脂肪酸合成酶在肿瘤细胞中的作用

脂肪酸合成酶( fatty acid synthase,FASN)是重要的生物合成酶,是肿瘤脂质生成的一种关键酶,在催化脂肪酸合成的过程中发挥重要作用。FASN在许多肿瘤细胞中过表达而在相应的正常细胞中却不表达。有证据表明FASN是一个代谢性癌基因,在癌细胞中高表达,在肿瘤生长和存活中有重要的作用。最初发现的肿瘤细胞特殊代谢表型称Warburg效应。异常脂肪酸代谢与肿瘤生长、存活及侵袭相关,表明异常脂肪酸代谢为肿瘤生长提供了至关重要的物质和能量来源。FASN的过度表达与肿瘤的发生、演变、侵袭和预后有关。在多种肿瘤中观察到脂肪酸代谢途径中FASN的表达和活性提高,并且与不良预后密切相关,通过下调这些代谢酶的表达或利用特异性抑制剂抑制代谢酶活性,可抑制肿瘤的生长。研究发现,利用FASN抑制剂可明显抑制肿瘤的复发和转移。通过抑制FASN的酶活性而导致肿瘤细胞脂类饥饿,从而有效地抑制癌细胞增殖,促使其脱离恶性分裂周期并走向凋亡。正确认识FASN在肿瘤细胞中的表达调节,研究新的FASN抑制剂,可为肿瘤治疗提供新的方案。本文就脂肪酸合成酶及脂肪酸合成酶抑制剂在肿瘤细胞中的作用作一综述。     

肝细胞癌患者血清脂肪酸合成酶的表达水平及其临床意义

目的:分析脂肪酸合成酶(fatty acid synthase，FASN)在肝细胞癌患者血清中的表达情况及与肿瘤病理特征的关系，以探讨FASN在肝癌诊断及治疗中的意义。方法:选取经过临床病理检查证实诊断的60例肝细胞癌患者为研究组，另选30名健康志愿者为对照组。采用酶联免疫吸附法(enzyme-linked immunosorbent assay，ELISA)检测血清FASN水平，分析肝细胞癌患者血清FASN表达情况与其临床病理特征的关系。结果:ELISA结果显示FASN在肝细胞癌患者血清中的表达均明显上调，研究组FASN水平为（36.83±10.52）mg/L，对照组FASN水平为（11.37±7.21）mg/L，差异有统计学意义(P<0.05)；FASN表达水平与肝癌患者临床病理特征的关系分析显示FASN在血清中高表达可能与肝癌的转移有关；FASN和AFP联合检测有可能提高肝癌的早期诊断率。结论:FASN有可能作为新的生物标志物应用于肝癌的预测转移和早期诊断，并可能作为防治肝癌的分子标靶之一。     

罗汉果醇通过激活AMPK信号通路调控肝细胞癌HepG2 细胞的脂代谢

[摘要] 目的：研究罗汉果醇(MO)对肝细胞癌HepG2 细胞脂代谢的调控作用及其分子机制。方法：采用油酸(OA)诱导肝细胞癌HepG2 细胞脂肪累积,建立脂肪变性细胞模型。运用CCK-8 法检测MO对HepG2 的细胞毒性,筛选其无明显细胞毒性的实验工作浓度。不同工作浓度MO作用后运用油红O染色法观察模型细胞内脂质累积情况,测定细胞内甘油三酯（TG）、胆固醇（TC）含量。运用高通量转录组测序方法筛选参与脂代谢的关键基因,运用qPCR检测模型及给药细胞SREBP-1c、FASN mRNA的表达、WB法检测p-AMPKα、SREBP-1c、FASN等蛋白的表达水平。结果：运用OA诱导的模型HepG2 细胞内脂质大量累积,TG、TC含量显著升高。OA诱导后参与肝癌细胞脂代谢的关键基因SREBP-1c、FASN mRNA表达升高;p-AMPKα 蛋白表达降低,SREBP-1c、FASN等蛋白的表达显著升高。工作浓度MO干预后,细胞内脂质累积显著减少、TG和TC含量降低,SREBP-1c、FASN mRNA表达降低,p-AMPKα 蛋白表达升高而SREBP-1c、FASN等蛋白的表达明显降低。结论：MO能够通过激活HepG2细胞中AMPK信号通路相关因子SREBP-1c、FASN的表达抑制脂肪酸合成,从而发挥调节脂代谢的作用。     

