FDFT1 inhibits macrophage M1 polarization and promotes colorectal cancer progression

GAO Yuan; HUANG Yulan; ZHAO Kun; SHI Rongchen; MIAO Hongming

doi:10.16016/j.2097-0927.202410018

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FDFT1 inhibits macrophage M1 polarization and promotes colorectal cancer progression

Basic Medicine | 更新时间：2025-02-26

- FDFT1 inhibits macrophage M1 polarization and promotes colorectal cancer progression
- Journal of Army Medical University Vol. 47, Issue 3, Pages: 205-215(2025)
- 作者机构：
  
  陆军军医大学（第三军医大学）高原军事医学系病理生理学教研室，极端环境医学教育部重点实验室，重庆
- 作者简介：
  
  MIAO Hongming， E-mail： hongmingmiao@sina.com
- 基金信息：
  
  the Science and Technology Research Project of Chongqing Education Committee(KJQN202412809)
- DOI：10.16016/j.2097-0927.202410018
  CLC： R392.13;R730.23;R735.35
- Received：09 October 2024，
  
  Revised：26 December 2024，
  
  Published：15 February 2025
- 稿件说明：
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‍高源，黄玉兰，赵昆，等.FDFT1抑制巨噬细胞M1极化促进小鼠结直肠癌进展［J］.陆军军医大学学报，2025，47（03）：205-215.DOI：10.16016/j.2097-0927.202410018.

‍GAO Y，HUANG Y L，ZHAO K，et al.FDFT1 inhibits macrophage M1 polarization and promotes colorectal cancer progression［J］.J Army Med Univ，2025，47（03）：205-215.DOI：10.16016/j.2097-0927.202410018.
‍高源，黄玉兰，赵昆，等.FDFT1抑制巨噬细胞M1极化促进小鼠结直肠癌进展［J］.陆军军医大学学报，2025，47（03）：205-215.DOI：10.16016/j.2097-0927.202410018. DOI：

‍GAO Y，HUANG Y L，ZHAO K，et al.FDFT1 inhibits macrophage M1 polarization and promotes colorectal cancer progression［J］.J Army Med Univ，2025，47（03）：205-215.DOI：10.16016/j.2097-0927.202410018. DOI：

摘要

目的

筛选出结直肠癌（colorectal cancer， CRC）细胞中抑制巨噬细胞向M1方向极化的胆固醇合成途径代谢酶相关靶点，并验证干预效果及其作用机制。

方法

将小鼠CRC细胞株（MC38）分为对照（si-NC）组和多个胆固醇合成途径相关代谢酶表达干扰（siRNA干扰相应靶点）组，RT-qPCR检测转染后MC38细胞相应干扰靶点的mRNA水平；6周龄C57BL/6雄性小鼠（体质量13~18 g）提取原代腹腔巨噬细胞，利用siRNA转染后MC38细胞的条件培养基处理巨噬细胞，RT-qPCR检测巨噬细胞中IL-1β、IL-6和TNF-α的mRNA水平以评估对其M1方向极化的影响。将MC38细胞分为对照组（OE-NC和sh-NC组）、法尼基焦磷酸转移酶1（farnesyl-diphosphate farnesyltransferase 1，FDFT1）过表达组（OE-FDFT1组）和FDFT1敲低组（sh-FDFT1组），RT-qPCR检测FDFT1的mRNA水平，Western blot检测FDFT1蛋白水平；将C57BL/6小鼠通过随机数字表法按照细胞分组方式分别构建皮下荷瘤模型（

=5）、腹腔种植转移瘤模型（

=5），对肿瘤质量进行检测；流式细胞术检测肿瘤细胞增殖和凋亡情况；Transwell实验检测肿瘤细胞迁移能力变化；将C57BL/6巨噬细胞清除鼠（氯膦酸盐脂质体悬液尾静脉注射）通过随机数字表法按照细胞分组方式构建腹腔种植转移瘤模型（

