脂肪酸合成酶与前列腺癌

脂肪酸合成酶(fatty acid synthase,FAS)是新近发现的脂肪酸生物合成过程中一种关键酶,其过度表达导致酶活力的增高,导致肿瘤组织的恶性行为与其特殊的物质代谢和能量代谢。FAS在PCa组织中的表达远高于正常前列腺组织,说明FAS可以作为一种PCa的肿瘤标记物,用于PCa的早期诊断。FAS在PCa中异常的表达增高,可能为PCa的药物治疗提供新的靶位,为PCa的患者提供一种新的治疗方式。     

脂肪酸合成酶在三阴性乳腺癌中的表达及其预后价值

目的探讨脂肪酸合成酶（fatty acid synthase,FAS）在三阴性乳腺癌（triple-negative breast cancer,TNBC）中的表达及其预后价值。方法回顾性分析安徽省滁州市第一人民医院及江苏省肿瘤医院2006年1月至2012年12月手术病理确诊的TNBC176例的免疫组化检测FAS的表达情况,统计学分析FAS的不同表达情况与临床病理特征及预后的相关性。结果 TNBC中FAS的阳性率为68%。FAS与肿瘤大小、组织学分级、淋巴结转移有相关性。随访显示,FAS阳性者的5年总生存率和无病生存率均低于FAS阴性者（55% vs.84%,21% vs.73%,均P〈0.01）。结论 TNBC中FAS阳性者预后差,FAS可能成为TNBC新的治疗靶点及预后指标。     

脂肪酸合酶在前列腺癌中的作用及其临床意义

前列腺癌(PCa)是男性最常见的恶性肿瘤之一,在西方国家是致死率排第二的恶性肿瘤,在我国的发病率和病死率也逐年升高。PCa进展为去势抵抗性前列腺癌(CRPC)和发生转移一直是其治疗的难点,目前尚无有效治疗方法。因此,亟需对PCa进展的机制进行更加广泛且深入的研究,以寻找新的治疗靶点。脂肪酸合酶(FASN)作为长链脂肪酸...     

脂肪酸合成酶在乳腺良恶性病变组织中的表达

为探究脂肪酸合成酶（FAS）在乳腺良、恶性病变中表达的差异。笔者对乳腺癌和乳腺良性病变（各46例）病理石蜡标本中的FAS进行免疫组化染色，评估两组FAS的染色水平，比较其表达的差异。结果示：乳腺良性病变中FAS阳性率为15.2%，乳腺癌组织中FAS表达为71.7%（P＜0.001）;FAS染色阳性病例中，乳腺癌组FAS染色强度显著高于乳腺良性病变组（P＝0.037）。提示相对于乳腺良性病变，FAS在乳腺癌组织中明显过度表达。FAS的表达状况有可能成为乳腺良、恶性病变的鉴别方法之一。     

前列腺素合成酶2在前列腺癌和前列腺增生中的表达及其意义

目的研究前列腺素合成酶(COX)-2在前列腺癌和前列腺增生组织中的表达及与临床的关系.方法随机选择42份前列腺增生和16份前列腺癌患者的手术标本,从定性和定量两个方面分别采用免疫组织化学和蛋白印记方法对COX-2蛋白的表达进行研究.结果16份前列腺癌标本中,15份COX-2呈阳性表达,占93.8%;42份前列腺增生的组织中,只有11份有COX-2的表达,占26%,两者差异有非常显著意义(直接概率法P＜0.01).且COX-2高表达的前列腺癌患者预后不佳.结论COX-2在前列腺癌组织中表达增强,且与癌的临床分期有关.     