基于生物信息学和免疫组化分析FASN在膀胱癌组织中的表达及临床意义

目的:利用生物信息学和免疫组化方法分析脂肪酸合酶（fatty acid synthase,FASN）在膀胱癌组织中的表达及临床意义。方法:利用Oncomine数据库分析FASN mRNA在正常膀胱组织和膀胱癌组织中的表达差异,并进行Meta分析;收集2019年01月至2021年03月在我院泌尿外科行手术治疗的86例膀胱癌患者的手术切除组织石蜡切片,利用免疫组化法检测FASN蛋白在膀胱癌组织和相应癌旁组织中的表达,并分析其与膀胱癌患者若干临床病理特征的关系;利用LinkedOmics数据库分析FASN mRNA表达与临床病理特征的关系;结合免疫组化和病历资料分析FASN蛋白表达与临床病理特征的关系;基于UALCAN和LinkedOmics平台分析该基因与膀胱癌患者生存的关系;基于LinkedOmics和Metascape平台做富集分析;String数据库构建蛋白互作网络。结果:与正常膀胱组织相比,FASN mRNA在膀胱癌组织中的表达显著增加（P＜0.05）。免疫组化结果提示FASN蛋白在膀胱癌组织中显著增加。FASN mRNA的表达与膀胱癌患者的肿瘤纯度和年龄相关（P＜0.05）,而与病理分级和TNM分期无关（P＞0.05）。FASN蛋白的表达与膀胱癌患者的年龄和性别有关（P＜0.05）,而与病理分级、肌层浸润和淋巴结转移无关（P＞0.05）。在膀胱癌患者中,FASN高表达者的总生存期要明显低于FASN低表达者（P＜0.05）。FASN正相关基因主要与SREBF激活基因表达、辅酶A代谢、细胞脂质分解代谢过程、激素分泌等有关。结论:FASN在膀胱癌组织中高表达,并且与膀胱癌患者的不良预后有关,FASN可能成为膀胱癌诊治的新的生物标志物。     

-脂肪酸合成酶在乳腺浸润性微乳头状癌中的表达及作用研究

  目的  探讨脂肪酸合成酶（fatty acid synthase,FASN）表达与乳腺浸润性微乳头状癌（invasive micropapillary carcinoma,IMPC）临床病理学特征及预后的相关性。  方法  选取2010年1月至2015年12月天津医科大学肿瘤医院105例乳腺IMPC组及105例乳腺浸润性导管癌-非特殊类型（invasive ductal carcinoma-no special type, IDC-NOS）组的病例,行FASN免疫组织化学法染色后进行统计学分析。利用CCK8、划痕实验检测FASN对T47D乳腺癌细胞增殖、迁移能力的影响。利用蛋白免疫印迹实验检测FASN对Wnt/β-catenin信号通路及上皮间质转化（epithelial-mesenchymal transition, EMT）的影响。  结果  FASN在IMPC中的表达为61.0%（64/105）,显著高于IDC-NOS的31.4%(33/105),两者比较差异具有统计学意义（P<0.001）。IMPC中的FASN表达与患者脉管癌栓、N分期、Ki-67表达呈正相关（P<0.05）,与IMPC患者的无病生存（disease-free survival, DFS）期和总生存（overall survival, OS）期呈负相关（P<0.01）。FASN高表达是IMPC患者DFS和OS降低的独立危险因素（P<0.05）。敲低FASN后T47D细胞的增殖、迁移能力显著下降（P<0.001）。FASN促进T47D细胞中Wnt/β-catenin通路及EMT。  结论  FASN通过Wnt/β-catenin信号通路促进EMT导致乳腺癌细胞增殖、迁移。FASN高表达与IMPC高侵袭、高转移等临床病理学特征呈正相关,是预测IMPC患者预后的独立危险因素。      

