The Role of SNCG in the Carcinogenesis of Uterine Papillary Serous Carcinoma

SNCG 在子宫乳头状浆液性癌发生中的作用

• 批准号: 7740003
• 负责人: Barbara M Buttin
• 金额: $ 24.32万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-08 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740003
• 关键词: Accounting; Address; Aggressive behavior; Anchorage-Independent Growth; Aneuploidy; Antineoplastic Agents; Apoptosis; Behavior; Benign; Biological Markers; Biopsy; Breast; Cancer cell line; Carcinoma; Cell Line; Cell Proliferation; Cells; Cessation of life; Chromosomes; Clinical; Complementary DNA; Data; Decision Making; Development; Diagnostic; Disease; Drug Delivery Systems; Early identification; Endometrial Carcinoma; Endometrium; Epithelium; Estrogens; Event; Exhibits; FOLR1 gene; First Name; Follow-Up Studies; Genes; Genetic; Genetic Risk; Gynecologic; Histologic; Histology; Laboratories; Lead; Length; Link; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Messenger RNA; Methods; Microtubules; Molecular; Mutation; Oligonucleotides; Oncogenes; Operative Surgical Procedures; Outcome; PLAU gene; PTEN gene; Paclitaxel; Papillary; Paraffin Embedding; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Plasmid Cloning Vector; Platinum; Process; Prognostic Factor; Progression-Free Survivals; Proteins; Recording of previous events; Recurrence; Relative (related person); Resistance; Risk; Role; SNCG gene; STK6 gene; Screening procedure; Series; Serous; Serum; Signal Pathway; Specimen; Staging; Staining method; Stains; TP53 gene; Taxane Compound; Testing; Tetanus Helper Peptide; Tetracyclines; Time; Tissues; Triage; United States; Uterine Cancer; Woman; advanced disease; base; breast lesion; carcinogenesis; cell motility; chemotherapeutic agent; chemotherapy; cohort; high risk; improved; malignant breast neoplasm; mortality; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; outcome forecast; overexpression; patient population; prognostic; prophylactic; public health relevance; research study; response; small hairpin RNA; synuclein; taxane; tertiary care; treatment strategy; tumor

DESCRIPTION (provided by applicant): Endometrial cancer is the most common gynecologic malignancy with an estimated 40,100 new cases expected in the United States in 2008. Uterine papillary serous carcinoma (UPSC) is an aggressive histologic subtype accounting for about 10% of all cases but almost 40% of endometrial cancer deaths. Unlike for the more common endometrioid endometrial carcinomas, the pathogenesis of UPSC is largely unknown. These cancers often present in advanced stages and exhibit poor response to chemotherapy. Effective and tailored treatment strategies are lacking. We performed a focused, real time PCR array comparing an endometrioid (Ishikawa) and a UPSC (SPEC2) cell line which revealed that the most highly expressed gene in SPEC2 over Ishikawa was the pro-metastatic oncogene synuclein-3 (SNCG). We also showed that SNCG mRNA and protein were highly expressed in SPEC2 versus endometrioid endometrial cancer cell lines. Similar expression data was obtained by Immunohistochemical staining. Finally, silencing of SNCG by shRNA caused a significant decrease in cell proliferation in SPEC2 cells and increased sensitivity of SPEC2 cells to paclitaxel induced apoptosis. SNCG is well studied in breast cancer where it correlates with advanced stage and aggressive disease as well as resistance to microtubule-disrupting agents. In this study, we will correlate SNCG expression in a series of 300 UPSC tumors and serum specimens with clinical and pathologic prognostic factors, response to chemotherapy, and outcomes in UPSC patients. Since SNCG was first described in breast cancer and a link between breast cancer and UPSC has long been suspected, we will also investigate SNCG expression in UPSC patients with a personal history of breast cancer. We will then study the molecular mechanisms by which SNCG influences proliferation, invasion, and sensitivity to antimicrotubule drugs in UPSC tumor cells by using various methods to inhibit SNCG in the SPEC2 cell line and compare results to two additional UPSC cell lines as well as a tet-inducible Ishikawa cell line overexpressing SNCG. We will also investigate the differential effect of other chemotherapeutics and targeted agents on the cell lines. In summary, we hypothesize that SNCG expression in UPSC is associated with its aggressive tumor phenotype, poor prognosis, and chemoresistance and that inhibition of its expression decreases the invasive and metastatic potential of the tumor and improves its sensitivity to microtubule targeting chemotherapy. SNCG may be a novel prognostic biomarker in UPSC correlating with advanced disease, decreased progression-free survival, and decreased response to standard chemotherapy. Additionally, SNCG could be developed as a novel therapeutic target. Its expression in UPSC could be used to hel guide our decision making in choosing the most effective chemotherapy. PUBLIC HEALTH RELEVANCE: By investigating the mechanism of action of SNCG in UPSC, we hope to lay the groundwork for a new therapeutic approach to UPSC that may ultimately have to be different than our current approach to treating all endometrial cancers. We believe that SNCG has potential as a biomarker for aggressive behavior in UPSC and may be able to help direct the choices of antineoplastic agents used to treat it. In addition, we will attempt to show that SNCG expression may link UPSC and breast cancer which would have implications regarding screening and prophylactic surgery in the two patient populations.