膀胱移行细胞癌中脂肪酸合成酶表达的临床意义及判断预后的价值

脂肪酸合成酶（FAS）在许多肿瘤高度表达，其表达水平增高可能是某些肿瘤预后不良的一个标志。我们采用免疫组织化学技术对膀胱移行细胞癌中FAS表达进行检测。[第一段]     

PLK1在前列腺癌中的表达及其临床意义

目的 探讨丝氨酸/苏氨酸蛋白激酶1(PLK1)在前列腺癌中的表达及其临床意义.方法 应用免疫组化PV-9000两步法检测PLK1在51例前列腺癌组织,35例良性前列腺增生组织中的表达.结果 PLK1在前列腺癌组织中呈过表达,与良性前列腺增生组织相比,差异十分显著(P＜0.05).在前列腺癌组织高、中、低分化组的表达均有显著性差异(P＜0.05),在C～D期的表达明显高于A～B期的表达,有显著性差异(P＜0.05);其表达与病理Glease评分呈正相关(r=0.622,P＜0.01),与临床分期呈正相关(r =0.522,P＜0.01),与年龄、术前PSA无明显相关性.结论 PLK1在前列腺癌中高表达,与肿瘤的增值活性相关,在前列腺癌的发生发展中起重要作用,可能成为治疗前列腺癌的一个新的理想靶点.     

PTEN蛋白在前列腺癌中的表达及临床意义

目的　探讨PTEN蛋白表达与前列腺癌临床病理特征及临床分期的关系。方法　应用免疫组织化学法检测 3 2例前列腺癌及 5例良性前列腺增生组织中PTEN蛋白的表达。结果　 3 2例前列腺癌中有 8例 (2 5 .0 % )呈不同程度的阳性表达。随肿瘤细胞病理分级 ,临床分期增高 ,PTEN蛋白表达率降低 ,高分化组与中分化间表达率的差异无显著性 ,但高、中分化组与低分化组间的差异有显著性 (P <0 .0 5 )。在A、B期的表达率明显高于C、D期 (P <0 .0 5 )。结论　抑癌基因PTEN的表达缺乏在前列腺癌的发生、发展中起重要作用 ,检测PTEN蛋白的表达有助于判断病情及预后。     

三阴性乳腺癌组织中脂肪酸合成酶的表达及其意义

目的:探讨三阴性乳腺癌中脂肪酸合成酶(FAS)的表达及FAS与三阴性乳腺癌发生和进展的关系。方法:采用免疫组织化学法从蛋白水平检测30例三阴性乳腺癌和25例非三阴性乳腺癌及10例三阴性乳腺癌旁正常乳腺组织中FAS的表达情况。结果:FAS在三阴性乳腺癌中高表达,阳性表达率60%(18/30);FAS在非三阴性乳腺癌组织中低表达,阳性率为24%(6/25);FAS在癌旁组织中表达最低,阳性率为10%(1/10);三者阳性率的比较差异均有统计学意义(P<0.05)。在有远处转移的5例三阴性乳腺癌中,有4例FAS表达阳性,表达率为80.0%;在无远处转移的25例三阴性乳腺癌中,FAS表达阳性有5例,表达率为20.0%。三阴性乳腺癌FAS的表达率越高,其远处转移的发生率越高(P<0.05)。结论:FAS的表达可能在三阴性乳腺癌的发生、发展及转移中发挥作用,并且其表达还可能与三阴性乳腺癌的预后有关。     

TLR4在前列腺癌中的表达及临床意义

目的：探讨TLR4在前列腺癌（PCa）中的表达情况及意义。方法：采用免疫组化法检测TLR4与Survivin蛋白在41例PCa及20例良性前列腺增生（BPH）组织中的表达,同时分析TLR4和Survivin蛋白表达与Gleason系统分级的关系。结果：TLR4与Survivin蛋白在BPH组织中的阳性表达例数分别为15例（75％）与0例（O）,在PCa组织中的阳性表达例数分别为18例（43．9％）与28例（68．3％）,TLR4表达与PCa的Gleason系统分级有显著相关性（P〈0．05）,随着Gleason评分增高,TLR4表达降低。Survivin蛋白的表达与Gleason系统分级无关（P〉O．05）。结论：TLR4表达与PCaGleason系统分级相关,其表达与PCa的发生发展密切相关,可成为估计肿瘤预后的一项指标。     