脂肪酸合成酶在肿瘤EMT中作用机制的研究进展

脂肪酸合成酶(fatty acid synthase,FASN)是脂肪酸从头合成代谢中唯一的关键酶,在多种肿瘤中呈高水平表达。EMT（epithelial to mesenchymal transition）是指已分化的上皮细胞转化形成具有间充质细胞特点的过程,在肿瘤中,产生间充质样细胞的EMT进程与肿瘤转移前的多种特性相关,包括侵袭、迁移、抗凋亡等,EMT已成为近年来肿瘤学研究的热点之一。有研究表明,FASN在肿瘤EMT中起到关键作用,抑制FASN可以逆转多种肿瘤EMT,同时抑制肿瘤细胞的侵袭、转移、抗药性。FASN可通过两个途径调节肿瘤EMT:第一,通过调控脂筏的组成和稳定性,进而影响定位于脂筏的蛋白,最终对EMT进行调控;第二,通过调节蛋白质的棕榈酰化状态,影响其功能发挥,从而调控EMT的发生和进展。     

TGF-β1通过调控脂肪酸合酶促进胃癌细胞的迁移及侵袭

  目的:  探讨TGF-β1通过调控脂肪酸合酶对胃癌细胞迁移及侵袭的影响。  方法:  收集南方医科大学顺德医院2016年1月至2018年12月存档的胃癌手术切除的石蜡标本54例，采用免疫组织化学法检测人胃癌组织中转化生长因子β1（transforminggrowth factor β1，TGF-β1）及脂肪酸合成酶（fatty acid synthetase，FASN）的表达情况，分析两者之间的相关性。构建TGF-β1基因过表达及siRNA沉默载体转染胃癌细胞株，用Real-time PCR和Western blot法分别检测对FASN mRNA及蛋白表达的影响。利用siRNA行FASN做基因沉默后，采用划痕及Transwell实验检测对胃癌细胞迁移及侵袭能力的影响。  结果:  免疫组织化学结果显示，TGF-β1与FASN在胃癌组织中的表达呈显著正相关。转染TGF-β1过表达质粒能明显上调FASN mRNA及蛋白的表达水平。反之，TGF-β1 siRNA则明显抑制FASN的表达。共转染FASN siRNA后，能减弱TGF-β1引起的N-cadherin蛋白表达、增强E-cadherin蛋白表达；划痕及Transwell实验显示能明显减弱TGF-β1所上调的细胞迁移及侵袭能力。  结论:   FASN在TGF-β1调控的胃癌细胞的迁移及侵袭过程中发挥重要作用。      

脂肪酸合成相关酶与乳腺癌的研究进展

乳腺癌是女性最常见的恶性肿瘤,随着肿瘤代谢研究的深入,脂代谢在乳腺癌发生发展中的作用越来越受到重视。内源性脂肪酸合成是肿瘤细胞脂肪酸的主要来源,也是肿瘤细胞的一个重要特征,靶向内源性脂肪酸合成治疗乳腺癌已经成为了一个研究热点。脂肪酸合成途径的相关酶包括ATP-柠檬酸裂解酶(adenosine triphosphate-citrate lyase,ACL)、乙酰辅酶A羧化酶1(acetyl-CoA carboxylase 1,ACC1)、脂肪酸合酶(fatty acid synthase,FASN)和硬脂酰辅酶A去饱和酶1(stearoyl-CoA desaturase-1,SCD1)在乳腺癌发生发展中发挥重要的作用,成为了乳腺癌治疗的新靶点。本文综述了ACL、ACC1、FASN和SCD1与乳腺癌的临床相关性及意义,在乳腺癌发生发展中的作用和分子机制及其抑制剂治疗乳腺癌的研究进展。     

