脂肪酸通过FABPs/PPARγ介导前列腺癌选择性骨转移发生的分子机制研究

Prostate cancer special selectivity of bone metastases is related to bone marrow microenvironment, and fatty acid is rich in the bone marrow microenvironment. Fatty acid β- oxidation is already a predominant source of energy for prostate cancer cells. Based on the documents, we put forward the hypothesis that fatty acid combined with FABPs will be transported into the nucleus, Binding of fatty acid to PPAR γ make it be activated. Once activated, PPAR γ heterodimerizes with retinoid X receptor (RXR) in nucleus and then binds to PPRE located on target genes that up-regulate expression of FABPs and lipid metabolism relevant enzymes to promote fatty acid β- oxidation to produce ATP, which decrease the cellular AMP/ATP ratio to inhibit AMPK activity that improve expression of PPAR γ. Newly PPAR γ would be activated by binding of fatty acid which be transported into nucleus through associating with up-regulating FABPs. Once again, PPAR γ heterodimerizes with retinoid X receptor (RXR) in nucleus and then binds to PPRE located on target genes to promote cancer cells proliferation and differentiation. Therefore, we investigate the molecular mechanism of prostate cancer bone metastasis is mediated by Fatty acids through FABPs/PPARγ by selecting the PC3 - M series cells and obesity and prostate cancer bone metastases in situ animal experimental model, through respectively raised/lowered expressed AMPK/FABPs/PPARγ, to explore effect of fatty acid inducing cancer cells and influence on lipid metabolism and tumor characteristic biological phenotype, and to compare primary tumor characteristic biological phenotype and expression level of AMPK/FABPs/PPARγ with metastasis tumor.

PCa选择性骨转移发生与骨髓富含FA有关，FA氧化是PCa细胞主要的能量产生途径。结合文献提出假设：FA与FABPs结合后入核与PPARγ结合使之激活，活化的PPARγ与RXR形成二聚体与PPRE结合，上调FABPs和脂代谢相关酶的表达，促进FA的β-氧化产生ATP，使AMP/ATP比值降低，抑制AMPK活性，激活PPARγ转录；新生PPARγ又可与被FABPs转运入核的FA结合而被激活，再与RXR形成二聚体与PPRE结合，通过调节靶基因转录活性，促进癌细胞增殖。本研究选用PC3-M系细胞和PCa原位骨转移动物模型，分别上/下调FABPs/PPARγ表达，检测FA对PCa细胞的趋化诱导作用以及对其脂代谢、肿瘤特征生物学表型的影响，并比较转移灶与原发灶PCa组织肿瘤特征生物学表型和FABPs/PPARγ表达水平的变化，阐明FA通过FABPs/PPARγ介导PCa选择性骨转移发生的分子机制。

肥胖后循环中增加的游离脂肪酸与前列腺癌（Prostate Cancer, PCa)选择性骨转移发生的密切相关，但其具体的分子机制目前尚不完全清楚，而阐明此机制，对预防和治疗PCa骨转移的发生和降低PCa的死亡率具有积极的意义。本研究通过体内外实验研究得出以下实验结论：通过本项目的实施，得到如下结论：（1）肥胖后血清中增加的棕榈酸和辛酸可能是PCa发生发展的重要危险因素；肥胖后升高的血清游离脂肪酸含量，可通过增强PCa细胞的成瘤能力能力，以及改变骨髓微环境（增加脂肪细胞含量减少成骨细胞含量），导致PCa细胞更容易在骨髓腔中成瘤；（2）棕榈酸可通过上调FABP4、AMPK和PPARγ表达，促进VEGF-A、mTOR和Vimentin的表达，增强人前列腺癌细胞PC-3的增殖、迁移和侵袭能力；（3）高浓度的辛酸可通过GPR84上调KLF7、IL-6表达，下调p21表达，促进PCa细胞的生物学行为；（4）辛酸可通过促进骨髓间充质干细胞向脂肪细胞分化成熟，同时抑制骨髓间充质干细胞向成骨细胞分化成熟，使骨髓微环境发生改变，促进前列腺癌骨转移；（5）高浓度棕榈酸可通过上调骨髓脂肪细胞中GPR40/GPR120/ KLF7/CCL2的表达，促进PCa细胞骨转移；（6）没食子可逆转骨髓来源脂肪细胞对PCa细胞生物学行为的促进作用。通过本项目的实施，对肥胖导致前列腺癌骨转移的可能分子机制进行了初步探究，将为治疗靶点及药物的筛选提供了理论依据。依托本项目，共发表科研论文 6 篇，其中 SCI 收录 2 篇（JCR 1 区 1 篇，3 区 1 篇），申请国家发明专利1项，科研获奖5项，培养硕士研究生 4 名，本科生10名。