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cyp24a1 Involvement in Inflammatory Factor Regulation Occurs via the Wnt Signaling Pathway

Current Medical Science 2022年第5期42卷 1022-1032页

作者： Xue-qi CHEN Jia-yu MAO Chun-saier WANG Wen-bin LI Tao-tao HAN Ke LV Jing-nan LI Department of Medical Ultrasound Peking Union Medical College HospitalPeking Union Medical College and Chinese Academy of Medical ScienceBeijing100730China Department of Critical Care Medicine Peking Union Medical College HospitalPeking Union Medical College and Chinese Academy of Medical ScienceBeijing100730China Department of Gastroenterology Beijing Friendship HospitalCapital Medical UniversityBeijing100050China Department of Gastroenterology Beijing HospitalNational Center of GerontologyInstitute of Geriatrics MedicineChinese Academy of Medical SciencesBeijing100730China Department of Gastroenterology Peking Union Medical College HospitalPeking Union Medical College and Chinese Academy of Medical Science Key Laboratory of Gut Microbiota Translational Medicine Research Chinese Academy of Medical ScienceBeijing100730China

Objective While the upregulation of cytochrome P450 family 24 subfamily A member 1(cyp24a1)gene expression has been reported in colon cancer,its role in tumorigenesis remains largely unknown.In this study,we aimed to investigate the involvement of cyp24a1 in Wnt pathway regulation via the nuclear factor kappa B(NF-κB)pathway.Methods The human colon cancer cell lines HCT-116 and Caco-2 were subjected to stimulation with interleukin-6(IL-6)as well as tumor necrosis factor alpha(TNF-α),with subsequent treatment using the NF-κB pathway-specific inhibitor ammonium pyrrolidinedithiocarbamate(PDTC).Furthermore,cyp24a1 expression was subjected to knockdown via the use of small interfering RNA(siRNA).Subsequently,NF-κB pathway activation was determined by an electrophoretic mobility shift assay,and the transcriptional activity ofβ-catenin was determined by a dual-luciferase reporter assay.A mouse ulcerative colitis(UC)-associated carcinogenesis model was established,wherein TNF-αand the NF-κB pathway were blocked by anti-TNF-αmonoclonal antibody and NF-κB antisense oligonucleotides,respectively.Then the tumor size and protein level of cyp24a1 were determined.Results IL-6 and TNF-αupregulated cyp24a1 expression and activated the NF-κB pathway in colon cancer cells.PDTC significantly inhibited this increase in cyp24a1 expression.Additionally,knockdown of cyp24a1 expression by siRNA could partially antagonize Wnt pathway activation.Upregulated cyp24a1 expression was observed in the colonic epithelial cells of UC-associated carcinoma mouse models.Anti-TNF-αmonoclonal antibody and NF-κB antisense oligonucleotides decreased the tumor size and suppressed cyp24a1 expression.Conclusion Taken together,this study suggests that inflammatory factors may increase cyp24a1 expression via NF-κB pathway activation,which in turn stimulates Wnt signaling.

关键词： cyp24a1 Wnt/β-catenin signaling pathway colorectal neoplasms

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Squalene epoxidase promotes colorectal cancer cell proliferation through accumulating calcitriol and activating cyp24a1-mediatedMAPK signaling

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Cancer Communications 2021年第8期41卷 726-746页

作者： Luwei He Huaguang Li Chenyu Pan Yutong Hua Jiayin Peng Zhaocai Zhou Yun Zhao Moubin Lin Center for Clinical Research and Translational Medicine Yangpu HospitalTongji University School of MedicineShanghai 200090P.R.China Institute of Gastrointestinal Surgery and Translational Medicine Tongji University School of MedicineShanghai 200090P.R.China Department of General Surgery Yangpu HospitalTongji University School of MedicineShanghai 200090P.R.China The State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031P.R.China State Key Laboratory of Genetic Engineering School of Life SciencesZhongshan HospitalFudan UniversityShanghai 200438P.R.China School of Life Science and Technology ShanghaiTech UniversityShanghai 201210P.R.China