FASN和p97在骨肉瘤组织中的表达及其与骨肉瘤远处转移的关系

目的探讨FASN和p97蛋白在骨肉瘤组织中表达的相关性及其与骨肉瘤远处转移的关系。方法应用免疫组织化学SP方法,检测60例骨肉瘤组织中FASN和p97蛋白表达情况,以21例骨软骨瘤组织作为对照。结果 FASN在骨肉瘤和骨软骨瘤组织中阳性表达率分别为60.0%（36/60）和28.6%（6/21）,有统计学差异。p97蛋白在骨肉瘤与骨软骨瘤组织中阳性表达率分别为68.3%（41/60）和8.1%（4/21）,有统计学差异。发生远处转移的骨肉瘤组织中FASN和p97蛋白阳性表达率分别为85.7%、92.9%,明显高于无远处转移骨肉瘤组织中FASN（52.2%,24/46）和p97（60.9%,28/46）阳性表达率,两者差异有显著意义（P〈0.05）,FASN和p97蛋白表达在骨肉瘤组织中呈显著正相关（γ=0.7）。FASN和p97蛋白阳性表达与骨肉瘤病理组织学分型无关,而与骨肉瘤的远处转移呈正相关。结论 FASN和p97蛋白在骨肉瘤组织中呈高表达,并且两者间显著相关,与骨肉瘤的发生及远处转移密切相关。     

肿瘤脂质代谢关键酶的研究进展

脂质代谢对肿瘤细胞的发生、发展有着重要的影响。正常细胞通过循环系统中的脂质来提供能量,而肿瘤通过自身的从头合成来提供能量,这种异常的脂质代谢不仅为其快速增殖提供能量,而且相关的脂质是参与肿瘤信号通路的重要分子。越来越多的研究发现脂质代谢与肿瘤细胞的发生、发展关系密切,其中脂质代谢过程中的一些关键酶如脂肪合成酶（FASN）、硬脂酰辅酶A脱氢酶1（SCD1）成为研究热点。这些关键酶在肿瘤组织中的表达较正常组织升高,有望作为肿瘤诊断及治疗的新靶点。文章将对脂质代谢与肿瘤发生、发展的关系进行综述。     

A novel inhibitor of fatty acid synthase shows activity against HER2+ breast cancer xenografts and is active in anti-HER2 drug-resistant cell lines

Introduction  

Inhibiting the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of breast carcinoma cells, and this is linked to human epidermal growth factor receptor 2 (HER2) signaling pathways in models of simultaneous expression of FASN and HER2.     

Fatty acid synthase phosphorylation: a novel therapeutic target in HER2-overexpressing breast cancer cells

Introduction

The human epidermal growth factor receptor 2 (HER2) is a validated therapeutic target in breast cancer. Heterodimerization of HER2 with other HER family members results in enhanced tyrosine phosphorylation and activation of signal transduction pathways. HER2 overexpression increases the translation of fatty acid synthase (FASN), and FASN overexpression markedly increases HER2 signaling, which results in enhanced cell growth. However, the molecular mechanism and regulation of HER2 and FASN interaction are not well defined. Lapatinib is a small-molecule tyrosine kinase inhibitor that blocks phosphorylation of the epidermal growth factor receptor and HER2 in breast cancer cells, resulting in apoptosis. We hypothesized that FASN is directly phosphorylated by HER2, resulting in enhanced signaling and tumor progression in breast cancer cells.

Methods

Using mass spectrometry, we identified FASN as one of the proteins that is dephosphorylated by lapatinib in SKBR3 breast cancer cells. Immunofluorescence, immunoprecipitation, Western blotting, a kinase assay, a FASN enzymatic activity assay, an invasion assay, a cell viability assay and zymography were used to determine the role of FASN phosphorylation in invasion of SKBR3 and BT474 cells. The FASN inhibitor C75 and small interfering RNA were used to downregulate FASN expression and/or activity.

