弥漫性大 B 细胞淋巴瘤中 chromobox 家族的综合生物信息学研究和实验验证。

An integrative bioinformatics investigation and experimental validation of chromobox family in diffuse large B-cell lymphoma.

机构信息

Institute of Hematology, Jinan University, HuangPu Da Dao Xi, Guangzhou, Guangdong, 510632, People's Republic of China.

Departpent of Vascular Surgery, The Second Xiangya Hospital, Central South University, Hunan Province, No. 139, Renmin Road, Changsha, China.

出版信息

BMC Cancer. 2023 Jul 10;23(1):641. doi: 10.1186/s12885-023-11108-6.

DOI:10.1186/s12885-023-11108-6

PMID:37430195

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10331996/

Abstract

BACKGROUND

Diffuse large B-cell lymphoma (DLBCL) is one of the most aggressive malignant tumors. Chromobox (CBX) family plays the role of oncogenes in various malignancies.

METHODS

The transcriptional and protein levels of CBX family were confirmed by GEPIA, Oncomine, CCLE, and HPA database. Screening of co-expressed genes and gene function enrichment analysis were performed by GeneMANIA and DAVID 6.8. The prognostic value, immune cell infiltration and drug sensitivity analysis of CBX family in DLBCL were performed by Genomicscape, TIMER2.0, and GSCALite database. Confirmatory Tests of CBX family protein expression in DLBCL were performed by immunohistochemistry.

RESULTS

The mRNA and protein expressions of CBX1/2/3/5/6 were higher in DLBCL tissues than control groups. Enrichment analysis showed that the functions of CBX family were mainly related to chromatin remodeling, methylation-dependent protein binding, and VEGF signaling pathway. The high mRNA expressions of CBX2/3/5/6 were identified to be associated with short overall survival (OS) in DLBCL patients. Multivariate COX regression indicated that CBX3 was independent prognostic marker. Immune infiltration analysis revealed that the mRNA expressions of CBX family (especially CBX1, CBX5, and CBX6) in DLBCL were significantly correlated with the infiltration of most immune cells (including B cells, CD8 + T cells, CD4 + T cells, neutrophils, monocytes, macrophages, and Treg cells). Meanwhile, there was a strong correlation between the expression levels of CBX1/5/6 and surface markers of immune cells, such as the widely studied PVR-like protein receptor/ligand and PDL-1 immune checkpoint. Notably, our study found that DLBCL cells with CBX1 over-expression were resistant to the common anti-tumor drugs, but CBX2/5 had two polarities. Finally, we confirmed the higher expressions of CBX1/2/3/5/6 in DLBCL tissues compared with control groups by immunohistochemistry.

CONCLUSION

We provided a detailed analysis of the relationship between the CBX family and the prognosis of DLBCL. Distinguished from other studies, We found that high mRNA expressions of CBX2/3/5/6 were associated with poor prognosis in DLBCL patients, and Multivariate COX regression indicated that CBX3 was independent prognostic marker. Besides, our study also found an association between the CBX family and anti-tumour drug resistance, and provided a relationship between CBX family expression and immune cell infiltration.

摘要

背景

弥漫性大 B 细胞淋巴瘤（DLBCL）是最具侵袭性的恶性肿瘤之一。染色质盒（CBX）家族在各种恶性肿瘤中发挥癌基因的作用。

方法

通过 GEPIA、Oncomine、CCLE 和 HPA 数据库证实 CBX 家族的转录和蛋白水平。通过 GeneMANIA 和 DAVID 6.8 进行共表达基因筛选和基因功能富集分析。通过 Genomicscape、TIMER2.0 和 GSCALite 数据库进行 CBX 家族在 DLBCL 中的预后价值、免疫细胞浸润和药物敏感性分析。通过免疫组织化学验证 CBX 家族蛋白在 DLBCL 中的表达。

结果

与对照组相比，DLBCL 组织中 CBX1/2/3/5/6 的 mRNA 和蛋白表达水平更高。富集分析表明，CBX 家族的功能主要与染色质重塑、甲基化依赖性蛋白结合和 VEGF 信号通路有关。CBX2/3/5/6 的高 mRNA 表达与 DLBCL 患者的总生存期（OS）较短有关。多变量 COX 回归表明 CBX3 是独立的预后标志物。免疫浸润分析表明，CBX 家族的 mRNA 表达（特别是 CBX1、CBX5 和 CBX6）与大多数免疫细胞（包括 B 细胞、CD8+T 细胞、CD4+T 细胞、中性粒细胞、单核细胞、巨噬细胞和 Treg 细胞）的浸润呈显著相关。同时，CBX1/5/6 的表达水平与免疫细胞的表面标志物之间存在很强的相关性，如广泛研究的 PVR 样蛋白受体/配体和 PD-L1 免疫检查点。值得注意的是，我们的研究发现，过表达 CBX1 的 DLBCL 细胞对常见的抗肿瘤药物有耐药性，但 CBX2/5 有两种极性。最后，我们通过免疫组织化学证实了 CBX1/2/3/5/6 在 DLBCL 组织中的表达高于对照组。

结论

我们对 CBX 家族与 DLBCL 预后之间的关系进行了详细分析。与其他研究不同的是，我们发现 CBX2/3/5/6 的高 mRNA 表达与 DLBCL 患者的不良预后相关，多变量 COX 回归表明 CBX3 是独立的预后标志物。此外，我们的研究还发现 CBX 家族与抗肿瘤药物耐药性之间存在关联，并提供了 CBX 家族表达与免疫细胞浸润之间的关系。