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Article(id=1322934570802356495, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322934544927687233, articleNumber=null, orderNo=null, doi=10.16016/j.2097-0927.202410018, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1728403200000, receivedDateStr=2024-10-09, revisedDate=1735142400000, revisedDateStr=2024-12-26, acceptedDate=null, acceptedDateStr=null, onlineDate=1793341780615, onlineDateStr=2026-10-30, pubDate=1739548800000, pubDateStr=2025-02-15, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1793341780615, onlineIssueDateStr=2026-10-30, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1793341780615, creator=13701087609, updateTime=1793341780615, updator=13701087609, issue=Issue{id=1322934544927687233, tenantId=1146029695717560320, journalId=1319373162502258839, year='2025', volume='47', issue='3', pageStart='193', pageEnd='284', issueExtLink='null', onlineDate='null', pubDate='1739548800000', pubDateStr='2025-02-15', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1793341774446, creator='13701087609', updateTime=1793341774446, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext=null, issueFiles=null, downloadFileDto=null}, startPage=205, endPage=215, ext={EN=ArticleExt(id=1322934571012071696, articleId=1322934570802356495, tenantId=1146029695717560320, journalId=1319373162502258839, language=EN, title=FDFT1 inhibits macrophage M1 polarization and promotes colorectal cancer progression, columnId=1320434418116837551, journalTitle=Journal of Army Medical University, columnName=Basic Medicine, runingTitle=null, highlight=null, articleAbstract=
‍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.

, authors=Yuan GAO, Yulan HUANG, Kun ZHAO, Rongchen SHI, Hongming MIAO, authorsList=Yuan GAO, Yulan HUANG, Kun ZHAO, Rongchen SHI, Hongming MIAO, authorCompany=null, correspAuthors=Hongming MIAO, authorNote=null, correspAuthorsNote=null, copyrightStatement=© 2025 Journal of Army Medical University, copyrightOwner=Editorial Office of Journal of Army Medical University, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1322934575479005469, articleId=1322934570802356495, tenantId=1146029695717560320, journalId=1319373162502258839, language=CN, title=FDFT1抑制巨噬细胞M1极化促进小鼠结直肠癌进展, columnId=1322185528879993170, journalTitle=陆军军医大学学报, columnName=基础医学, runingTitle=null, highlight=null, articleAbstract=
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（n=5）、腹腔种植转移瘤模型（n=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（n=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（P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（P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（P均<0.01）；而与sh-NC组相比，sh-FDFT1组肿瘤质量显著下调（P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。

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‍缪洪明，E-mail：
MIAO Hongming，E-mail：
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a：P<0.05，b：P<0.01，c：P<0.001，与si-NC组比较A：FDPS表达干扰组的FDPS mRNA水平检测；B：LSS表达干扰组的LSS mRNA水平检测；C：LBR表达干扰组的LBR mRNA水平检测；D：MVK表达干扰组的MVK mRNA水平检测；E：FDFT1表达干扰组的FDFT1 mRNA水平检测；F：MSMO1表达干扰组的MSMO1 mRNA水平检测；G：SREBP2表达干扰组的SREBP2 mRNA水平检测；H：ACAT2表达干扰组的ACAT2 mRNA水平检测；I：DHCR7表达干扰组的DHCR7 mRNA水平检测；J：HMGCR表达干扰组的HMGCR mRNA水平检测

, figureFileSmall=TDmDBlW2eLLBHSaQzKUU8A==, figureFileBig=d4EmJFPDsPKccAnpnDxEQw==, tableContent=null), ArticleFig(id=1322934580239540550, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934570802356495, language=EN, label=null, caption=null, figureFileSmall=05XcOP5c2Tv/XylXsUoT9Q==, figureFileBig=XfzB+/gcQDO1FvjYB0Se0w==, tableContent=null), ArticleFig(id=1322934580306649415, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934570802356495, language=CN, label=图2, caption=胆固醇合成途径重要代谢酶对巨噬细胞M1极化调控作用检测（n=3，x¯±s）

a：P<0.05，b：P<0.01，c：P<0.001，与si-NC组比较A~J：不同代谢酶基因表达干扰MC38的细胞条件培养基处理巨噬细胞后巨噬细胞的IL-1β、IL-6和TNF-α mRNA水平检测

, figureFileSmall=05XcOP5c2Tv/XylXsUoT9Q==, figureFileBig=XfzB+/gcQDO1FvjYB0Se0w==, tableContent=null), ArticleFig(id=1322934580398924104, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934570802356495, language=EN, label=null, caption=null, figureFileSmall=EVpS26sTRorx0BHxGp+pCw==, figureFileBig=hR48i4JAy4YBoGLDbeoVUQ==, tableContent=null), ArticleFig(id=1322934580470227273, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934570802356495, language=CN, label=图3, caption=FDFT1稳定过表达及敲低细胞系构建及验证

a：P<0.05，b：P<0.01，c：P<0.001，与OE-NC组比较；d：P<0.001，与sh-NC组比较A、B：OE-FDFT1组的FDFT1蛋白水平检测及灰度值统计（n=6，x¯±s）；C：OE-FDFT1组的FDFT1 mRNA水平检测（n=3，x¯±s）；D、E：sh-FDFT1组的FDFT1蛋白水平检测及灰度值统计（n=6，x¯±s）；F：sh-FDFT1组的FDFT1 mRNA水平检测（n=3，x¯±s）；G：OE-NC、OE-FDFT1组MC38细胞条件培养基处理巨噬细胞后巨噬细胞的IL-1β、IL-6和TNF-α mRNA水平检测（n=3，x¯±s）；H：sh-NC、sh-FDFT1组MC38细胞条件培养基处理巨噬细胞后巨噬细胞的IL-1β、IL-6和TNF-α mRNA水平检测（n=3，x¯±s）