Results

Our data demonstrated that FASN is phosphorylated when it is in complex with HER2. FASN phosphorylation was induced by heregulin in HER2-overexpressing SKBR3 and BT474 breast cancer cells. Heregulin-induced FASN phosphorylation resulted in increased FASN enzymatic activity, which was inhibited by lapatinib. The FASN inhibitor C75 suppressed FASN activity by directly inhibiting HER2 and FASN phosphorylation. Blocking FASN phosphorylation and activity by lapatinib or C75 suppressed the activity of matrix metallopeptidase 9 and inhibited invasion of SKBR3 and BT474 cells.

Conclusions

FASN phosphorylation by HER2 plays an important role in breast cancer progression and may be a novel therapeutic target in HER2-overexpressing breast cancer cells.     

Fatty acid synthase (FASN) levels in serum of colorectal cancer patients: correlation with clinical outcomes

Fatty acid synthase (FASN) is a common phenotype to many kinds of human cancers, such as those of the breast, ovary, pancreas, prostate, colon, and so on. Increased FASN levels have been detected in the serum of the patients with breast and pancreatic cancers. The relationship between the FASN level in serum and the clinicopathological characteristics of colorectal cancer is investigated in this study. FASN levels in serum were examined with enzyme-linked immunosorbent assay (ELISA) in 74 patients with colorectal cancer and 40 healthy persons. Pathological and clinical factors associated with FASN concentrations in serum were investigated and analyzed by statistical analysis. The FASN level in colorectal cancer patients’ serum is significantly higher than that in healthy persons’ serum. FASN levels in the serum of colorectal cancer patients are associated with tumor extent, lymph node metabasis status, distant metastasis, and tumor clinical stage. The 5-year overall survival rate and 5-year disease-free survival rate among patients with low FASN levels in serum are significantly higher than those among patients with high FASN levels in serum (log-rank P?=?0.003). The high FASN level in serum is a promising independent predictor of colorectal cancers with advanced phases, late clinical stages, and shorter survival. These results suggest that FASN concentration in serum may be a potential and useful tumor marker.     

Increased expression of fatty acid synthase provides a survival advantage to colorectal cancer cells via upregulation of cellular respiration

Fatty acid synthase (FASN), a lipogenic enzyme, is upregulated in colorectal cancer (CRC). Increased de novo lipid synthesis is thought to be a metabolic adaptation of cancer cells that promotes survival and metastasis; however, the mechanisms for this phenomenon are not fully understood. We show that FASN plays a role in regulation of energy homeostasis by enhancing cellular respiration in CRC. We demonstrate that endogenously synthesized lipids fuel fatty acid oxidation, particularly during metabolic stress, and maintain energy homeostasis. Increased FASN expression is associated with a decrease in activation of energy-sensing pathways and accumulation of lipid droplets in CRC cells and orthotopic CRCs. Immunohistochemical evaluation demonstrated increased expression of FASN and p62, a marker of autophagy inhibition, in primary CRCs and liver metastases compared to matched normal colonic mucosa. Our findings indicate that overexpression of FASN plays a crucial role in maintaining energy homeostasis in CRC via increased oxidation of endogenously synthesized lipids. Importantly, activation of fatty acid oxidation and consequent downregulation of stress-response signaling pathways may be key adaptation mechanisms that mediate the effects of FASN on cancer cell survival and metastasis, providing a strong rationale for targeting this pathway in advanced CRC.     

The fatty acid synthase inhibitor orlistat reduces experimental metastases and angiogenesis in B16-F10 melanomas