=5），对肿瘤质量进行检测。

结果

与si-NC组MC38细胞相比，各胆固醇合成途径相关代谢酶表达干扰组中MC38细胞对应靶点的mRNA水平显著下调（

均

0.05）；与si-NC组巨噬细胞相比，FDFT1表达干扰组巨噬细胞中IL-1β、IL-6和TNF-α的mRNA水平显著上调（

均

0.05）。相比于OE-NC组MC38细胞，OE-FDFT1组MC38细胞的增殖、凋亡和迁移能力未发生显著变化；相比于sh-NC组MC38细胞，sh-FDFT1组MC38细胞的增殖、凋亡和迁移能力未发生显著变化。在野生型C57BL/6小鼠皮下荷瘤模型、腹腔种植转移瘤模型中，与OE-NC组相比，OE-FDFT1组肿瘤质量显著上调（

均

0.01）；而与sh-NC组相比， sh-FDFT1组肿瘤质量显著下调（

均

0.01）。在巨噬细胞清除小鼠肿瘤模型中，与OE-NC组相比，OE-FDFT1组肿瘤质量未发生显著变化；与sh-NC组相比，sh-FDFT1组肿瘤质

量未发生显著变化。

结论

CRC肿瘤细胞中胆固醇合成途径代谢酶FDFT1是靶向巨噬细胞的肿瘤免疫治疗潜在靶点，通过调控巨噬细胞促进肿瘤进展。

Abstract

‍Objective‍

To screen the targets related to the metabolic enzymes involved in the cholesterol synthesis pathway that inhibits the polarization of macrophages towards M1 phenotype

and verify the intervention effects and underlying mechanisms in colorectal cancer cells.

Methods‍

Mouse colorectal cancer MC38 cells were divided into control group (si-NC) and experimental groups (the expression of enzymes in cholesterol synthesis pathway was interfered with siRNA for corresponding targets). RT-qPCR was used to detect the mRNA levels of corresponding targets in MC38 cells after transfection. After peritoneal macrophages were extracted from male C57BL/6 mice (6 weeks old

weighing 13~18 g)

the macrophages were then treated with the conditioned media of MC38 cells transfected with different siRNAs for 48 h. RT-qPCR was employed to detect the mRNA levels of IL-1β

IL-6 and TNF-α in the macrophages so as to evaluate the effect of the culture media on the M1 polarization. MC38 cells were divided into control groups (OE-NC and sh-NC)

farnesyl-diphosphate farnesyltransferase 1 (FDFT1) overexpression group (OE-FDFT1) and FDFT1 knockdown group (sh-FDFT1). RT-qPCR was applied to detect the mRNA expression of FDFT1

and Western blotting was conducted to measure the protein level of FDFT1. C57BL/6 mice were subjected randomly to construct a subcutaneous tumor-bearing model and a model of intraperitoneal metastatic tumor (n=5) respectively. The growth of tumor mass was then measured. Flow cytometry was used to observe the proliferation and apoptosis of MC38 cells

and Transwell assay to detect migration ability of MC38 cells. Five C57BL/6 macrophage-depleted mice (established with injection of clodronate liposome suspension through tail vein) received intraperitoneal implantation to construct a metastasis model

and then the obtained tumor masses were then weighted.

Results‍

Compared with MC38 cells after si-NC transfection

the mRNA levels of corresponding targets in MC38 cells in the experimental groups were significantly reduced (P<0.05). Significant increases were found in the mRNA levels of IL-1β

IL-6 and TNF-α of the macrophages with FDFT1 interference than the control cells (P<0.05). There were no statistical differences in the proliferation

apoptosis and migration of MC38 cells in the control group (OE-NC and sh-NC) and the cells of the FDFT1 overexpression group and FDFT1 knockdown group (P>0.05). In both the subcutaneous tumor-bearing model and the model of intraperitoneal metastatic tumor

the mass weight was significantly heavier in the OE-FDFT1 group than the OE-NC group (P<0.01)

and was notably smaller in the sh-FDFT1 group than the sh-NC group (P<0.01). For the macrophage-depleted mouse tumor model

no remarkable change was observed in the tumor weight between the OE-FDFT1 group and the OE-NC group as well as the sh-FDFT1 group and the sh-NC group.

Conclusion‍

FDFT1

the metabolic enzyme in the cholesterol synthesis pathway of colorectal cancer tumor cells

is a potential target for tumor immunotherapy targeting macrophages

which promotes tumor progression by regulating macrophages.

关键词

Keywords

references

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