, figureFileSmall=EVpS26sTRorx0BHxGp+pCw==, figureFileBig=hR48i4JAy4YBoGLDbeoVUQ==, tableContent=null), ArticleFig(id=1322934580541530442, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934570802356495, language=EN, label=null, caption=null, figureFileSmall=vGucgOEwxN/T0xJ3FGGhww==, figureFileBig=rX4+fTLhN98f4R3/uzn0UA==, tableContent=null), ArticleFig(id=1322934580629610827, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934570802356495, language=CN, label=图4, caption=FDFT1过表达或敲低对肿瘤进展的影响（n=5，x¯±s）

a：P<0.01，与OE-NC组比较；b：P<0.01，c：P<0.001，与sh-NC组比较A~D：OE-NC、OE-FDFT1组MC38细胞皮下肿瘤模型和腹腔种植转移肿瘤模型的肿瘤组织观察及质量统计； E~H：sh-NC、sh-FDFT1组MC38细胞皮下肿瘤模型和腹腔种植转移肿瘤模型的肿瘤组织观察及质量统计

, figureFileSmall=vGucgOEwxN/T0xJ3FGGhww==, figureFileBig=rX4+fTLhN98f4R3/uzn0UA==, tableContent=null), ArticleFig(id=1322934580717691212, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934570802356495, language=EN, label=null, caption=null, figureFileSmall=4KD1cBT6lAt/lBePSW6ywA==, figureFileBig=ESFRtmNwtBDldWmrn7qojw==, tableContent=null), ArticleFig(id=1322934580788994381, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934570802356495, language=CN, label=图5, caption=FDFT1敲低和过表达对MC38细胞增殖、凋亡、迁移的影响

A、B：流式分析术检测OE-NC、OE-FDFT1组的MC38细胞增殖能力及占比统计（n=3，x¯±s）；C、D：流式分析术检测检测sh-NC、sh-FDFT1组的MC38细胞增殖能力及占比统计（n=3，x¯±s）；E、F：流式分析术检测OE-NC、OE-FDFT1组的MC38细胞凋亡率及占比统计（n=3，x¯±s）；G、H：流式分析术检测sh-NC、sh-FDFT1组的MC38细胞凋亡率及占比统计（n=3，x¯±s）；I：Transwell实验检测OE-NC、OE-FDFT1组的细胞纵向迁移能力；J：Transwell实验检测sh-NC、sh-FDFT1组的细胞纵向迁移能力

, figureFileSmall=4KD1cBT6lAt/lBePSW6ywA==, figureFileBig=ESFRtmNwtBDldWmrn7qojw==, tableContent=null), ArticleFig(id=1322934580881269070, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934570802356495, language=EN, label=null, caption=null, figureFileSmall=ajFMbd/yxuL3hDTkm6bOyQ==, figureFileBig=VbvMivIay5fyWzks5ODjgg==, tableContent=null), ArticleFig(id=1322934580952572239, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934570802356495, language=CN, label=图6, caption=巨噬细胞对FDFT1的促瘤效应的影响（n=5，x¯±s）

A、B：OE-NC、OE-FDFT1组的MC38细胞在巨噬细胞清除小鼠上构建腹腔种植转移肿瘤模型肿瘤组织观察及质量统计；C、D：sh-NC、sh-FDFT1组的MC38细胞在巨噬细胞清除小鼠上构建腹腔种植转移肿瘤模型肿瘤组织观察及质量统计

, figureFileSmall=ajFMbd/yxuL3hDTkm6bOyQ==, figureFileBig=VbvMivIay5fyWzks5ODjgg==, tableContent=null), ArticleFig(id=1322934581023875408, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934570802356495, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
基因序列（5’→3’）
ACAT2上游：GGUCCUUAUGAAGAAGACA
下游：UGUCUUCUUCAUAAGGACC
LSS上游：UCUCAGAAUCCUGGGUAUU
下游：AAUACCCAGGAUUCUGAGA
HMGCR上游：CAUUAGUGGUGGAAGCAGA
下游：UCUGCUUCCACCACUAAUG
FDPS上游：GGCUUUCUUCCUUGUGUCA
下游：UGACACAAGGAAGAAAGCC
MVK上游：GCAAGGUGAUGUCUCGGUA
下游：UACCGAGACAUCACCUUGC
LBR上游：GCGACUUGGUGCUUUCGAU
下游：AUCGAAAGCACCAAGUCGC
DHCR7上游：GGAAGUGGUUUGACUUCAA
下游：UUGAAGUCAAACCACUUCC
MSMO1上游：GCACAGCGGUUAUGAUAUU
下游：AAUAUCAUAACCGCUGUGC
SREBP2上游：GCGUCUUUGUGAAGCUGUU
下游：AACAGCUUCACAAAGACGC
FDFT1上游：GCTATCATATACCAGTACATA
下游：GTGTTTAACTTCTGTGCTATT
), ArticleFig(id=1322934581124538705, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934570802356495, language=CN, label=表1, caption=

