SSTR2 is a prognostic factor and a promising therapeutic target in glioma

Abstract

Gliomas are the most prevalent primary malignant central nervous system tumors among all tumors occurring in the brain and spinal cord. The poor outcome of glioma requires the discovery of novel biomarkers with potential therapeutic value. Somatostatin receptor subtype 2 (SSTR2) represents a diagnostic biomarker and potential therapeutic target in many cancers, such as meningioma and neuroendocrine tumors (NETs). However, the relationship of SSTR2 and glioma was unclear. Therefore, this study aimed to investigate the expression of SSTR2 and assess its prognostic and potential therapeutic value in a large cohort of patients with WHO grade I to IV glioma from a single Chinese center. Immunohistochemical analysis revealed that SSTR2 was highly expressed in 23.84% (72 of 302) of glioma (I-IV grade) samples. Among all glioma subtypes, high SSTR2 expression was detected mainly in oligodendroglioma, anaplastic oligodendroglioma, and astrocytoma, whereas SSTR2 was expressed at a low level, or not at all, in glioblastoma. Western blotting also confirmed the low expression of SSTR2 in glioblastoma cell lines. Statistical analysis showed that SSTR2 protein expression correlated significantly with WHO grade, the location of the tumor, epilepsy syndrome, mitosis (PHH3), proliferation index (Ki-67), IDH and 1p/19q-codeleted status. Kaplan-Meier analysis indicated that SSTR2 high expression was a good prognostic factor in glioma. In summary, this study demonstrated that SSTR2 might be a valuable prognostic factor and therapeutic target in certain glioma subtypes.

Keywords: IDH; SSTR2; glioma; immunohistochemistry.

Figure 1

The protein expression of SSTR2 in paraffin-embedded glioma tissues. A and B. Strong staining of SSTR2 in oligodendroglioma; C and D. No staining in GBM.

Figure 2

SSTR2 protein expression in human astrocyte (HA) and seven GBM cell lines, including SF767, LN229, A172, U87, U251, DBTRG and T98G. Protein levels were evaluated by western blotting. In general, SSTR2 protein expression in glioblastoma cell lines was lower than that in HA (astrocyte cell line). However, SSTR2 protein expression varies between different glioblastoma cell lines. Among the above glioblastoma cell lines, SSTR2 protein expression was relatively higher in U251 and U87 cell lines than the others, while it can hardly be detected in T98G, DBTRG and SF767 cell lines.

Figure 3

The expression pattern of SSTR2 in different histological subtypes of glioma. An ANOVA test revealed the statistical significance of the SSTR2 expression differences between oligodendroglioma and glioblastoma, anaplastic oligodendroglioma and glioblastoma, and diffuse astrocytoma and glioblastoma. A-C. Our data; D-F. CGGA RNAseq; G-I. TCGA RNAseq; GBM: glioblastoma multiforme; AO: anaplastic oligodendroglioma; O: oligodendroglioma; A: astrocytoma.

Figure 4

T test for SSTR2 expression and molecular alterations. Significantly higher expression of SSTR2 was observed in glioma tissue with IDH mutations (A), a Ki-67 label index < 10% (B), PHH3 < 5/10 HPF (C), and 1p/19q codeleted (D).

Figure 5

Kaplan-Meier curves for univariate analysis. High SSTR2 expression correlated with better prognosis in both of grade II to IV glioma (A, our data, P < 0.001; C, CGGA RNAseq, P < 0.001; E, TCGA RNAseq, P < 0.001; log-rank test) and grade III to IV glioma (B, our data, P = 0.042; D, CGGA RNAseq, P < 0.001; F, TCGA RNAseq, P < 0.001; log-rank test).

Figure 6

Bioinformatic analysis of the SSTR2-related differentially expressed genes (DEGs) in gliomas. A. Venn diagram showing the DEGs, including 485 in the TCGA, 429 in the CGGA ,and 272 belonging to both the TCGA and the CGGA. B. Protein-protein interaction (PPI) network of SSTR2-directly related genes. C. GO pathway enrichment analysis of DEGs. D. KEGG pathway enrichment analysis of DEGs.

Figure 7

Survival analysis of DEGs in grade II-IV glioma in the TCGA dataset. Survival analysis of DEGs in the TCGA dataset revealed that the SST (A), SSTR1 (B), SHANK2 (C), HTR5A (D), HTR1A (E), HRH3 (F), GLP1R (G), GABBR2 (H), CHGA (J), and CCK (K) genes are good prognostic markers for glioma. While the high expression of CXCL10 (I) and ANXA1 (L) are correlated with poor outcome.