Increased fatty acid synthase as a therapeutic target in androgen-independent prostate cancer progression

BACKGROUND: Fatty acid synthase (FAS) performs the anabolic conversion of dietary carbohydrate or protein to fat. FAS expression is low in most normal tissues, but is elevated in many human cancers, including androgen-sensitive and androgen-independent prostate cancer. METHODS: Immunohistochemical evaluation of FAS expression was performed in human prostate cancer specimens under various states of androgen ablation. In vitro and in vivo prostate cancer models were evaluated for FAS expression and activity under androgenic and androgen-depleted conditions, and were tested for sensitivity to antimetabolite drugs that target fatty acid synthesis. RESULTS: While FAS expression in the prostate was androgen responsive, it persisted or was reactivated in human prostate carcinoma after androgen ablation, and was high in 82% of lethal tumors examined at autopsy. Similar patterns of FAS expression and fatty acid synthesis were seen in cell culture and xenograft models of human prostate cancer. Pharmacologic inhibition of FAS resulted in a dose-dependent reduction of tumor growth in these models, including fourfold inhibition of an androgen-independent human prostate cancer xenograft with little associated toxicity. CONCLUSIONS: The data suggest that FAS expression/FA synthesis provides an important functional aspect of the malignant phenotype in prostate cancer, perhaps supporting cell growth or survival. FAS expression may be upregulated by alternate signaling pathways important for prostate cancer growth under androgen withdrawal. The re-emergence of FAS expression and activity during the development of androgen independence demonstrate that FAS may serve as a novel target for antimetabolite therapy in prostate cancer.     

Speckle-type POZ protein suppresses lipid accumulation and prostate cancer growth by stabilizing fatty acid synthase

Fatty acid synthase (FASN) is vital for maintaining lipid homeostasis in prostate cancer (PCa) cells, which have an increased rate of de novo fatty acid (FA) synthesis. Mutations in the gene encoding the tumor suppressor speckle-type POZ protein (SPOP), which is a E3 ubiquitin ligase, are a critical feature of PCa. Here, we provide evidence that FASN is a substrate of SPOP and that interaction of these proteins induces FASN ubiquitination and proteasome-dependent degradation. We showed that SPOP mutants commonly found in PCa cannot bind to FASN. Moreover, a decrease in SPOP levels upregulated FASN expression and triggered lipid accumulation in PCa cells. These results demonstrate that FASN is a crucial mediator of SPOP-induced inhibition of PCa cell growth. Our data provide evidence that SPOP regulates lipid metabolism by decreasing FASN expression and FA synthesis, resulting in tumor suppression. Taken together, our study indicates that this pathway may be a new therapeutic target for treating PCa.     

Increased fatty acid synthase expression and activity during progression of prostate cancer in the TRAMP model

BACKGROUND: Fatty acid synthase (FAS) is the major enzyme required to convert carbohydrates to fatty acids. Recent evidence suggests that FAS activity is essential for prostate cancer growth and survival, since blocking the enzyme activity results in cell death. In this study, the role of FAS up-regulation during prostate tumor progression in the transgenic adenocarcinoma of mouse prostate (TRAMP) model was investigated. Sensitivity to FAS anti-metabolites was also analyzed in TRAMP prostate tumor cells and tissue to determine therapeutic potential of FAS inhibition in the treatment of prostate cancer. METHODS: FAS expression was evaluated by immunohistochemistry of TRAMP tissues, including primary and metastatic lesions in mice of varying ages. FAS pathway activity was studied in vitro using TRAMP-derived cell lines and in vivo in TRAMP tissues. The sensitivity of TRAMP cell lines and tissues to the antimetabolite drugs (2R,3S)-2,3-epoxy-4-oxo-7,10-trans, transdodecadienamide (cerulenin) and C-75, which target FAS, was determined by FAS antimetabolite inhibition of 14C-acetate conversion to fatty acids, cell growth inhibition, and apoptosis analyses. RESULTS: High FAS expression and activity in the TRAMP mouse prostate was evident at 12 weeks of age compared with nontransgenic littermates and further increased with age, tumor progression, and in metastatic lesions. FAS pathway inhibition resulted in a dose-dependent reduction in cell survival and decreased enzyme activity in these models. CONCLUSIONS: These data suggest that the up-regulation of FAS expression play a role in tumorigenesis of the prostate in the TRAMP model and hence can provide valuable insight into human prostate cancer. Given the response of tumor cells to FAS antimetabolites, FAS may serve as a novel target for prostate cancer therapy.     