siRNA序列

, figureFileSmall=null, figureFileBig=null, tableContent=
基因序列（5’→3’）
ACAT2上游：GGUCCUUAUGAAGAAGACA
下游：UGUCUUCUUCAUAAGGACC
LSS上游：UCUCAGAAUCCUGGGUAUU
下游：AAUACCCAGGAUUCUGAGA
HMGCR上游：CAUUAGUGGUGGAAGCAGA
下游：UCUGCUUCCACCACUAAUG
FDPS上游：GGCUUUCUUCCUUGUGUCA
下游：UGACACAAGGAAGAAAGCC
MVK上游：GCAAGGUGAUGUCUCGGUA
下游：UACCGAGACAUCACCUUGC
LBR上游：GCGACUUGGUGCUUUCGAU
下游：AUCGAAAGCACCAAGUCGC
DHCR7上游：GGAAGUGGUUUGACUUCAA
下游：UUGAAGUCAAACCACUUCC
MSMO1上游：GCACAGCGGUUAUGAUAUU
下游：AAUAUCAUAACCGCUGUGC
SREBP2上游：GCGUCUUUGUGAAGCUGUU
下游：AACAGCUUCACAAAGACGC
FDFT1上游：GCTATCATATACCAGTACATA
下游：GTGTTTAACTTCTGTGCTATT
), ArticleFig(id=1322934581221007698, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934570802356495, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
引物引物序列（5’→3’）
ACAT2上游：CCCGTGGTCATCGTCTCAG
下游：GGACAGGGCACCATTGAAGG
HMGCR上游：AGCTTGCCCGAATTGTATGTG
下游：TCTGTTGTGAACCATGTGACTTC
LSS上游：GGAGCACGTTTCTCGGATCA
下游：AACTCAGGTCTGTGGTGTGC
FDPS上游：GGAGGTCCTAGAGTACAATGCC
下游：AAGCCTGGAGCAGTTCTACAC
MVK上游：GGTGTGGTCGGAACTTCCC
下游：CCTTGAGCGGGTTGGAGAC
LBR上游：ATGCCAAGTAGGAAGTTTGTTGA
下游：GATTTGTTGTCGTGGCTCAGA
DHCR7上游：AGGCTGGATCTCAAGGACAAT
下游：GCCAGACTAGCATGGCCTG
MSMO1上游：AAACAAAAGTGTTGGCGTGTTC
下游：AAGCATTCTTAAAGGGCTCCTG
SREBP2上游：GCAGCAACGGGACCATTCT
下游：CCCCATGACTAAGTCCTTCAACT
FDFT1上游：AGAGTGGCGGTTCACTGAGA
下游：GAGAAAGGCCAATTCCCACCA
GAPDH上游：TGTGTCCGTCGTGGATCTGA
下游：CCTGCTTCACCACCTTCTTGAT
TNF-α上游：CTGAGGTCAATCTGCCCAAGTAC
下游：CTTCACAGAGCAATGACTCCAAAG
IL-6上游：CTCATTCTGCTCTGGAGCCC
下游：CAACTGGATGGAAGTCTCTTGC
IL-1β上游：TGCCACCTTTTGACAGTGATG
下游：TGATGTGCTGCTGCGAGATT
), ArticleFig(id=1322934581304893779, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322934570802356495, language=CN, label=表2, caption=

