Abstract：
OBJECTIVE: Cholesterol metabolism reprograming has been acknowledged as a novel feature of cancers. Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a high demand of cholesterol for rapid growth. The underlying mechanism of how cholesterol metabolism homestasis are disturbed in PDAC is explored.
METHODS: The relevance between PDAC and cholesterol was confirmed in TCGA database. The expression and clinical association were discovered in TCGA and GEO datasets. Knockdown and overexpression of AGFG1 was adopted to perform function studies. RNA sequencing, cholesterol detection, transmission electron microscope, co-immunoprecipitation, and immunofluorescence et al. were utilized to reveal the underlying mechanism.
RESULTS: AGFG1 was identified as one gene positively correlated with cholesterol metabolism in PDAC as revealed by bioinformatics analysis. AGFG1 expression was then found associated with poor prognosis in PDAC. AGFG1 knockdown led to decreased proliferation of tumor cells both in vitro and in vivo. By RNA sequencing, we found AGFG1 upregulated expression leads to enhanced intracellular cholesterol biosynthesis. AGFG1 knockdown suppressed cholesterol biosynthesis and an accumulation of cholesterol in the ER. Mechanistically, we confirmed that AGFG1 interacted with CAV1 to relocate cholesterol for the proceeding of cholesterol biosynthesis, therefore causing disorders in intracellular cholesterol metabolism.
CONCLUSIONS: Our study demonstrates the tumor-promoting role of AGFG1 by disturbing cholesterol metabolism homestasis in PDAC. Our study has present a new perspective on cancer therapeutic approach based on cholerstrol metabolism in PDAC.
METHODS: The relevance between PDAC and cholesterol was confirmed in TCGA database. The expression and clinical association were discovered in TCGA and GEO datasets. Knockdown and overexpression of AGFG1 was adopted to perform function studies. RNA sequencing, cholesterol detection, transmission electron microscope, co-immunoprecipitation, and immunofluorescence et al. were utilized to reveal the underlying mechanism.
RESULTS: AGFG1 was identified as one gene positively correlated with cholesterol metabolism in PDAC as revealed by bioinformatics analysis. AGFG1 expression was then found associated with poor prognosis in PDAC. AGFG1 knockdown led to decreased proliferation of tumor cells both in vitro and in vivo. By RNA sequencing, we found AGFG1 upregulated expression leads to enhanced intracellular cholesterol biosynthesis. AGFG1 knockdown suppressed cholesterol biosynthesis and an accumulation of cholesterol in the ER. Mechanistically, we confirmed that AGFG1 interacted with CAV1 to relocate cholesterol for the proceeding of cholesterol biosynthesis, therefore causing disorders in intracellular cholesterol metabolism.
CONCLUSIONS: Our study demonstrates the tumor-promoting role of AGFG1 by disturbing cholesterol metabolism homestasis in PDAC. Our study has present a new perspective on cancer therapeutic approach based on cholerstrol metabolism in PDAC.
摘要：
目的：胆固醇代谢重编程被认为是癌症的一个新特征。胰腺导管腺癌（PDAC）是一种对胆固醇需求高的癌症。探讨了PDAC中胆固醇代谢抑制的潜在机制。
方法：在TCGA数据库中证实了PDAC与胆固醇之间的相关性。在TCGA和GEO数据集中发现了表达和临床关联。采用敲低和过表达AGFG1进行功能研究。RNA测序，胆固醇检测,透射电子显微镜,免疫共沉淀,和免疫荧光等。被用来揭示潜在的机制。
结果：生物信息学分析显示，AGFG1基因与PDAC中的胆固醇代谢呈正相关。然后发现AGFG1表达与PDAC的不良预后相关。AGFG1敲低导致肿瘤细胞在体外和体内的增殖降低。通过RNA测序，我们发现AGFG1上调表达导致细胞内胆固醇生物合成增强。AGFG1敲低抑制胆固醇生物合成和胆固醇在ER中的积累。机械上,我们证实AGFG1与CAV1相互作用以重新定位胆固醇进行胆固醇生物合成，因此导致细胞内胆固醇代谢紊乱。
结论：我们的研究证明了AGFG1通过干扰PDAC中胆固醇代谢引起的肿瘤促进作用。我们的研究提出了基于PDAC中胆固醇代谢的癌症治疗方法的新视角。
方法：在TCGA数据库中证实了PDAC与胆固醇之间的相关性。在TCGA和GEO数据集中发现了表达和临床关联。采用敲低和过表达AGFG1进行功能研究。RNA测序，胆固醇检测,透射电子显微镜,免疫共沉淀,和免疫荧光等。被用来揭示潜在的机制。
结果：生物信息学分析显示，AGFG1基因与PDAC中的胆固醇代谢呈正相关。然后发现AGFG1表达与PDAC的不良预后相关。AGFG1敲低导致肿瘤细胞在体外和体内的增殖降低。通过RNA测序，我们发现AGFG1上调表达导致细胞内胆固醇生物合成增强。AGFG1敲低抑制胆固醇生物合成和胆固醇在ER中的积累。机械上,我们证实AGFG1与CAV1相互作用以重新定位胆固醇进行胆固醇生物合成，因此导致细胞内胆固醇代谢紊乱。
结论：我们的研究证明了AGFG1通过干扰PDAC中胆固醇代谢引起的肿瘤促进作用。我们的研究提出了基于PDAC中胆固醇代谢的癌症治疗方法的新视角。