Background:Colorectal cancer(CRC)is one of the most malignant tumorswith high incidence,yet its molecular mechanism is not fully understood,hindering the development of targeted therapy.Metabolic abnormalities are a hallmark of cancer.Targeting dysregulated metabolic features has become an important direction for modern anticancer therapy.In this study,we aimed to identify a new metabolic enzyme that promotes proliferation of CRC and to examine the related molecular mechanisms.Methods:We performed RNA sequencing and tissue microarray analyses of human CRC samples to identify new genes involved in CRC.Squalene epoxidase(SQLE)was identified to be highly upregulated in CRC patients.The regulatory function of SQLE in CRC progression and the therapeutic effect of SQLE inhibitors were determined by measuring CRC cell viability,colony and organoid formation,intracellular cholesterol concentration and xenograft tumor growth.Themolecularmechanism of SQLE functionwas explored by combining transcriptome and untargeted metabolomics analysis.Western blotting and realtime PCR were used to assess MAPK signaling activation by SQLE.Results:SQLE-related control of cholesterol biosynthesis was highly upregulated in CRC patients and associated with poor prognosis.SQLE promoted CRC growth in vitro and in vivo.Inhibition of SQLE reduced the levels of calcitriol(active form of vitamin D3)and cyp24a1,followed by an increase in intracellular Ca2+concentration.Subsequently,MAPK signaling was suppressed,resulting in the inhibition of CRC cell growth.Consistently,terbinafine,an SQLE inhibitor,suppressed CRC cell proliferation and organoid and xenograft tumor growth.Conclusions:Our findings demonstrate that SQLE promotes CRC through the accumulation of calcitriol and stimulation of cyp24a1-mediated MAPK signaling,highlighting SQLE as a potential therapeutic target for CRC treatment.

关键词： calcitriol cell proliferation cholesterol biosynthesis colorectal cancer cyp24a1 MAPK signaling squalene epoxidase terbinafine

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Association between cyp24a1 polymorphisms and the risk of colonic polyps and colon cancer in a Chinese population

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World Journal of Gastroenterology 2017年第28期23卷 5179-5186页

作者： Xue-Qi Chen Jia-Yu Mao Wen-Bin Li Jian Li Hong Yang Jia-Ming Qian Jing-Nan Li Department of Gastroenterology Peking Union Medical College Hospital Department of General Surgery Henan Cancer Hospital

AIM To determine the pathogenesis and potential single nucleotide polymorphisms(SNPs) as screening sites for colonic polyps,colon cancer and ulcerative colitis,and to analyze the possible association between these genetic polymorphisms and the three diseases. METHODS We evaluated genetic polymorphisms in 144 newly diagnosed colonic polyp patients,96 colon cancer patients and 44 ulcerative colitis patients. The four SNPs genotyped were rs4809957,rs6068816,rs6091822 and rs8124792. The control group consisted of 504 East Asians enrolled in the 1000 Genomes Project. Correlations between cyp24a1 SNPs and the diseases were analyzed by Fisher's exact probability test.RESULTS cyp24a1 polymorphisms rs4809957 A/G and rs6068816 C/T showed a statistically significant association with risk of the three diseases,when both the genotypes and allele frequencies were considered. With regard to rs6091822 G/T,all three diseases were related to risk allele carriers(GT + TT) vs wild-type(GG),but the associations between the allele frequencies and the diseases were not significant. The risk of colonic polyps and colon cancer was related to the allele frequencies of rs8124792 G/A,and this association remained for genotype frequencies of this SNP. CONCLUSION Four SNPs are related to the risk of colonic polyps and colon cancer. G allele in rs6091822 G/T may play an anti-cancer role only if it is homozygous. The A allele,which is a minor component of rs8124792,may be indicated in the diagnosis of colonic polyps or colon cancer rather than ulcerative colitis.

关键词： cyp24a1 Single nucleotide polymorphisms Colonic polyps Colon cancer

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低氧对妊娠SD大鼠维生素D代谢的影响及可能机制

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中国高原医学与生物学杂志 2024年第2期45卷 90-97页

作者：王雪妮陈文静李丹李建华青海大学西宁810016

目的探讨低氧对妊娠SD大鼠维生素D代谢的影响及可能机制。方法选择成年SD雌性大鼠20只,将其分为常氧组(Normoxia组,8只)和低氧组(Hypoxia组,12只),按雌雄比例2∶1将10只成年SD雄性大鼠分配到以上两组,与雌鼠合笼饲养建立妊娠动物模型。... 详细信息