RT-qPCR引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
引物引物序列（5’→3’）
ACAT2上游：CCCGTGGTCATCGTCTCAG
下游：GGACAGGGCACCATTGAAGG
HMGCR上游：AGCTTGCCCGAATTGTATGTG
下游：TCTGTTGTGAACCATGTGACTTC
LSS上游：GGAGCACGTTTCTCGGATCA
下游：AACTCAGGTCTGTGGTGTGC
FDPS上游：GGAGGTCCTAGAGTACAATGCC
下游：AAGCCTGGAGCAGTTCTACAC
MVK上游：GGTGTGGTCGGAACTTCCC
下游：CCTTGAGCGGGTTGGAGAC
LBR上游：ATGCCAAGTAGGAAGTTTGTTGA
下游：GATTTGTTGTCGTGGCTCAGA
DHCR7上游：AGGCTGGATCTCAAGGACAAT
下游：GCCAGACTAGCATGGCCTG
MSMO1上游：AAACAAAAGTGTTGGCGTGTTC
下游：AAGCATTCTTAAAGGGCTCCTG
SREBP2上游：GCAGCAACGGGACCATTCT
下游：CCCCATGACTAAGTCCTTCAACT
FDFT1上游：AGAGTGGCGGTTCACTGAGA
下游：GAGAAAGGCCAATTCCCACCA
GAPDH上游：TGTGTCCGTCGTGGATCTGA
下游：CCTGCTTCACCACCTTCTTGAT
TNF-α上游：CTGAGGTCAATCTGCCCAAGTAC
下游：CTTCACAGAGCAATGACTCCAAAG
IL-6上游：CTCATTCTGCTCTGGAGCCC
下游：CAACTGGATGGAAGTCTCTTGC
IL-1β上游：TGCCACCTTTTGACAGTGATG
下游：TGATGTGCTGCTGCGAGATT
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FDFT1抑制巨噬细胞M1极化促进小鼠结直肠癌进展
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高源 , 黄玉兰 , 赵昆 , 时荣臣 , 缪洪明
陆军军医大学学报 | 基础医学 2025,47(3): 205-215
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陆军军医大学学报 |基础医学 2025 , 47 (3) : 205 -215
FDFT1抑制巨噬细胞M1极化促进小鼠结直肠癌进展
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高源, 黄玉兰, 赵昆, 时荣臣, 缪洪明
作者信息
  • 1陆军军医大学（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
通讯作者:
‍缪洪明，E-mail：
MIAO Hongming，E-mail：
FDFT1 inhibits macrophage M1 polarization and promotes colorectal cancer progression
Yuan GAO, Yulan HUANG, Kun ZHAO, Rongchen SHI, Hongming MIAO
Affiliations
  • 1Department of Pathophysiology，Key Laboratory of Extreme Environment Medicine of Ministry of Education，Faculty of High Altitude Military Medicine，Army Medical University （Third Military Medical University），Chongqing，China
出版时间: 2025-02-15 doi: 10.16016/j.2097-0927.202410018
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摘要
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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（n=5）、腹腔种植转移瘤模型（n=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（n=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（P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（P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（P均<0.01）；而与sh-NC组相比，sh-FDFT1组肿瘤质量显著下调（P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。

‍结直肠癌  /  胆固醇代谢  /  法尼基焦磷酸转移酶1  /  巨噬细胞  /  M1极化
‍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.