Prostatic levels of fatty acids and the histopathology of localized prostate cancer

PURPOSE: The consumption of various fatty acids has been associated with advanced stage and fatal prostate cancer. While numerous mechanisms have been postulated, to our knowledge there physiological data linking exposure and prognosis in humans are lacking. We examined prostatic levels of individual fatty acids in relation to the prevalence of histopathological characteristics associated with invasiveness and the risk of progression in 49 men undergoing radical prostatectomy for localized prostate cancer. MATERIALS AND METHODS: Fatty acids were measured using capillary gas chromatography in fresh nonmalignant prostate tissue collected at surgery. Markers of invasiveness and increased risk of progression (Gleason sum 7 or greater, perineural invasion, anatomical or surgical margin involvement, extracapsular extension, seminal vesical involvement and stage T3 tumor) were evaluated separately. Each marker was dichotomized into a yes (case) and no (control) level with patients grouped accordingly. Mean concentrations were compared using the Wilcoxon rank sum test. RESULTS: The percent of total prostatic polyunsaturated fat and polyunsaturated-to-saturated fat ratios were significantly lower in the presence of perineural invasion, seminal vesical involvement and stage T3 tumor (p = 0.02 to 0.049). alpha-Linolenic acid was significantly lower when tumor extended to an anatomical or surgical margin (p = 0.008). The omega-3 and omega-3-to-omega-6 fatty acid ratios were 1.5 to 3.3-fold lower in cases than in controls, reaching borderline significance in nearly all comparisons (p = 0.052 to 0.097). Saturated and monounsaturated fatty acids were not associated with the traits examined. CONCLUSIONS: These data suggest that polyunsaturated fatty acids and perhaps essential fatty acids in particular help to regulate prostate carcinogenesis in humans.     

Elevated expression of inhibin alpha in prostate cancer

PURPOSE: Less than 50% of men who undergo radical prostatectomy for prostate cancer are cured of disease. We evaluate tumor expression of inhibin alpha, a putative tumor suppressor, and the related protein, follistatin, to determine whether expression correlated with failure to be cured by surgery. MATERIALS AND METHODS: Tissues were selected from an archival collection of 379 prostatectomy specimens from men with followup of at least 5 years after surgery. Since previous studies showed that such men with only Gleason grade 3 cancer had a greater than 95% chance of no biochemical recurrence (increase in serum prostate specific antigen), our investigation was confined to 174 men with 2% or greater grade 4/5 cancer. These men had an intermediate rate of failure, providing an opportunity to analyze the potential contribution of inhibin alpha or follistatin to progression. Intensity of immunohistochemical labeling for inhibin alpha and follistatin in each cancer was compared with that in normal glands within the same tissue section. RESULTS: The majority of cases showed more intense expression of inhibin alpha in cancer than in normal glands. Those individuals whose cancers had the most elevated expression of inhibin alpha had a higher risk of recurrence, although this association was not statistically significant. Follistatin was expressed equivalently in normal and cancer cells in the majority of cases and did not correlate with recurrence. CONCLUSIONS: Our finding that inhibin alpha is frequently overexpressed in high grade prostate cancer suggests that the role of inhibin alpha as a tumor suppressor needs to be reevaluated. Furthermore, assessment of inhibin alpha as a serum marker of prostate cancer, as used to diagnose ovarian cancer, may be warranted.