目的探讨低氧对妊娠SD大鼠维生素D代谢的影响及可能机制。方法选择成年SD雌性大鼠20只,将其分为常氧组(Normoxia组,8只)和低氧组(Hypoxia组,12只),按雌雄比例2∶1将10只成年SD雄性大鼠分配到以上两组,与雌鼠合笼饲养建立妊娠动物模型。应用ELISA法检测雌鼠血清维生素D水平;采用Real-time qPCR技术分析与肝、肾、胎盘维生素D代谢相关基因的表达情况;通过常规染色和免疫组织化学技术对胎盘进行形态学观察、分析。结果Normoxia组血清维生素D代谢活性物25(OH)2D3含量低于Hypoxia组,差异有统计学意义(Pcyp2R1基因表达量上调(Pcyp27B1基因表达量上调(Pcyp24a1基因表达量下调(Pcyp2R1、cyp27B1基因表达量在两组无明显差异(P>0.05);胎盘的免疫组织化学结果显示,与Normoxia组相比,Hypoxia组cyp2R1、cyp27B1蛋白在胎盘的表达增加(Pcyp24a1蛋白表达下降(Pcyp24a1介导的维生素D负反馈机制;胎盘滋养层细胞中存在维生素D代谢系统和自分泌调节系统,且滋养层细胞可能是妊娠母体1,25(OH)2D3的来源。

关键词：低氧妊娠维生素D cyp2R1 cyp27B1 cyp24a1 实时荧光定量聚合酶链式反应大鼠

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cyp24a1 inhibition facilitates the anti-tumor effect of vitamin D3 on colorectal cancer cells

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World Journal of Gastroenterology 2013年第17期19卷 2621-2628页

作者： János P Kósa Péter Horváth János Wlfling Dóra Kovács Bernadett Balla Péter Mátyus Evelin Horváth Gábor Speer István Takács Zsolt Nagy Henrik Horváth Péter Lakatos 1 st Department of Internal Medicine Semmelweis University Department of Organic Chemistry University of Szeged Department of Organic Chemistry Semmelweis University

AIM:The effects of vitamin D3 have been investigated on various tumors, including colorectal cancer (CRC). 25-hydroxyvitamin-D3-24-hydroxylase (cyp24a1), the enzyme that inactivates the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25-D3), is considered to be the main enzyme determining the biological halflife of 1,25-D3. During colorectal carcinogenesis, the expression and concentration of cyp24a1 increases significantly, suggesting that this phenomenon could be responsible for the proposed efficacy of 1,25-D3 in the treatment of CRC. The aim of this study was to investigate the anti-tumor effects of vitamin D3 on the human CRC cell line Caco-2 after inhibition of the cytochrome P450 component of cyp24a1 activity. METHODS:We examined the expression of cyp24a1 mRNA and the effects of 1,25-D3 on the cell line Caco-2 after inhibition of cyp24a1. Cell viability and proliferation were determined by means of sulforhodamine-B staining and bromodeoxyuridine incorporation, respectively, while cytotoxicity was estimated via the lactate dehydrogenase content of the cell culture supernatant. cyp24a1 expression was measured by realtime reverse transcription polymerase chain reaction. A number of tetralone compounds were synthesized to investigate their CP24A1 inhibitory activity. RESULTS:In response to 1,25-D3, cyp24a1 mRNA expression was enhanced significantly, in a time- and dose-dependent manner. Caco-2 cell viability and proliferation were not influenced by the administration of 1,25-D3 alone, but were markedly reduced by coadministration of 1,25-D3 and KD-35, a cyp24a1-inhibiting tetralone. Our data suggest that the mechanism of action of co-administered KD-35 and 1,25-D3 does not involve a direct cytotoxic effect, but rather the inhibition of cell proliferation. CONCLUSION:These findings demonstrate that the selective inhibition of cyp24a1 by compounds such as KD-35 may be a new approach for enhancement of the anti-tumor effect of 1,25-D3 on CRC.

关键词： Colorectal cancer cyp24a1 inhibition Vitamin D3 Tetralone derivatives Caco-2 cell culture

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cyp24a1基因多态性与结直肠息肉和结直肠癌的相关性研究

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医学检验与临床 2023年第2期34卷 8-11页

作者：张雪花广西壮族自治区妇幼保健院检验科广西南宁530000

目的:分析cyp24a1基因多态性与结直肠息肉、结直肠癌发病的关系。方法:以110例健康者、118例结直肠息肉患者、139例结直肠癌患者作为本次研究对象,健康者纳入对照组,结直肠息肉患者纳入结直肠息肉组,结直肠癌患者纳入结直肠癌组,三组对... 详细信息

目的:分析cyp24a1基因多态性与结直肠息肉、结直肠癌发病的关系。方法:以110例健康者、118例结直肠息肉患者、139例结直肠癌患者作为本次研究对象,健康者纳入对照组,结直肠息肉患者纳入结直肠息肉组,结直肠癌患者纳入结直肠癌组,三组对象均行cyp24a1基因检测,对比三组对象rs114368325、rs2296239二个位点的基因多态性。结果:测序结果显示,cyp24a1基因rs114368325、rs2296239两个位点分别测出2种、3种基因型,前2种基因型分别为GG、AG,后3种基因型分别为CC、CT、TT,这些位点测序结果符合哈.温平衡定律与酶切结果。且各组位点突变基因型AG和等位基因A的携带频率在对比均无显著差异(P>0.05)。结论:cyp24a1rs114368325、rs2296239二个位点的基因多态性与结直肠息肉和结直肠癌无明显相关性。