‍colorectal cancer  /  cholesterol metabolism  /  farnesyl-diphosphate farnesyltransferase 1  /  macrophage  /  M1 polarization
高源, 黄玉兰, 赵昆, 时荣臣, 缪洪明. FDFT1抑制巨噬细胞M1极化促进小鼠结直肠癌进展. 陆军军医大学学报, 2025 , 47 (3) : 205 -215 . DOI: 10.16016/j.2097-0927.202410018
Yuan GAO, Yulan HUANG, Kun ZHAO, Rongchen SHI, Hongming MIAO. FDFT1 inhibits macrophage M1 polarization and promotes colorectal cancer progression[J]. Journal of Army Medical University, 2025 , 47 (3) : 205 -215 . DOI: 10.16016/j.2097-0927.202410018
正文
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恶性肿瘤是危害人类健康的重大疾病，其中结直肠癌（colorectal cancer，CRC）在所有恶性肿瘤中发病率排第3，死亡率排第2［1］。尽管随着CRC诊疗技术的不断进步，CRC患者的5年生存率有了一定程度的提高，但晚期患者预后仍然不佳［1-2］。因此，进一步研究CRC发生发展相关机制仍然迫在眉睫。
肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs）及其前体在大多数人类实体恶性肿瘤的免疫浸润细胞中占据最大比例［3］，具有高度的异质性和可塑性，对肿瘤微环境（tumor microenvironment，TME）的形成以及肿瘤进展较重要，是潜在的肿瘤免疫治疗靶点［4-5］。在体外，巨噬细胞被激活后可呈现多种表型：脂多糖或干扰素-γ激活的巨噬细胞具有体外促炎抗瘤效应，即M1活化表型；而IL-4处理后的巨噬细胞具有体外抗炎促瘤效应，即M2活化表型［4］。在体内TME中，肿瘤细胞可以通过分泌细胞因子［6］和影响代谢物浓度［4］等方式使TAMs向M2方向极化进而促进肿瘤进展。因此，对TAMs进行重编程使其向M1方向极化以发挥促炎抗瘤效应成为了以巨噬细胞为靶点的免疫治疗的重要策略之一。
胆固醇是细胞膜的重要成分，也是多种激素的前体，在细胞存活、增殖以及生物体的各种生理过程中发挥着至关重要的作用［7］。有证据表明，肿瘤细胞存在胆固醇合成平衡失调，并且这种平衡失调会影响肿瘤发生、发展、转移和耐药［8-12］。此外，还有研究报道发现，TAMs中同样存在胆固醇合成代谢重编程进而促进TAMs向M2方向极化［13］的情况。但CRC肿瘤细胞的胆固醇合成代谢紊乱对巨噬细胞极化以及肿瘤进展的调控效应和机制尚不完全清楚。
基于此，本研究以CRC肿瘤细胞（MC38）中胆固醇合成途径相关代谢酶为切入点，探讨CRC肿瘤细胞中胆固醇合成代谢变化对巨噬细胞极化方向的调控作用，拟干预相关靶点以驱动巨噬细胞向发挥促炎抗瘤效应的M1方向极化，为CRC靶向巨噬细胞免疫治疗的新靶点开发提供理论参考和实验依据。
1　材料与方法
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1.1　材料
6周龄C57BL/6雄性小鼠（体质量13~18 g）购自重庆恩斯维尔生物公司。所有实验动物严格按照SPF级饲养条件喂养于陆军军医大学实验动物中心。所有实验步骤经过陆军军医大学实验动物福利伦理委员会审核批准（AMUWEC20230037），符合动物伦理要求。
小鼠CRC细胞系（MC38）由缪洪明课题组保存［14］。胎牛血清购自武汉普诺赛生物公司；所有靶点的siRNA、si-NC购自北京擎科生物公司，siRNA序列见表1；法尼基焦磷酸转移酶1（farnesyl-diphosphate farnesyltransferase 1，FDFT1）过表达病毒（OE-FDFT1）、FDFT1敲低病毒（sh-FDFT1）和对照病毒（OE-NC、sh-FDFT1）均购自上海汉恒生物公司；7-AAD和Lipofectamine™ 3000转染试剂购自美国赛默飞世尔科技公司；TaKaRa反转录试剂盒和定量PCR扩增试剂盒购自日本TaKaRa公司；Western blot试剂盒购自上海雅酶公司；抗鼠FDFT1抗体和直标抗鼠GAPDH抗体购自武汉三鹰生物公司；山羊抗兔抗体购自北京中杉金桥生物公司；TRIzol和EdU增殖检测试剂盒购自上海碧云天生物公司；Annexin V和Annexin V Blinding Buffer购自美国Biolegend公司；Transwell小室购自美国康宁公司；氯膦酸盐脂质体购自上海翌圣生物公司。
1.2　细胞培养及转染
用含10%胎牛血清、1%双抗的DMEM培养基（即完全培养基），37 ℃、5%CO2培养MC38。收集对数生长期的MC38细胞，以5×105个/孔的细胞数均匀接种于6孔板中继续培养，待贴壁细胞长满底部面积50%~60%时进行转染。
1.2.1　siRNA转染
