瘦素在乳腺癌发病中的作用

瘦素是一种由肥胖基因(ob基因)编码表达的小分子蛋白,在调控机体的摄食行为和脂肪代谢方面具有重要作用.近来大量研究发现瘦素在体外可促进乳腺细胞转化、癌细胞增生并促进血管生成.这表明瘦素在乳腺癌的发生发展中可能起重要作用,但具体机制尚未阐明.本文主要从体外实验、动物试验和乳腺癌病理组织研究3方面对瘦素在乳腺癌发病中的作用的近年相关研究进展进行综述.     

瘦素在乳腺癌发病中的作用

瘦素是一种由肥胖基因(ob基因)编码表达的小分子蛋白,在调控机体的摄食行为和脂肪代谢方面具有重要作用.近来大量研究发现瘦素在体外可促进乳腺细胞转化、癌细胞增生并促进血管生成.这表明瘦素在乳腺癌的发生发展中可能起重要作用,但具体机制尚未阐明.本文主要从体外实验、动物试验和乳腺癌病理组织研究3方面对瘦素在乳腺癌发病中的作用的近年相关研究进展进行综述.     

瘦素与乳腺癌的相关性及其致癌机理

肥胖是乳腺癌的一个危险因素，瘦素是肥胖基因编码的蛋白产物，与肥胖密切相关，瘦素与乳腺癌有什么样的关系呢？本文就瘦素在乳腺癌体外细胞系、活体血清及组织中的表达及其相关性作了详细阐述，同时从瘦素与雌激素、瘦素与IGF1及LPR基因的多态性等方面对瘦素可能的作用机理进行概述。     

乳腺癌和瘦素相关性研究进展

肥胖是乳腺癌的一个危险因素,瘦素作为肥胖基因的产物,与肥胖密切相关。在乳腺癌患者中,血清中瘦素水平显著升高;乳腺癌患者的脂肪组织和乳腺上皮细胞中也发现有Lpm RNA和瘦素受体表达。研究还证实:瘦素可以通过旁分泌和内分泌作用于乳腺上皮细胞,促使乳腺癌细胞的生长。结果表明,瘦素作为肥胖因子可能在肥胖致乳腺癌的过程中起重要作用。提供了一个为什么肥胖症与乳腺癌相关的解释。     

乳腺癌和瘦素相关性研究进展

肥胖是乳腺癌的一个危险因素，瘦素作为肥胖基因的产物，与肥胖密切相关。在乳腺癌患者中，血清中瘦素水平显著升高；乳腺癌患者的脂肪组织和乳腺上皮细胞中也发现有LpmRNA和瘦素受体表达。研究还证实：瘦素可以通过旁分泌和内分泌作用于乳腺上皮细胞，促使乳腺癌细胞的生长。结果表明，瘦素作为肥胖因子可能在肥胖致乳腺癌的过程中起重要作用。提供了一个为什么肥胖症与乳腺癌相关的解释。     

瘦素与胃肠运动

瘦素是由肥胖基因编码、脂肪细胞分泌的一种蛋白质类激素,在调节摄食、体重、能量消耗和神经内分泌方面发挥着重要的作用.研究证实,瘦素可以改变胃肠神经肌肉的反应性,从而调节胃排空及肠动力.表明瘦素是与胃肠的生理功能及胃肠疾病密切相关的一种新的胃肠激素.本文就瘦素与胃肠运动的关系进行简要综述.     

小RNA干扰VEGF-C基因表达对乳腺癌细胞增殖及凋亡的体外研究

目的:利用质粒pSilencer3.0-H1构建人血管内皮生长因子-C(VEGF-C)基因经小RNA干扰(siRNA)的表达载体,体外研究其对人乳腺癌细胞MDA-MB-435的增殖及凋亡作用,为乳腺癌VEGF-C基因靶向RNA干扰治疗的可行性作初步探讨.方法:构建3组针对VEGF-C的pSilencer3.0.VEGF-C/siRNA表达载体和1组阴性对照序列.测序鉴定后.将脂质体介导转染人乳腺癌细胞株MDA-MB-435.用RT-PCR和Western Blot检测转染前后VEGF-C基因的表达.挑选干扰效率最强的一组表达载体.以MTT法和流式细胞仪检测经siRNA干扰的VEGF-C对人乳腺癌细胞MDA-MB-435的体外作用.结果:经测序鉴定,VEGF-C基因的siRNA表达载体构建成功,转染人乳腺癌细胞MDA-MB-435后,检测显示VEG-C基因和蛋白水平表达量明显降低,抑制率最高达854%,细胞体外生长缓慢,72 h后凋亡率达60%.结论:针对人VEGF-C基因的siRNA表达载体能抑制VEGF-C的基因表达.促进了人乳腺癌细胞MDA-MB-435的凋亡,可进一步发挥治疗作用.     