关键词：结直肠癌结直肠息肉 cyp24a1 基因多态性相关性

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cyp4F2和cyp24a1基因多态性与肺结核并糖尿病的相关性

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河南大学学报（医学版） 2023年第3期42卷 203-207页

作者：赵琼魏文海李静芸牛慧敏王磊柴国祥韩婕李兴芳甘肃中医药大学兰州730030 兰州市肺科医院兰州730030 兰州大学第一医院兰州730030 甘肃省中医院兰州730050

目的:探讨cyp4F2和cyp24a1基因单核苷酸多态性(SNP)与肺结核并糖尿病的关系。方法:选取230例肺结核并糖尿病患者作为肺结核并糖尿病(Case)组,同期212例体检健康者作为对照(Control)组。采用聚合酶链反应-限制性片段长度多态性技术检测CY... 详细信息

目的:探讨cyp4F2和cyp24a1基因单核苷酸多态性(SNP)与肺结核并糖尿病的关系。方法:选取230例肺结核并糖尿病患者作为肺结核并糖尿病(Case)组,同期212例体检健康者作为对照(Control)组。采用聚合酶链反应-限制性片段长度多态性技术检测cyp4F2和cyp24A基因多态性,采用Logistic回归分析两组间各SNP位点等位基因频率和基因型频率的分布差异,并按不同遗传模型对rs1570669位点基因型分布进行分析。结果:cyp4F2 rs2108622和rs3093106位点、cyp24a1 rs2296241位点的基因型和等位基因频率在Case组和Control组中无均统计学差异。cyp24a1 rs2762934位点AG基因型频率Case组高于Control组,GG和AA基因型频率Case组低于Control组,组间差异具有统计学意义。rs2762934位点A等位基因的频率Case组高于Control组,差异具有统计学意义(Pcyp4F2 rs2108622和rs3093106位点、cyp24a1 rs2296241位点与肺结核并糖尿病均不相关。cyp24a1位点多态性与肺结核并糖尿病相关,基因型杂合子个体比纯合子个体发生肺结核并糖尿病的风险高,A等位基因可能增加患病风险。

关键词：肺结核糖尿病 cyp4F2 cyp24a1 单核苷酸多态性

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角鲨烯环氧酶通过积累骨化三醇和激活cyp24a1介导的MAPK信号通路促进结直肠癌细胞增殖

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癌症 2022年第11期41卷 509-529页

作者：何璐薇李华光潘晨宇华雨桐彭甲银周兆才赵允林谋斌同济大学医学院附属杨浦医院临床研究与转化医学中心上海200090 同济大学医学院胃肠外科与转化医学研究所上海200090 中国科学院大学上海生物化学与细胞生物学研究所中国科学院分子细胞科学卓越创新中心细胞生物学国家重点实验室上海200031 复旦大学中山医院生命科学学院基因工程国家重点实验室上海200438 上海科技大学生命科学与技术学院上海201210 同济大学医学院附属杨浦医院普外科上海200090

背景与目的结直肠癌(colorectal cancer,CRC)是一种高发的恶性肿瘤,其分子机制和靶向治疗有待进一步研究。代谢紊乱是癌症的重要特征。靶向调节肿瘤代谢途径已成为现代肿瘤治疗的重要方向。在本研究中,我们旨在研究一种新的促进CRC增殖... 详细信息

背景与目的结直肠癌(colorectal cancer,CRC)是一种高发的恶性肿瘤,其分子机制和靶向治疗有待进一步研究。代谢紊乱是癌症的重要特征。靶向调节肿瘤代谢途径已成为现代肿瘤治疗的重要方向。在本研究中,我们旨在研究一种新的促进CRC增殖的代谢酶及相关的分子机制。方法我们对人CRC组织样本进行了RNA测序和组织微阵列分析,来筛选CRC相关的新基因。角鲨烯环氧酶(squalene monooxygenase,SQLE)在CRC患者组织中高表达。通过检测CRC细胞的细胞活力、集落和类器官形成、细胞内胆固醇浓度和异种移植肿瘤生长,来明确SQLE在CRC进展过程中的调节功能和SQLE抑制剂的治疗效果。通过转录组和非靶向代谢组学联合分析,探讨SQLE发挥功能的分子机制。应用蛋白质免疫印迹和实时荧光定量PCR评估SQLE对MAPK信号通路的激活。结果在CRC患者中SQLE相关的胆固醇生物合成被上调,并且与预后不良相关。SQLE在体外和体内促进CRC生长。抑制SQLE可降低骨化三醇(维生素D3的活性形式)和cyp24a1的水平,使细胞内Ca2+浓度增加。抑制MAPK信号通路可抑制CRC细胞生长。SQLE抑制剂terbinafine可抑制CRC细胞增殖、类器官和异种移植肿瘤的生长。结论SQLE通过积累骨化三醇和激活cyp24a1介导的MAPK信号通路促进CRC生长,提示SQLE可作为潜在的CRC治疗靶点。

