通过多组学泛癌分析鉴定 CREB5 作为胶质瘤的预后和免疫治疗生物标志物。

Identification of CREB5 as a prognostic and immunotherapeutic biomarker in glioma through multi-omics pan-cancer analysis.

机构信息

Department of Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China; Department of Burns and Skin Repair Surgery, The Third Affiliated Hospital of Wenzhou Medical University, Ruian, 325200, Zhejiang, China; The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, Zhejiang, 324000, China.

Department of Burns and Skin Repair Surgery, The Third Affiliated Hospital of Wenzhou Medical University, Ruian, 325200, Zhejiang, China.

出版信息

Comput Biol Med. 2024 May;173:108307. doi: 10.1016/j.compbiomed.2024.108307. Epub 2024 Mar 21.

DOI:10.1016/j.compbiomed.2024.108307

PMID:38547657

Abstract

BACKGROUND

The functional relevance of cyclic adenosine monophosphate (cAMP)-response element-binding protein 5 (CREB5) in cancers remains elusive, despite its significance as a member of the CREB family. The current research aims to explore the role of CREB5 in multiple cancers.

METHODS

Pan-cancer analysis was performed to explore the expression patterns, prognostic value, mutational landscape as well as single-cell omic, immunologic, and drug sensitivity profiles of CREB5. Furthermore, we incorporated five distinct machine learning algorithms and determined that the least absolute shrinkage and selection operator-COX (LASSO-COX) algorithm, which exhibited the highest C index, was the optimal selection. Subsequently, we constructed a prognostic model centered around CREB5-associated genes. To elucidate the biological function of CREB5 in glioma cells, several assays including cell counting kit-8 (CCK-8), wound healing, transwell, flow cytometric were performed.

RESULTS

CREB5 was overexpressed in pan-cancer and was linked to unfavorable prognosis, particularly in glioma. Furthermore, genetic alterations were determined in various types of cancer, and modifications in the CREB5 gene were linked to the prognosis. The single-cell omics and enrichment analyses showed that CREB5 was predominantly expressed in malignant glioma cells and was critically involved in the regulation of various oncogenic processes. Elevated levels of CREB5 were strongly linked with the infiltration of cancer-associated fibroblasts and the Th1 subset of CD4 T cells. The validated CREB5-associated prognostic model reliably predicted the prognosis and drug response of glioma patients. The in vitro experiments showed that CREB5 promoted glioma cell proliferation, invasion, migration, and gap phase 2/mitotic (G2/M) phase arrest and recruited M2 macrophages into glioma cells.

CONCLUSION

CREB5 has the potential to act as an oncogene and a biological marker in multiple cancers, particularly glioma.

摘要

背景

尽管环腺苷酸反应元件结合蛋白 5（CREB5）作为 CREB 家族的成员具有重要意义，但它在癌症中的功能相关性仍然难以捉摸。本研究旨在探索 CREB5 在多种癌症中的作用。

方法

进行泛癌分析，以探讨 CREB5 的表达模式、预后价值、突变景观以及单细胞组学、免疫和药物敏感性特征。此外，我们整合了五种不同的机器学习算法，确定具有最高 C 指数的最小绝对收缩和选择算子-COX（LASSO-COX）算法是最佳选择。随后，我们构建了一个以 CREB5 相关基因为中心的预后模型。为了阐明 CREB5 在神经胶质瘤细胞中的生物学功能，进行了细胞计数试剂盒-8（CCK-8）、划痕愈合、transwell、流式细胞术等实验。

结果

CREB5 在泛癌中过表达，并与不良预后相关，尤其是在神经胶质瘤中。此外，在各种类型的癌症中发现了遗传改变，并且 CREB5 基因的改变与预后相关。单细胞组学和富集分析表明，CREB5 主要在恶性神经胶质瘤细胞中表达，并在各种致癌过程的调节中起关键作用。CREB5 水平升高与癌症相关成纤维细胞和 CD4 T 细胞的 Th1 亚群的浸润密切相关。经过验证的 CREB5 相关预后模型能够可靠地预测神经胶质瘤患者的预后和药物反应。体外实验表明，CREB5 促进神经胶质瘤细胞的增殖、侵袭、迁移和间隙期 2/有丝分裂（G2/M）期阻滞，并招募 M2 巨噬细胞进入神经胶质瘤细胞。