描述（由申请人提供）：子宫内膜癌是最常见的妇科恶性肿瘤，预计 2008 年美国将出现 40,100 例新发病例。子宫乳头状浆液性癌 (UPSC) 是一种侵袭性组织学亚型，约占所有病例的 10%，但占子宫内膜癌死亡人数的近 40%。与更常见的子宫内膜样子宫内膜癌不同，UPSC 的发病机制很大程度上未知。这些癌症通常处于晚期并且对化疗反应不佳。缺乏有效且量身定制的治疗策略。我们进行了聚焦实时 PCR 阵列比较子宫内膜样细胞系 (Ishikawa) 和 UPSC (SPEC2) 细胞系，结果表明 SPEC2 中表达量最高的基因是促转移癌基因 synuclein-3 (SNCG)。我们还表明，与子宫内膜样子宫内膜癌细胞系相比，SNCG mRNA 和蛋白质在 SPEC2 中高表达。通过免疫组织化学染色获得了类似的表达数据。最后，shRNA沉默SNCG导致SPEC2细胞的细胞增殖显着下降，并且SPEC2细胞对紫杉醇诱导的细胞凋亡的敏感性增加。 SNCG 在乳腺癌中得到了充分研究，它与晚期和侵袭性疾病以及对微管破坏剂的耐药性相关。在这项研究中，我们将 300 个 UPSC 肿瘤和血清标本中的 SNCG 表达与 UPSC 患者的临床和病理预后因素、化疗反应和结局相关联。由于 SNCG 首次在乳腺癌中被描述，并且长期以来人们怀疑乳腺癌与 UPSC 之间的联系，因此我们还将研究有乳腺癌个人史的 UPSC 患者中的 SNCG 表达。然后，我们将通过使用各种方法抑制 SPEC2 细胞系中的 SNCG，研究 SNCG 影响 UPSC 肿瘤细胞增殖、侵袭和抗微管药物敏感性的分子机制，并将结果与​​另外两种 UPSC 细胞系以及过表达 SNCG 的 tet 诱导 Ishikawa 细胞系进行比较。我们还将研究其他化疗药物和靶向药物对细胞系的不同影响。总之，我们假设 UPSC 中 SNCG 的表达与其侵袭性肿瘤表型、不良预后和化疗耐药相关，抑制其表达可降低肿瘤的侵袭和转移潜力，并提高其对微管靶向化疗的敏感性。 SNCG 可能是 UPSC 中的一种新型预后生物标志物，与晚期疾病、无进展生存期缩短以及对标准化疗的反应降低相关。此外，SNCG 可以开发为新的治疗靶点。它在 UPSC 中的表达可用于帮助指导我们选择最有效的化疗方案。公共健康相关性：通过研究 SNCG 在 UPSC 中的作用机制，我们希望为 UPSC 的新治疗方法奠定基础，该方法最终可能会不同于我们目前治疗所有子宫内膜癌的方法。我们相信 SNCG 有潜力作为 UPSC 攻击行为的生物标志物，并且可能能够帮助指导用于治疗它的抗肿瘤药物的选择。此外，我们将尝试证明 SNCG 表达可能与 UPSC 和乳腺癌有关，这将对两个患者群体的筛查和预防性手术产生影响。