Inhibition of hyaluronic acid degradation pathway suppresses glioma progression by inducing apoptosis and cell cycle arrest

Tao Yan; He Yang; Caixia Xu; Junsi Liu; Yun Meng; Qing Jiang; Jinxing Li; Guiqiong Kang; Liangjian Zhou; Shuai Xiao; Yanpeng Xue; Jiayi Xu; Xin Chen; Fengyuan Che

doi:10.1186/s12935-023-02998-4

Inhibition of hyaluronic acid degradation pathway suppresses glioma progression by inducing apoptosis and cell cycle arrest

Cancer Cell Int. 2023 Aug 11;23(1):163. doi: 10.1186/s12935-023-02998-4.

Authors

Tao Yan^#^{1

2}, He Yang^#^{3

4

5}, Caixia Xu^#^{3

4

5}, Junsi Liu^#^{3

4

5}, Yun Meng^{1

2}, Qing Jiang^{3

4

5}, Jinxing Li⁶, Guiqiong Kang^{1

2}, Liangjian Zhou⁷, Shuai Xiao⁷, Yanpeng Xue^{3

4

5}, Jiayi Xu^{3

4

5}, Xin Chen^{8

9

10}, Fengyuan Che^{11

12

13}

Affiliations

¹ Central Laboratory, Linyi People's Hospital, Guangzhou University of Chinese Medicine, Linyi, 276000, Shandong Province, China.
² Linyi Key Laboratory of Neurophysiology, Linyi People's Hospital, Linyi, 276000, Shandong Province, China.
³ Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China.
⁴ Key Colleges and Universities Laboratory of Neurosurgery in Heilongjiang Province, Harbin, 150001, Heilongjiang Province, China.
⁵ Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, 150001, Heilongjiang Province, China.
⁶ Department of Neurosurgery, Linyi People's Hospital, Linyi, 276000, Shandong Province, China.
⁷ Scientific Research Management Office, Linyi People's Hospital, Linyi, 276000, Shandong Province, China.
⁸ Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China. chenxin_tracy@hrbmu.edu.cn.
⁹ Key Colleges and Universities Laboratory of Neurosurgery in Heilongjiang Province, Harbin, 150001, Heilongjiang Province, China. chenxin_tracy@hrbmu.edu.cn.
¹⁰ Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, 150001, Heilongjiang Province, China. chenxin_tracy@hrbmu.edu.cn.
¹¹ Central Laboratory, Linyi People's Hospital, Guangzhou University of Chinese Medicine, Linyi, 276000, Shandong Province, China. che1971@126.com.
¹² Linyi Key Laboratory of Neurophysiology, Linyi People's Hospital, Linyi, 276000, Shandong Province, China. che1971@126.com.
¹³ Department of Neurology, Linyi People's Hospital, Linyi, 276000, Shandong Province, China. che1971@126.com.

^# Contributed equally.

Abstract

Background: Abnormal hyaluronic acid (HA) metabolism is a major factor in tumor progression, and the metabolic regulation of HA mainly includes HA biosynthesis and catabolism. In glioma, abnormal HA biosynthesis is intimately involved in glioma malignant biological properties and the formation of immunosuppressive microenvironment; however, the role of abnormal HA catabolism in glioma remains unclear.

Methods: HA catabolism is dependent on hyaluronidase. In TCGA and GEPIA databases, we found that among the 6 human hyaluronidases (HYAL1, HYAL2, HYAL3, HYAL4, HYALP1, SPAM1), only HYAL2 expression was highest in glioma. Next, TCGA and CGGA database were further used to explore the correlation of HYAL2 expression with glioma prognosis. Then, the mRNA expression and protein level of HYAL2 was determined by qRT-PCR, Western blot and Immunohistochemical staining in glioma cells and glioma tissues, respectively. The MTT, EdU and Colony formation assay were used to measure the effect of HYAL2 knockdown on glioma. The GSEA enrichment analysis was performed to explore the potential pathway regulated by HYAL2 in glioma, in addition, the HYAL2-regulated signaling pathways were detected by flow cytometry and Western blot. Finally, small molecule compounds targeting HYAL2 in glioma were screened by Cmap analysis.

Results: In the present study, we confirmed that Hyaluronidase 2 (HYAL2) is abnormally overexpressed in glioma. Moreover, we found that HYAL2 overexpression is associated with multiple glioma clinical traits and acts as a key indicator for glioma prognosis. Targeting HYAL2 could inhibit glioma progression by inducing glioma cell apoptosis and cell cycle arrest.

Conclusion: Collectively, these observations suggest that HYAL2 overexpression could promote glioma progression. Thus, treatments that disrupt HA catabolism by altering HYAL2 expression may serve as effective strategies for glioma treatment.

Keywords: Apoptosis; Cell cycle; Glioma; HYAL2; Hyaluronic acid.

Abstract

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