P4HA3 promotes colon cancer cell escape from macrophage phagocytosis by increasing phagocytosis immune checkpoint CD47 expression.

IF 3.5 2区 生物学 Q3 CELL BIOLOGY
Molecular and Cellular Biochemistry Pub Date : 2024-12-01 Epub Date: 2024-02-12 DOI:10.1007/s11010-024-04927-z
Hailang Zhou, Junwei Zou, Jingli Han, Aijun Zhou, Shu Huang
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引用次数: 0

Abstract

Cancer immunotherapies have greatly changed the prospects for the therapy of many malignancies, including colon cancer. Macrophages as the effectors of cancer immunotherapy provide considerable promise for cancer treatment. Prolyl 4-hydroxylase subunit alpha 3 (P4HA3) plays a cancer-promoting role in a variety of cancers, including colon cancer. In the present work, we provided evidence for the first time that P4HA3 promoted colon cancer cell escape from macrophage phagocytosis, and preliminarily explored its possible molecular mechanism. Immunohistochemistry was used to detect the expression of P4HA3 in tissues. Bioinformatics methods were used to analyze the tumor public databases (including TCGA database and GEO database). Macrophage phagocytosis assay and flow cytometric analysis were used to detect the phagocytic capacity of macrophages. Western blot and qRT-PCR were used to detect the expression of related markers (such as P4HA3, CD47, CD24, IL-34, and M-CSF). First, we found that P4HA3 was significantly and highly expressed in both colon cancer tissues and cells, and that P4HA3 had a positive correlation with lymph node metastasis, Dukes stage and also strongly correlated with poorer survival. Subsequently, we found that P4HA3 was strongly associated with the macrophage infiltration level in colon cancer. Immediately we also found that decreasing P4HA3 expression promoted macrophage phagocytosis in colon cancer cells, whereas P4HA3 overexpression produced the opposite effect. Finally, we demonstrated that P4HA3 promoted the expression of cluster of differentiation 47 (CD47) in colon cancer cells. Moreover, P4HA3 caused colon cancer cells to secrete Interleukin 34 (IL34) and Macrophage colony stimulating factor (M-CSF), which further induced macrophages to differentiate to M2 type and thereby contributed to the progression of colon cancer. We have demonstrated that P4HA3-driven CD47 overexpression may act as an escape mechanism, causing colon cancer cells to evade phagocytosis from macrophages.

Abstract Image

P4HA3 通过增加吞噬免疫检查点 CD47 的表达,促进结肠癌细胞逃避巨噬细胞的吞噬。
癌症免疫疗法大大改变了包括结肠癌在内的许多恶性肿瘤的治疗前景。巨噬细胞作为癌症免疫疗法的作用因子,为癌症治疗带来了巨大的希望。脯氨酰 4-羟化酶亚基α3(P4HA3)在包括结肠癌在内的多种癌症中发挥着促癌作用。在本研究中,我们首次提供了 P4HA3 促进结肠癌细胞逃避巨噬细胞吞噬的证据,并初步探讨了其可能的分子机制。研究采用免疫组织化学方法检测了P4HA3在组织中的表达。生物信息学方法分析了肿瘤公共数据库(包括TCGA数据库和GEO数据库)。巨噬细胞吞噬试验和流式细胞分析用于检测巨噬细胞的吞噬能力。Western 印迹和 qRT-PCR 用于检测相关标记物(如 P4HA3、CD47、CD24、IL-34 和 M-CSF)的表达。首先,我们发现 P4HA3 在结肠癌组织和细胞中均有显著的高表达,并且 P4HA3 与淋巴结转移、Dukes 分期呈正相关,与较差的生存期也密切相关。随后,我们发现 P4HA3 与结肠癌的巨噬细胞浸润水平密切相关。随即我们还发现,P4HA3 的表达减少会促进结肠癌细胞中巨噬细胞的吞噬作用,而 P4HA3 的过表达则会产生相反的效果。最后,我们证实 P4HA3 能促进结肠癌细胞中分化簇 47(CD47)的表达。此外,P4HA3 还会导致结肠癌细胞分泌白细胞介素 34(IL34)和巨噬细胞集落刺激因子(M-CSF),从而进一步诱导巨噬细胞向 M2 型分化,进而促进结肠癌的发展。我们已经证明,P4HA3 驱动的 CD47 过表达可能是一种逃逸机制,导致结肠癌细胞逃避巨噬细胞的吞噬。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular and Cellular Biochemistry
Molecular and Cellular Biochemistry 生物-细胞生物学
CiteScore
8.30
自引率
2.30%
发文量
293
审稿时长
1.7 months
期刊介绍: Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell. In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.
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