将MC38细胞分为对照组（si-NC组），多个胆固醇合成途径相关代谢酶干扰组：法尼基焦磷酸合酶（farnesyl pyrophosphate synthase，FDPS）表达干扰组（si-FDPS组）、羊毛固醇合酶（lanosterol synthase，LSS）表达干扰组（si-LSS组）、δ（14）-固醇还原酶LBR［delta（14）-sterol reductase，LBR］表达干扰组（si-LBR组）、甲羟戊酸激酶（mevalonate kinase，MVK）表达干扰组（si-MVK组）、FDFT1表达干扰组（si-FDFT1组）、甲基固醇单加氧酶1（methylsterol monooxygenase 1，MSMO1）表达干扰组（si-MSMO1组）、固醇调节元件结合蛋白2（sterol regulatory element-binding protein 2，SREBP2）表达干扰组（si-SREBP2组）、乙酰辅酶A乙酰转移酶（acetyl-CoA acetyltransferase，ACAT2）表达干扰组（si-ACAT2组）、7-脱氢胆固醇还原酶（7-dehydro-cholesterol reductase，DHCR7）表达干扰组（si-DHCR7组）以及3-羟基-3-甲基戊二酰辅酶A还原酶（3-hydroxy-3-methylglutaryl-coenzyme A reductase，HMCCR）表达干扰组（si-HMGCR组）。操作严格按照Lipofectamine™ 3000转染试剂盒说明书进行，细胞转染后更换新鲜完全培养基继续培养48 h。收集细胞进行RNA提取和RT-qPCR实验，用于转染效率检测；收集培养基进行巨噬细胞条件培养基处理实验，用于检测胆固醇合成途径相关代谢酶对巨噬细胞极化的影响。
1.2.2　病毒转染
将MC38细胞分为OE-NC组、sh-NC组和OE-FDFT1组以及sh-FDFT1组。按照分组在DMEM培养基中加入对应的病毒4×107 IU，摇匀后继续培养6 h，转染完成后收集细胞接种于25 T细胞培养瓶培养扩增，以用于后续的Western blot实验、RNA提取和RT-qPCR检测、巨噬细胞条件培养基处理实验、皮下荷瘤模型构建、腹腔种植转移瘤模型构建、流式细胞术检测细胞增殖、凋亡率以及Transwell实验、巨噬细胞清除小鼠腹腔种植转移瘤模型构建。
1.3　腹腔巨噬细胞提取
3%巯基乙酸盐培养基［15］37 ℃复温后以3 mL/只的剂量腹腔注射至C57BL/6小鼠体内。3 d后用CO2吸入法麻醉小鼠，脱颈法处死，将处死的小鼠于75%酒精中浸泡5 min以消毒。将消毒后的小鼠置于超净工作台中，无菌剪刀剪开小鼠皮肤，暴露壁层腹膜；另一把无菌剪刀于小鼠剑突下方剪一0.5 cm的小孔，将PBS通过小孔注入小鼠腹腔，冲洗收集液体。收集到腹腔冲洗液在4 ℃以600×g离心5 min，收集沉淀细胞，将收集到的细胞以4×107个/皿的细胞数接种于10 cm细胞培养皿中，使用完全培养基，37 ℃、5%CO2进行培养，2 h后去除培养基，PBS洗涤去除未贴壁细胞，剩余的贴壁细胞即为小鼠腹腔巨噬细胞。
1.4　巨噬细胞条件培养基处理实验
分别收集siRNA转染和病毒转染后MC38细胞的肿瘤细胞条件培养基，将收集的肿瘤细胞条件培养基在4 ℃以200×g离心5 min，收集上清液与新鲜完全培养基以1∶1的体积比进行混合制备条件培养基用于后续处理小鼠腹腔巨噬细胞的实验。
收集小鼠腹腔巨噬细胞以2×106个/孔的细胞数接种于6孔板中完全培养基，37 ℃、5%CO2培养6 h。更换为条件培养基，37 ℃、5%CO2培养小鼠腹腔巨噬细胞48 h，收集细胞进行RNA提取和RT-qPCR检测IL-1β、IL-6和TNF-α的mRNA水平检测。
1.5　RNA提取和RT-qPCR检测
分别收集siRNA转染和病毒转染后的MC38细胞提取RNA后通过RT-qPCR检测相应靶点的mRNA水平。收集相应条件培养基处理后的巨噬细胞提取RNA后通过RT-qPCR检测IL-1β、IL-6和TNF-α的mRNA水平，引物序列见表2。RT-qPCR流程：使用TRIzol法提取细胞总RNA；按照TaKaRa反转录试剂盒说明，以1 μg RNA为上样量；PCR程序：37 ℃ 15 min，85 ℃ 5 s，4 ℃保存；将RNA反转录为cDNA；再进行RT-qPCR检测（PCR程序：95 ℃，30 s预变性；95 ℃ 5 s，60 ℃ 34 s，95 ℃ 15 s，重复40个循环；4 ℃保存），运用2－ΔΔCt对结果进行量化并统计分析。
1.6　Western blot检测
收集病毒转染MC38细胞，利用RIPA缓冲液从细胞中提取总蛋白，BCA法定量后将蛋白标定为同一浓度后将蛋白变性。在SDS-PAGE凝胶中按30 μg进行点样，进行电泳分离，50 V 电压30 min，120 V电压使样品跑至凝胶底部。结束电泳后，利用湿转装置，在电压200 V 条件下转膜90 min，将蛋白转至聚偏二氟乙烯膜，5%脱脂奶粉中常温封闭1 h。封闭后将膜转移至FDFT1一抗稀释液或GAPDH直标抗体稀释液中，4 ℃慢摇12 h。洗涤后孵育FDFT1一抗的条带加入对应的二抗，室温孵育2 h，洗涤后在化学发光仪上观察结果。一抗、二抗稀释比例均按照抗体说明书配制。利用Image J软件对图像进行分析，并计算目的蛋白的相对表达量。
1.7　腹腔种植转移瘤模型构建
将野生型C57BL/6小鼠通过随机数字表法按照1.2.2中的病毒转染MC38细胞分组方式进行分组（n=5）。将OE-NC、OE-FDFT1、sh-NC和sh-FDFT1肿瘤细胞以1×106 个/100 μL的细胞浓度重悬于PBS中，按照分组腹腔注射对应的MC38细胞悬液（100 μL/只）至小鼠左下腹中外1/3处，继续饲养14 d，CO2吸入法麻醉小鼠，脱颈法处死，取肿瘤组织进行称量观察。
1.8　皮下荷瘤模型构建
将野生型C57BL/6小鼠通过随机数字表法按照1.2.2中的病毒转染MC38细胞分组方式进行分组（n=5）。将OE-NC、OE-FDFT1、sh-NC和sh-FDFT1肿瘤细胞以1×106 个/100 μL的细胞浓度重悬于PBS中，按照分组皮下注射对应的MC38细胞悬液100 μL/只至小鼠左下肢腹股沟处，继续饲养14 d，CO2吸入法麻醉小鼠，脱颈法处死，取肿瘤组织进行称量观察。
