Targeting copper death genotyping associated gene RARRES2 suppresses glioblastoma progression and macrophages infiltration

Tao Yan; He Yang; Yun Meng; Huadong Li; Qing Jiang; Junsi Liu; Caixia Xu; Yanpeng Xue; Jiayi Xu; Yan Song; Xiaojie Chu; Lijuan Wang; Xin Chen; Fengyuan Che

doi:10.1186/s12935-023-02950-6

Targeting copper death genotyping associated gene RARRES2 suppresses glioblastoma progression and macrophages infiltration

Cancer Cell Int. 2023 May 29;23(1):105. doi: 10.1186/s12935-023-02950-6.

Authors

Tao Yan^#^{1

2}, He Yang^#^{3

4

5}, Yun Meng^#^{1

2}, Huadong Li^#⁶, Qing Jiang^{3

4

5}, Junsi Liu^{3

4

5}, Caixia Xu^{3

4

5}, Yanpeng Xue^{3

4

5}, Jiayi Xu^{3

4

5}, Yan Song⁷, Xiaojie Chu⁸, Lijuan Wang^{9

10

11}, Xin Chen^{12

13

14}, Fengyuan Che^{15

16

17}

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 Department of Nuclear Medicine, The Fourth Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China.
⁸ Department of Clinical Pharmacy, Daqing Oilfield General Hospital, Daqing, 163001, Heilongjiang Province, China.
⁹ Central Laboratory, Linyi People's Hospital, Guangzhou University of Chinese Medicine, Linyi, 276000, Shandong Province, China. [email protected].
¹⁰ Linyi Key Laboratory of Neurophysiology, Linyi People's Hospital, Linyi, 276000, Shandong Province, China. [email protected].
¹¹ Department of Hematology, Linyi People's Hospital, Guangzhou University of Chinese Medicine, Linyi, 276000, Shandong Province, China. [email protected].
¹² Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China. [email protected].
¹³ Key Colleges and Universities Laboratory of Neurosurgery in Heilongjiang Province, Harbin, 150001, Heilongjiang Province, China. [email protected].
¹⁴ Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, 150001, Heilongjiang Province, China. [email protected].
¹⁵ Central Laboratory, Linyi People's Hospital, Guangzhou University of Chinese Medicine, Linyi, 276000, Shandong Province, China. [email protected].
¹⁶ Linyi Key Laboratory of Neurophysiology, Linyi People's Hospital, Linyi, 276000, Shandong Province, China. [email protected].
¹⁷ Department of Neurology, Linyi People's Hospital, Guangzhou University of Chinese Medicine, Linyi, 276000, Shandong Province, China. [email protected].

^# Contributed equally.

Abstract

Background: Copper homeostasis is associated with malignant biological behavior in various tumors. The excessive accumulation of copper can induce tumor death, which is named cuproptosis, and it is also closely related to tumor progression and the formation of the immune microenvironment. However, the associations of cuproptosis with glioblastoma (GBM) prognosis and microenvironment construction are poorly understood.

Method: First, TCGA and GEO (GSE83300, GSE74187) merged datasets were used to analyze the association of cuproptosis-related genes (CRGs) with GBM. Then, we performed cluster analysis of CRGs in GBM from the GEO (GSE83300, GSE74187) and TCGA merged datasets. Subsequently, the prognostic risk model was constructed by least absolute shrinkage and selection operator (LASSO) according to gene expression features in CRG clusters. Next, we performed a series of in-depth analyses, including tumor mutational burden (TMB) analysis, cluster analysis, and GBM IDH status prediction. Finally, RARRES2 was identified as a target gene for GBM treatment, especially IDH wild-type GBM. In addition, we further analyzed the correlation of CRG clusters and RARRES2 expression with the GBM immune microenvironment by ESTIMATE and CIBERSORT analyses. In vitro experiments were conducted to demonstrate that targeting RARRES2 inhibits glioblastoma progression and macrophage infiltration, particularly IDH wild-type GBM.

Results: In the present study, we demonstrated that the CRG cluster was closely related to GBM prognosis and immune cell infiltration. Moreover, the prognostic risk model constructed with the three genes (MMP19, G0S2, RARRES2) associated with the CRG clusters could well evaluate the prognosis and immune cell infiltration in GBM. Subsequently, after further analyzing the tumor mutational burden (TMB) in GBM, we confirmed that RARRES2 in the prognostic risk model could be used as a crucial gene signature to predict the prognosis, immune cell infiltration and IDH status of GBM patients.

Conclusion: This study fully revealed the potential clinical impact of CRGs on GBM prognosis and the microenvironment, and determined the effect of the crucial gene (RARRES2) on the prognosis and tumor microenvironment construction of GBM, meanwhile, our study also revealed over-expressed RARRES2 is related to the IDH satus of GBM, which provides a novel strategy for the treatment of GBM, particularly IDH wild-type GBM.

Keywords: Cuproptosis; Glioblastoma; IDH status; Immune cell infiltration; RARRES2.

Abstract

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