’s Republic of China

    Feng Zhu

  4. Translational Research Institute, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, Henan, 450003, People’s Republic of China

    Xiaoying Liu

  5. Department of Ultrasound, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, Henan, 450003, People’s Republic of China

    Liyang Shao

  6. Department of Physical Examination and Health Management, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, Henan, 450003, People’s Republic of China

    Liuwei Hao

  7. Molecular Diagnostics Laboratory of Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 650 Xinsongjiang Road, Songjiang District, Shanghai, 201620, People’s Republic of China

    Jin Cheng

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  1. Xiao Feng
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Contributions

J. C. and X. F. conceived this work and designed the experiments; X. F., F. Z., L. D., X. L., L. S., and L. H. conducted the experiments; X. F. and S. C. conducted data analysis and interpretation; X. F. wrote the manuscript and J. C. and S. C. revised it; J. C. and S. C. supervised the whole project.

Corresponding authors

Correspondence to Shundong Cang or Jin Cheng.

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Feng, X., Zhu, F., Dai, L. et al. Caspase-3 in glioma indicates an unfavorable prognosis by involving surrounding angiogenesis and tumor cell repopulation. J Neurooncol 163, 313–325 (2023). https://doi.org/10.1007/s11060-023-04339-x

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