瘦素对骨代谢影响研究进展

瘦素及其受体在中枢和外周多个部位均有表达,具有多种生物学功能,对于骨代谢有着重要的影响作用.近来研究发现瘦素可促进人骨髓间质细胞向成骨细胞分化,抑制其向脂肪细胞分化;血清瘦素水平还与成骨细胞活性及骨骼发育相关.瘦素在外周作用于多种骨细胞促进成骨,在中枢系统则抑制骨形成.瘦素在妇女绝经后骨质疏松的发生中发挥一定作用.该文主要归纳介绍瘦素调节骨代谢基本作用及调控骨骼生长作用的一些较重要的研究发现,并对其机制作初步探讨.     

瘦素对成骨细胞增殖及Collagen I和Cbfa1 mRNA表达的影响

目的 研究瘦素在体外对原代培养乳鼠颅盖骨成骨细胞增殖及对CollagenI(I型胶原蛋白)和Cbfa1 mRNA表达的影响.方法 培养乳鼠成骨细胞,以乳鼠成骨细胞为体外实验模型,采用MTT法检测不同浓度瘦素(0、40、80和160 ng/ml)作用于成骨细胞后的增殖情况;通过RT-PCR方法检测不同浓度瘦素对CollagenI和Cbfa1 mRNA的表达的影响.结果 瘦素作用于成骨细胞后,可促进其增值,OD值显著增加(P<0.01);瘦素增加CollagenI和Cbfa1 mRNA的表达,呈剂量效应关系.结论 瘦素促进成骨细胞增殖,同时通过调节CollagenI和Cbfa1的表达,促进成骨细胞分化,进而促进骨形成.     

瘦素受体在睾丸的表达分布及其功能

瘦素是肥胖基因的蛋白产物,参与了机体体重和能量调节、免疫调节、血管生成、炎症反应和青春期启动及生殖调节等一系列重要生理活动。瘦素发挥的不同作用与其受体(Ob-R)表达分布的时空特征相关,瘦素在睾丸内发挥着多种重要的生物学作用。本文通过综述Ob-R在大、小鼠及人类睾丸的不同细胞和不同发育阶段以及生理和病理状态下的表达和分布情况,结合已有的体外实验结果,探讨了Ob-R与睾丸功能的关系,希望能为进一步研究人类睾丸的生理发育及男性不育的病理生理机制开拓思路。     

瘦素及瘦素受体在乳腺癌中的表达及临床意义

目的 探讨瘦素及其受体mRNA及蛋白的表达在乳腺癌发生、发展中的意义。方法 采用巢式逆转录-聚合酶链反应〈RT-PCR）和免疫组织化学方法检测39例乳腺癌及其周围正常乳腺组织瘦素及其受体的mRNA及蛋白表达，分析乳腺癌组织瘦素与瘦素受体表达的相关性及其与临床病理之间的关系。结果 瘦素mRNA及蛋白在正常乳腺及乳腺癌组织阳性表达率均为100．00％；瘦素受体mRNA和蛋白在乳腺癌组织阳性表达率为74．40％。正常乳腺组织mRNA阳性表达率7．69％；瘦素及其受体在乳腺癌组织的表达量高于正常组织。差异具有统计学意义（P〈0．01）；瘦素受体的表达与瘦素表达明显相关（P〈0．01）。瘦素及瘦素受体高表达与乳腺癌的转移及浸润明显相关（P〈0．01）。结论 瘦素在乳腺癌的发生发展中可能起着促进作用，瘦素及其受体表达情况可以作为乳腺癌诊断或预后的指标。     

Hormonal regulation of mammary differentiation and milk secretion

The endocrine system coordinates development of the mammary gland with reproductive development and the demand of the offspring for milk. Three categories of hormones are involved. The levels of the reproductive hormones, estrogen, progesterone, placental lactogen, prolactin, and oxytocin, change during reproductive development or function and act directly on the mammary gland to bring about developmental changes or coordinate milk delivery to the offspring. Metabolic hormones, whose main role is to regulate metabolic responses to nutrient intake or stress, often have direct effects on the mammary gland as well. The important hormones in this regard are growth hormone, corticosteroids, thyroid hormone, and insulin. A third category of hormones has recently been recognized, mammary hormones. It currently includes growth hormone, prolactin, PTHrP, and leptin. Because a full-term pregnancy in early life is associated with a reduction in breast carcinogenesis, an understanding of the mechanisms by which these hormones bring about secretory differentiation may offer clues to the prevention of breast cancer.     

