Tetrahydrocurcumin alleviates colorectal tumorigenesis by modulating the SPP1/CD44 axis and preventing M2 tumor-associated macrophage polarization

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-03-20 DOI:10.1016/j.phymed.2025.156674

Mengting Zhou , Rui Li , Guiyun Lian , Mengni Yang , Li Li , Zhujun Yin , Guiyu Li , Junning Zhao , Ruirong Tan

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引用次数: 0

Abstract

Background

Recent studies show that secreted phosphoprotein 1 (SPP1) is linked to the progression of various cancers, including colorectal cancer (CRC). SPP1 also promotes M2 macrophage polarization, contributing to immune evasion in the tumor microenvironment. Tetrahydrocurcumin (THC) has been reported to alleviate CRC, but the mechanism remains unclear.

Purpose

The study aimed to explore how THC modulated the SPP1/CD44 axis to inhibit M2 polarization and suppress CRC development.

Methods

Azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mouse model was used to assess the anti-CRC effects of THC. Transcriptome sequencing was conducted to identify the key targets of THC in CRC. The effects of THC on CRC cells were evaluated by CCK-8, colony formation, migration assays, immunofluorescence staining and flow cytometry. Human monocytic cells, THP-1, and colon cancer cell line, HCT116, were co-cultured, both directly or indirectly, to mimic the tumor-macrophage interactions, and investigate the role of SPP1/CD44 axis and the intervention effect of THC.

Results

THC significantly inhibited CRC carcinogenesis in mice and improved pathologic symptoms, serum inflammatory markers, and intestinal barrier integrity. THC inhibited CRC cell proliferation, migration and colony formation, while promoting apoptosis. Transcriptome analysis identified SPP1 as a key target of THC against CRC. SPP1 facilitated CRC progression by activating the ERK signaling pathway and maintaining the M2-like phenotype of macrophage, which further exacerbated this response. THC inhibited CRC development by targeting the SPP1/CD44 axis, rather than the integrin pathway.

Conclusions

SPP1 played a crucial role in maintaining the M2 phenotype of macrophage and promoting CRC cells proliferation. THC inhibited the activation of ERK signals in CRC cells and phenotypic transformation of M2-like macrophages through the SPP1/CD44 axis, thereby regulating the tumor immune microenvironment to exert anti-CRC effect.

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四氢姜黄素通过调节SPP1/CD44轴和抑制M2肿瘤相关巨噬细胞极化来缓解结直肠癌的发生

最近的研究表明，分泌磷酸化蛋白1 （SPP1）与包括结直肠癌（CRC）在内的多种癌症的进展有关。SPP1还促进M2巨噬细胞极化，促进肿瘤微环境中的免疫逃避。四氢姜黄素（THC）有缓解CRC的报道，但其机制尚不清楚。目的探讨四氢大麻酚如何调节SPP1/CD44轴抑制M2极化，抑制结直肠癌的发生。方法采用偶氮氧甲烷/葡聚糖硫酸钠（AOM/DSS）诱导小鼠模型，观察四氢大麻酚的抗结直肠癌作用。通过转录组测序来确定THC在CRC中的关键靶点。通过CCK-8、集落形成、迁移、免疫荧光染色和流式细胞术评价四氢大麻酚对结直肠癌细胞的影响。通过直接或间接共培养人单核细胞THP-1和结肠癌细胞系HCT116，模拟肿瘤-巨噬细胞相互作用，探讨SPP1/CD44轴的作用和THC的干预作用。结果四氢大麻酚显著抑制小鼠结直肠癌的癌变，改善病理症状、血清炎症指标和肠屏障完整性。四氢大麻酚抑制结直肠癌细胞增殖、迁移和集落形成，同时促进细胞凋亡。转录组分析发现SPP1是THC抗CRC的关键靶点。SPP1通过激活ERK信号通路和维持巨噬细胞的m2样表型来促进CRC的进展，这进一步加剧了这种反应。THC通过靶向SPP1/CD44轴而非整合素途径抑制结直肠癌的发展。结论spp1在维持巨噬细胞M2表型、促进结直肠癌细胞增殖中发挥了重要作用。四氢大麻酚通过SPP1/CD44轴抑制结直肠癌细胞中ERK信号的激活和m2样巨噬细胞的表型转化，从而调节肿瘤免疫微环境发挥抗结直肠癌作用。

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

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.