O-GLYCOSYLATION OF HCG AND CANCER

HCG 的 O-糖基化与癌症

• 批准号: 3186695
• 负责人: LAURENCE Anthony COLE
• 金额: $ 21.11万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-05-01 至 1994-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3186695
• 关键词: bioassay; biomarker; carbohydrate structure; cell differentiation; cell membrane; chemical structure function; choriocarcinoma; chorionic gonadotropin; colony stimulating factor; diagnosis design /evaluation; electrofocusing; enzyme mechanism; glycosylation; glycosyltransferase; growth factor; human pregnant subject; human tissue; hydatidiform mole; neoplasm /cancer diagnosis; neoplastic cell; oligosaccharides; pregnancy; prenatal diagnosis; radiotracer; tissue /cell culture; trophoblast; urine

Human chorionic gonadotropin (hCG) is produced by the trophoblast in pregnancy, mole and choriocarcinoma. Studies in this and other laboratories have shown that a specific O-linked oligosaccharide structure, NeuAc alpha2,3Ga1 beta1,3(NeuAc alpha2,3Gal beta1,4GlcNAc beta1,6)GalNAc, and N-linked oligosacchrides of the GlcNAc beta1,4Man alpha1,3 triantennary-type are consistently found on choriocarcinoma hCG molecules. Studies here show that these same structures may also be present on early pregnancy hCG, from 1-3 weeks following implantation, or the time of trophoblast invasion of the uterus. This led to the hypothesis that these structures are characteristic of invasive cells. Our objectives are: 1) To confirm the hypothesis that these structures are characteristic of invasive cells, we will examine the carbohydrate structures on further samples of hCG from early pregnancy and from testicular and other cancer patients. 2) To determine if these same oligosaccharides are more abundant on cancer cell plasma membranes, where they may effect cell-cell interaction and possibly cell invasiveness. 3) To compare pertinent glycosyltransferase activities, GlcNAc beta1,6GalNAc transferase, GlcNAc transferase-IV, and NeuAc alpha2,3 transferase in normal and malignant cells. 4) Trophoblast has CSF-I and PDGF receptors. Recent experiments suggest that CSF-I may promote trophoblast invasiveness in early pregnancy. The effect of CSF-1 and PDGF on hCG glycosylation and on trophoblast glycosyltransferase activities will be investigated. 5) Cytotrophoblast cells predominate and produce hCG in very early pregnancy, differentiated sycytial structures then take-over this function. Using culture models, the effects of trophoblast differentiation on hCG glycosylation will be examined. 6) To use immunoassays and chromatofocusing methods to monitor the levels of "invasive cell" hCG, in trophoblast disease (to follow the progression of hydatidiform mole to malignant disease), in early pregnancy (from women having persistent and spontaneously- aborting pregnancies), and in women with invasive placental disease (placenta accreta, increta or percreta). 7) Thyrotoxicosis and gynecomastia can develop from the "invasive cell" hCG production that occurs in choriocarcinoma and testicular cancer. To determine if "invasive cell" hCG has altered or additional biologic activities, the steroidogenic, cAMP-promoting, thyrotropic, receptor-binding and metabolic clearance rates of normal pregnancy and "invasive cell hormone will be compared.

人绒毛膜促性腺激素（hCG）是由滋养层产生的 怀孕、痣和绒癌。 在这方面的研究和其他 实验室已经证明，一种特定的O-连接寡糖 结构，NeuAc α 2，3Ga 1 β 1，3（NeuAc α 2，3Gal β 1，4GlcNAc β 1，6）GalNAc和N-连接寡糖 GlcNAc β 1，4 Man α 1，3三触角型始终存在 绒毛膜癌的hCG分子。 研究表明，这些 同样的结构也可能存在于早孕hCG上， 1-3植入后数周，或滋养层细胞 侵犯子宫。 这导致了一种假设， 结构是侵入性细胞的特征。 我们的目标 为： 1)为了证实这些结构是 作为侵入性细胞的特征，我们将检查碳水化合物 来自早期妊娠的hCG的进一步样品和来自 睾丸癌和其他癌症患者。 2)为了确定这些相同的寡糖是否比 在癌细胞质膜上，它们可以影响细胞间的 相互作用和可能的细胞侵袭性。 3)为了比较相关的糖基转移酶活性，GlcNAc β 1，6 GalNAc转移酶、GlcNAc转移酶-IV和NeuAc α 2，3转移酶在正常和恶性细胞中的表达。 4)滋养层细胞具有CSF-I和PDGF受体。 最近的实验 提示CSF-I可能促进早期滋养细胞侵袭， 怀孕 CSF-1和PDGF对hCG糖基化和细胞增殖的影响 对滋养层糖基转移酶活性的影响。 5)细胞滋养层细胞占优势，并在非常早期产生hCG。 怀孕，分化的合胞体结构，然后接管这个 功能 使用培养模型， 将检查对hCG糖基化的分化。 6)使用免疫测定和色谱聚焦方法监测 滋养层疾病中的“侵袭细胞”hCG水平（以下 葡萄胎发展为恶性疾病）， 早期妊娠（来自持续性和自发性- 流产），以及患有侵袭性胎盘疾病的女性 （胎盘植入、植入或渗透）。 7)甲状腺毒症和男性乳房发育症可以从“侵入性”发展而来， 绒毛膜癌和睾丸癌中发生的细胞”hCG产生 癌 为了确定“侵入性细胞”hCG是否改变或 另外的生物活性，类固醇生成，cAMP促进， 促甲状腺激素、受体结合和代谢清除率 将正常妊娠与“侵袭性细胞激素”进行比较。