1.9　流式细胞术检测细胞增殖、凋亡率
将病毒转染MC38细胞以5×105个/孔的细胞数接种至6孔板中，培养至细胞汇合度60%左右，用含有 2 μL/mL EdU的完全培养基继续培养2 h，收集细胞，按照EdU试剂盒说明书进行固定通透染色，流式检测，将EdU+的细胞视为增殖细胞。
将病毒转染MC38细胞以1×106个/孔的细胞数接种至6孔板中，培养12 h，按照分组收集细胞，用Annexin V Blinding Buffer进行洗涤，用含有1 μL Annexin V和2 μL 7-AAD的Annexin V Blinding Buffer在4 ℃下避光染色20 min，收集细胞进行流式检测，将Annexin V+的细胞视为凋亡细胞。
1.10　Transwell实验
将病毒转染MC38细胞以5×104 个/孔的数目种入Transwell小室的上室中，在上室中加入20 μL无血清DMEM培养基，下室中加入1 mL含10%胎牛血清的培养基，继续培养12 h后收集小室，利用含0.5%结晶紫的甲醇溶液对小室上下的细胞进行固定染色15 min，PBS洗涤3次，5 min/次，中间无时间间隔，用棉签去除上室中的剩余细胞，倒置晾干后用倒置显微镜进行拍摄观察。
1.11　巨噬细胞清除小鼠腹腔种植转移瘤模型构建
将野生型C57BL/6小鼠通过随机数字表法按照1.2.2中的病毒转染MC38细胞分组方式进行分组（n=5），将氯膦酸盐脂质体复温至室温，通过尾静脉注射（200 μL/只），每2天注射1次，注射3次后间隔1 d，将OE-NC、OE-FDFT1、sh-NC、sh-FDFT1肿瘤细胞以1×106 个/100 μL的细胞浓度重悬于PBS中，按照分组腹腔注射对应的MC38细胞悬液（100 μL/只）至小鼠左下腹中外1/3处，继续饲养14 d，CO2吸入法麻醉小鼠，脱颈法处死，取肿瘤组织进行称量观察。
1.12　统计学分析
采用GraphPad Prism 5.0软件进行统计分析，满足正态分布的计量资料数据以x¯±s表示，组间比较用双侧非配对t检验分析，P<0.05表示差异具有统计学意义。
2　结果
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2.1　胆固醇合成途径中重要代谢酶基因表达干扰和验证
以转染si-NC的MC38细胞为对照组，通过转染特异性siRNA干扰CRC细胞系MC38中胆固醇合成途径中重要代谢酶表达，通过RT-qPCR实验检测目标靶基因的mRNA水平。结果显示，相较于si-NC组，si-FDPS组的FDPS mRNA水平显著下调（P<0.01，图1A），si-LSS组的LSS mRNA水平显著下调（P<0.001，图1B），si-LBR组的LBR mRNA水平显著下调（P<0.01，图1C），si-MVK组的MVK mRNA水平显著下调（P<0.01，图1D），si-FDFT1组的FDFT1 mRNA水平显著下调（P<0.01，图1E），si-MSMO1组的MSMO1 mRNA水平显著下调（P<0.05，图1F），si-SREBP2组的SREBP2 mRNA水平显著下调（P<0.05，图1G），si-ACAT2组的ACAT2 mRNA水平显著下调（P<0.01，图1H），si-DHCR7组的DHCR7 mRNA水平显著下调（P<0.01，图1I），si-HMGCR组的HMGCR mRNA水平显著下调（P<0.05，图1J），提示运用上述siRNA转染可以有效干扰胆固醇合成途径中重要代谢酶基因的表达。
2.2　CRC细胞FDFT1表达干扰促进巨噬细胞向M1方向极化
分别利用对照组或胆固醇合成途径代谢酶表达干扰组的肿瘤细胞条件培养基处理巨噬细胞，48 h后检测巨噬细胞中IL-1β、IL-6、TNF-α等促炎细胞因子的mRNA水平。结果显示，相较于si-NC组，si-FDFT1组的巨噬细胞中IL-1β、IL-6、TNF-α的mRNA水平显著上调（P均<0.05），提示巨噬细胞向M1方向极化（图2A），并且上调幅度在所有酶中最为明显；同时，si-FDPS和si-HMGCR组的巨噬细胞则呈现出相反的结果，相应因子的mRNA水平发生显著下调（P均<0.05，图2B、C）；此外，除了以上分组，其余分组的巨噬细胞M1极化的部分指标发生了显著下调（P均<0.05，图2D~J）。以上结果提示，肿瘤细胞胆固醇合成途径中各个代谢酶的表达均会对巨噬细胞的极化方向产生影响，其中只有FDFT1的抑制可促进巨噬细胞向M1方向极化，并且效应最为明显，提示FDFT1可能是肿瘤细胞胆固醇合成途径中调控肿瘤进展的重要调节点。
2.3　FDFT1稳定过表达和敲低细胞系构建及验证
通过Western blot及RT-qPCR实验检测FDFT1稳定过表达、敲低MC38细胞的FDFT1蛋白及mRNA水平变化，结果显示相较于OE-NC组，OE-FDFT1组FDFT1蛋白及mRNA水平均显著上调（P均<0.01，图3A~C）；相较于sh-NC组，sh-FDFT1组FDFT1蛋白及mRNA水平均显著下调（P均<0.001，图3D~F），提示FDFT1稳定过表达和敲低细胞株构建成功。
分别利用OE-NC组、sh-NC组、OE-FDFT1组和sh-FDFT1组的肿瘤细胞条件培养基处理巨噬细胞，48 h后检测巨噬细胞中IL-1β、IL-6、TNF-α等促炎细胞因子的mRNA水平。结果显示，相较于OE-NC组，OE-FDFT1组的巨噬细胞IL-1β、IL-6、TNF-α的mRNA水平发生显著下调（P均<0.05，图3G）；相较于sh-NC组，sh-FDFT1组的巨噬细胞相关细胞因子的mRNA水平显著上调（P均<0.001），提示巨噬细胞向M1方向极化（图3H）。以上结果与前期筛选结果一致。
2.4　CRC肿瘤细胞FDFT1调控肿瘤进展