关键词：骨化三醇细胞增殖胆固醇生物合成结直肠癌 cyp24a1 MAPK信号通路鲨烯环氧酶 Terbinafine

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Association of Polymorphisms in cyp24a1 and Hyperuricemia: A case-control study

Association of Polymorphisms in CYP24A1 and Hyperuricemia: A...

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中国营养学会第十五届全国营养科学大会

作者： Yuanyuan Chai Chenling Qu Yinhua Feng Xing Li Wenjie Li Songcheng Yu Zhengzhou University Henan University of Technology

Objective This study aimed to investigate the association between single nucleotide polymorphisms(SNPs) of cyp24 A1 gene and hyperuricemia. Methods 130 patients with hyperuricemia in rural areas were included as the case group from a cross-sectional survey in Henan province of China. And 130 nonhyperuricemia people were selected as the control group for 1:1 case-control matching. Conditional logistic regression was used to investigate the association between the genetic variations and hyperuricemia. Additionally, multifactor dimensionality reduction(MDR) analysis was used to further evaluate the interaction of cyp24 A1 gene SNPs and body mass index(BMI). Results Our results indicated that the AG genotype of rs4809957 showed a higher risk of hyperuricemia after adjustment for BMI(Adjusted OR: 2.23, 95% CI: 1.03-4.85, P=0.043). The C-allele of rs6068816 was positively associated with the risk of hyperuricemia(CT: OR=3.19, 95% CI: 1.26-8.06, P=0.014;CC: OR =4.66, 95% CI: 1.74-12.48, P=0.002). In addition, MDR analysis results showed that SNPs of rs4809957 and rs6068816 and BMI had interaction among the risk factors of hyperuricemia. Conclusion Variations in cyp24 A1 are associated with hyperuricemia in the Chinese rural population, and there is an interaction between cyp24 A1 gene SNPs and BMI. Methods Study subjects A total of 1560 individuals were recruited in a cross-sectional study of chronic disease which was conducted in both Zhengzhou and Jiaozuo City, Henan Province. Hyperuricemia was defined as a serum urate level of >7.0 mg/dL for men and >6.0 mg/dL for women. 130 participants who were diagnosed with hyperuricemia were recruited as the case group, and 130 healthy people who had no history of cancer, nephropathy, diabetes or any other metabolic diseases were selected as control groups by 1:1 casecontrol matching with the principles of the same gender, similar age(no more than 5 years older or younger), same exposure to tobacco and alcohol. This study was conducted following the principle of the current vers

关键词： cyp24a1 hyperuricemia interactions SNP Vitamin D

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Vitamin D has synergistic effect on the expression levels of SIRT1 and cyp24a1 in human breast cancer

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Precision Medicine Research 2021年第3期3卷 1-6页

作者： Mandana Ameli Mojarad Melika Ameli Mojarad Mahnaz Noourbakhsh Department of Biology Faculty of Basics Science Kharrazi University TehranIran

Vitamin D has found to have a critical regula-tory role in genes expression by modifying cell proliferation,differentiation,and apoptosis.In this study,by using real-time polymerase chain reaction(PCR),the expression levels of SIRT1 and cyp24a1 genes and their correlation with clinical feature were evaluated before and after the vitamin D treatment in breast cancer(BC)cell lines(MCF-7 and MDA-MB-231)and in tissues.Our results indicated that the transcription of cyp24a1 and SIRT1 were affected by vitamin D treatment and,cyp24a1expression showed a significant correlation with tumor stages(P=0.02).Moreover,cyp24a1,SIRT1 showed a high diagnostic values based on the large area under the receiver operating char-acteristic(ROC)curve,(0.85,0.77)respectively,in conclusion,cyp24a1and SIRT1 can be used as potential biomarkers in the assessment of BC,and vitamin D treatment showed a regulatory role on the expression of cyp24a1 and SIRT1in BC cell lines.

关键词： Breast cancer cyp24a1 SIRT1 Biomarker

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