Leptin influences cellular differentiation and progression in prostate cancer

PURPOSE: Several studies have shown a positive association of dietary fat with prostate cancer. Leptin, a peptide hormone that has a role in the regulation of body weight, currently serves as a more accurate biomarker for total body fat. We designed a study to determine whether leptin influences cellular differentiation and the progression of prostate cancer. MATERIALS AND METHODS: In this study we investigated serum leptin in 21 patients with prostate cancer, 50 with benign prostatic obstruction and 50 healthy individuals matched for sex, body mass index and age. Patients with cancer were stratified into 2 groups by the disease spread, including groups 1--organ confined and 2--advanced disease, and into 3 groups by the differentiation degree, including groups 3--Gleason sum 2 to 4 or well differentiated, 4--Gleason sum 5 to 7 or moderately differentiated and 5--Gleason sum 8 to 10 or poorly differentiated. RESULTS: We noted significant differences in serum leptin in the cancer versus control and cancer versus benign prostatic obstruction groups. In addition, in the prostate cancer group serum leptin correlated with prostate specific antigen and biopsy Gleason score. We also observed significant differences in serum leptin in groups 1 versus 2, 3 versus 5 and 4 versus 5. CONCLUSION: Leptin may have roles in the development of prostate cancer through testosterone and factors related to obesity. It influences cellular differentiation and the progression of prostate cancer.     

übergewicht und Prostatakarzinom

Obesity is proposed as a possible risk factor for many tumors. The present review discusses the current knowledge on the clinical and biological impact of obesity on the development and progression of prostate cancer, the role of adipocyte-derived hormones (adipocytokines) in this scenario and the resulting clinical implications. In addition, the results of own experimental and clinical studies on the involvement of adipocytokines (e.g. leptin, adiponectin) in the pathophysiology of prostate cancer are presented. It was found that patients who were diagnosed with prostate cancer at this clinic had higher serum leptin and lower serum adiponectin concentrations. These investigations and other studies have further shown that higher serum levels of the adipocytokine leptin were associated with larger prostate cancer volumes, high-grade classification, biochemical recurrence, metastasis and progression of metastatic prostate tumors, as well as increased mortality. Moreover, there was a strong correlation between the serum level of leptin and serum levels of prostate specific antigen (PSA). Leptin stimulated in vitro the proliferation and inhibited the apoptosis of prostate cancer cells in a dose and time-dependent manner, however, androgen-resistant cell lines responded more strongly.At the molecular level, adipocytokines require the network of tyrosine kinases to accomplish the mitogenic and antiapoptotic effects in prostate cancer cells. Prominent members of the most important signal transduction cascades, such as MAPK, PI3-K and JAK/STAT are activated upon binding of leptin to its receptor on the cell membrane of prostate cancer cells. Adipocytokines such as leptin may serve as additional prognostic parameters for the evaluation of specific therapies for metastatic hormone refractory prostate cancer. The findings presented here are intended as a basis for further studies.     

Notch Signaling in Mammary Development and Oncogenesis

With the discovery of an activated Notch oncogene as a causative agent in mouse mammary tumor virus induced breast cancer in mice, the potential role for Notch signaling in normal and pathological mammary development was revealed. Subsequently, Notch receptors have been found to regulate normal development in many organ systems. In addition, inappropriate Notch signaling has been implicated in cancer of several tissues in humans and animal model systems. Here we review important features of the Notch system, and how it may regulate development and cancer in the mammary gland. A large body of literature from studies in Drosophila and C. elegans has not only revealed molecular details of how the Notch proteins signal to control biology, but shown that Notch receptor activation helps to define how other signaling pathways are interpreted. In many ways the Notch system is used to define the context in which other pathways function to control proliferation, differentiation, cell survival, branching morphogenesis, asymmetric cell division, and angiogenesis--all processes which are critical for normal development and function of the mammary gland.     

The Role of NRG3 in Mammary Development

The Neuregulin gene family encodes EGF-containing ligands which mediate their effects by binding to the ERBB receptor tyrosine kinases, a signalling network with important roles in both mammary gland development and breast cancer. Neuregulin3 (NRG3), a ligand for ERBB4, promotes early mammary morphogenesis and acts during specification of the mammary placode, an aggregate of epithelial cells that forms during mid-embryogenesis. Recent studies have shown that NRG3 can alter the cell fate of other epidermal progenitor populations when NRG3 is mis-expressed throughout the basal layer of the developing epidermis with the K14 promoter. Here evidence for a key function for NRG3 in promoting early mammary morphogenesis and the implication for the role of NRG3 in breast cancer and establishment of the mammary lineage are discussed.     

Next Stop, the Twilight Zone: Hedgehog Network Regulation of Mammary Gland Development

The hedgehog signal transduction network is a critical mediator of cell-cell communication during embryonic development. Evidence also suggests that properly regulated hedgehog network function is required in some adult organs for stem cell maintenance or renewal. Mutation, or misexpression, of network genes is implicated in the development of several different types of cancer, particularly that of skin, brain, lung, and pancreas. Recent studies in the mouse mammary gland have demonstrated roles for hedgehog network genes at virtually every phase of mammary gland development where it regulates such diverse processes as embryonic mammary gland induction, establishment of ductal histoarchitecture, and functional differentiation in lactation. Further, studies suggest a role for misregulated network function in the progression of breast cancer.