为进一步明确FDFT1表达对肿瘤进展的影响，利用OE-NC、OE-FDFT1、sh-NC和sh-FDFT1的MC38细胞在6~8周龄雄性C57BL/6小鼠构建CRC腹腔种植转移模型和皮下种植瘤模型。14 d后发现，相较于OE-NC组，OE-FDFT1组肿瘤质量显著上调（P均<0.01，图4A~D）；而相较于sh-NC组，sh-FDFT1组肿瘤质量显著下调（P均<0.01，图4E~H）。
2.5　CRC肿瘤细胞FDFT1敲低或过表达不影响自身细胞生物学行为
对FDFT1过表达和敲低后细胞生物学行为进行检测，流式细胞术检测结果显示，相较于OE-NC或sh-NC组，FDFT1过表达或敲低均未对肿瘤细胞增殖能力产生显著影响（图5A~D），FDFT1过表达或敲低组的细胞凋亡率差异无统计学意义（图5E~H）；Transwell迁移实验也显示FDFT1过表达或敲低未影响MC38细胞迁移能力（图5I~J）。上述结果提示，在CRC肿瘤细胞中敲低或过表达FDFT1，不影响细胞增殖、凋亡、迁移等细胞生物学行为。
2.6　CRC肿瘤细胞FDFT1以巨噬细胞依赖的方式促进肿瘤进展
利用OE-NC、sh-NC、OE-FDFT1和sh-FDFT1组中MC38细胞在巨噬细胞清除小鼠上分别构建腹腔种植转移肿瘤模型。结果显示，相较于OE-NC或sh-NC组，FDFT1过表达或敲低均未对巨噬细胞清除小鼠上MC38肿瘤进展造成影响（图6），结合FDFT1在野生型C57BL/6小鼠上的促肿瘤效应，提示FDFT1调控肿瘤进展是以巨噬细胞依赖的方式发挥作用的。
3　讨论
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3.1　FDFT1对CRC进展的影响
FDFT1在不同肿瘤中似乎发挥着不同的作用，有研究报道，FDFT1在肝癌、肺癌、前列腺癌等癌组织中高表达［16-18］，相反，在睾丸癌、子宫癌、胰腺癌、肾癌等癌组织中表达下调［18］。对于FDFT1在CRC中的研究相对较少，且存在一定的争议，有一项基于23例临床样本的研究显示，FDFT1在CRC组织中低表达［19］；有一项基于20例CRC癌患者的基因表达谱和临床数据研究显示，FDFT1的高表达与生存期较短相关［20］；同时，一项基于233例结肠腺癌患者的临床研究指出，FDFT1高表达患者的复发风险和死亡风险增加［21］。本研究表明，在小鼠CRC细胞系MC38中FDFT1的表达促进肿瘤进展，提示FDFT1可能是CRC的一个癌基因。结合临床研究以及本实验提示，FDFT1可能是CRC治疗的重要靶点。
3.2　FDFT1对CRC肿瘤细胞细胞生物学行为的影响
针对FDFT1调控肿瘤进展的机制探究主要集中在其表达水平与肿瘤细胞增殖、凋亡、迁移等肿瘤细胞细胞生物学行为的关系上［16-17］，如敲低乳腺癌细胞的FDFT1会导致乳腺癌细胞内源性胆固醇含量下调，进而导致细胞凋亡敏感性增加和癌细胞生长抑制［17］；此外，FDFT1的功能丧失或下调还会导致细胞侵袭、迁移和转移能力受到抑制，进而导致小鼠肺转移瘤数目显著减少［16］。本研究发现，FDFT1作为胆固醇合成途径中的重要代谢酶，其在小鼠CRC肿瘤细胞系MC38中的表达水平与肿瘤细胞的增殖、凋亡、迁移无明显相关性，其背后可能存在相应的代偿机制，还需要进一步探讨。
3.3　FDFT1对TME的影响
如前所述，到目前为止仍然缺乏FDFT1与肿瘤免疫逃逸间存在调控关系的证据，本研究表明，CRC肿瘤细胞中FDFT1的表达水平与TAMs的M1极化存在相关性，抑制FDFT1表达会促进TAMs向M1方向极化进而抑制肿瘤进展，提示FDFT1是CRC免疫治疗的潜在靶点，但其调控巨噬细胞极化的详细机制将继续探究。
3.4　肿瘤细胞胆固醇合成途径对巨噬细胞极化的影响
胆固醇通常在肝脏中合成，大量的研究表明，血液中的胆固醇水平与肿瘤恶性进展相关［22］，这导致关于胆固醇与肿瘤进展的相关研究大多聚焦于肿瘤细胞和免疫细胞对于胆固醇的摄取、外排以及酯化修饰等［23］。但实际上，也有研究表明，胆固醇生物合成在癌细胞中也发生了显著变化，抑制胆固醇生物合成可以抑制肿瘤发生［23］。本研究探讨了CRC肿瘤细胞中的胆固醇合成途径相关代谢酶表达对巨噬细胞极化的影响，这可能为后续相关代谢酶调控肿瘤进展的机制研究提供理论依据，但其具体调控效应还需要进一步探讨。
综上所述，本研究通过筛选发现了CRC细胞胆固醇合成途径中调控巨噬细胞极化的关键靶点FDFT1，并且通过动物实验证明，其以巨噬细胞依赖的方式促进CRC进展，这与部分临床研究的结果一致。这些结果为FDFT1调控肿瘤进展提供了新的机制，为靶向巨噬细胞的免疫治疗提供了新的靶点，可为未来基于FDFT1的临床治疗策略开发提供理论依据。

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2025年第47卷第3期
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doi: 10.16016/j.2097-0927.202410018
  • 接收时间：2024-10-09
  • 首发时间：2026-10-30
  • 出版时间：2025-02-15
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  • 收稿日期：2024-10-09
  • 修回日期：2024-12-26
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    1陆军军医大学（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

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