Background:Fatty acid synthase (FASN) is overexpressed and associated with poor prognosis in several human cancers. Here, we investigate the effect of FASN inhibitors on the metastatic spread and angiogenesis in experimental melanomas and cultured melanoma cells.Methods:The lung colonisation assay and cutaneous melanomas were performed by the inoculation of mouse melanoma B16-F10 cells in C57BL6 mice. Blood vessel endothelial cells (RAEC and HUVEC) were applied to determine cell proliferation, apoptosis, and the formation of capillary-like structures. Vascular endothelial growth factor A (VEGFA) expression was evaluated by quantitative RT-PCR and ELISA in B16-F10, human melanoma (SK-MEL-25), and human oral squamous carcinoma (SCC-9) cells. Conditioned media from these cancer cell lines were used to study the effects of FASN inhibitors on endothelial cells.Results:B16-F10 melanoma-induced metastases and angiogenesis were significantly reduced in orlistat-treated mice. Fatty acid synthase inhibitors reduced the viability, proliferation, and the formation of capillary-like structures by RAEC cells, as well as the tumour cell-mediated formation of HUVEC capillary-like structures. Cerulenin and orlistat stimulated the production of total VEGFA in B16-F10, SK-MEL-25, and SCC-9 cells. Both drugs also enhanced VEGFA(121), (165), (189,) and (165b) in SK-MEL-25 and SCC-9 cells.Conclusion:FASN inhibitors reduce metastasis and tumour-induced angiogenesis in experimental melanomas, and differentially modulate VEGFA expression in B16-F10 cells.     

Body mass index and risk of colorectal cancer according to fatty acid synthase expression in the nurses' health study

Fatty acid synthase (FASN) plays an important role in energy metabolism of fatty acids and is overexpressed in some colon cancers. We investigated whether associations between body mass index (BMI) and risk of colorectal cancer varied according to FASN expression. During follow-up of 109,051 women in the ongoing prospective Nurses' Health Study, a total of 1351 incident colon and rectal cancers were diagnosed between 1986 and 2004. We constructed tissue microarrays of the available resected tumor samples (n = 536), and FASN expression was analyzed by immunohistochemistry. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. All statistical tests were two-sided. High BMI was associated with an increased risk of FASN-negative (no or weak expression) colorectal cancer compared with normal BMI (high BMI [≥ 30 kg/m(2)], ie, obese vs normal BMI [18.5-22.9 kg/m(2)], HR = 2.25, 95% CI = 1.49 to 3.40, P(trend) < .001) but not with FASN-positive (moderate to strong expression) colorectal cancer. A statistically significant heterogeneity in colorectal cancer risks was observed between FASN-negative and FASN-positive tumors (P(heterogeneity) = .033). The age-adjusted incidence rates for FASN-positive and FASN-negative colorectal cancers were 10.9 and 7.1, respectively, per 100,000 person-years. This molecular pathological epidemiology study supports a role of energy metabolism in colorectal cancer pathogenesis.     

Caveolin-1 is required for the upregulation of fatty acid synthase (FASN), a tumor promoter, during prostate cancer progression

Prostate cancer is the second leading cause of cancer-related deaths in men. Fatty acid synthase (FASN) is normally upregulated during human prostate cancer onset and metastatic progression and its expression positively correlates with the development of advanced metastatic disease. However, it remains unknown what molecular factor(s) control FASN expression. It has been hypothesized that FASN functions as a tumor promoter during prostate cancer progression in humans. Consistently, an established mouse of model of prostate cancer, termed TRAMP mice, also shows the progressive upregulation of FASN levels during prostate cancer development. Here, we examine the role of caveolin-1 (Cav-1) in regulating FASN expression during prostate cancer progression. For this purpose, we crossed Cav-1-/- null mice with TRAMP mice to generate TRAMP/Cav-1+/+ and TRAMP/Cav-1-/- mice. Then, we assessed the expression of FASN in Cav-1+/+ and Cav-1-/- prostate tumors by immuno-histochemistry and Western blot analysis. Interestingly, our results indicate that FASN fails to be upregulated in Cav-1-/- tumors. Importantly, the tumors examined were the same morphological grade, but Cav-1-/- tumors were dramatically smaller and did not metastasize efficiently. We conclude that Cav-1 expression is normally required for the upregulation of FASN during prostate cancer progression. These results also mechanistically explain why TRAMP/Cav-1-/- mice are dramatically resistant to the development of prostate tumors and lung metastases, as they lack the expression of the FASN tumor promoter. Thus, TRAMP/Cav-1-/- mice will provide a novel model system to elucidate the role of FASN in prostate tumor progression. In addition, our results provide the first molecular genetic evidence that Cav-1 functions upstream of FASN during prostate cancer progression.