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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/44700完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 許輝吉 | |
| dc.contributor.author | Wei Cheng | en |
| dc.contributor.author | 鄭威 | zh_TW |
| dc.date.accessioned | 2021-06-15T03:53:09Z | - |
| dc.date.available | 2015-09-09 | |
| dc.date.copyright | 2010-09-09 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-07-05 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/44700 | - |
| dc.description.abstract | Glypican-3 (GPC3) 磷脂肌醇聚糖3是一種可經由糖基磷脂酰肌醇glycosyl-phosphatidylinositol (GPI) 鍵連結在細胞膜上的糖蛋白。且是導致Simpson- Golabi - Behmel增生綜合症的突變基因。之前我們經由北方墨點試驗發現在超過70% 肝細胞癌中會大量表現GPC3。Glypican - 3（GPC3）GPC3在肝細胞癌，威姆氏瘤 (Wilms’ tumor)，肝母細胞癌,及絨毛膜癌中呈現過度表現，且可促進癌細胞的生長。GPC3曾被報導過與Wnt，Hedgehog，BMPs及類胰島素生長激素(IGF)的路徑有關，但真正的機轉仍不清楚。在本研究中，我們進一步闡明了GPC3引發腫瘤的可能機轉。
我們發現GPC3的表現可促成NIH3T3細胞株細胞的生長快速，細胞的核質比增加，細胞可在洋菜膠中長成細胞團塊，且可在祼鼠體內會長成腫瘤，而無GPC3表現的載體NIH3T3細胞則無此等現象。在表現GPC3之PLC-PRF-5細胞中亦會有細胞生長快速的現象。反之，在GPC3 調降(knockdown)的HuH – 7肝細胞癌細胞株會減少其致癌性。 我們發現GPC3可經由IGF2刺激IGF-1R及其下游ERK造成這些分子的磷酸化。在GPC3 調降的肝癌細胞其IGF-1R和ERK會減少磷酸化。因此顯示GPC3是經由IGF2及其受體，以及隨後激活的胰島素樣生長因子信號通路而具有致癌性。我們亦發現GPC3可經由其N端富含脯氨酸的區域(proline-rich domain)與第2型類胰島素生長激素(IGF2)及類胰島素生長激素一型受器(IGF-1 receptor (IGF-1R))接合並共同促進肝癌細胞的生長，而此區域亦會影下游胞外信號調節激酶(ERK)的活化及AP-1的活性。 GPC3是一可分泌的分子，我們發現GPC3轉染的乳癌細胞株MCF7細胞的conditioned media可促進MCF7及HA22T/VGH細胞的細胞團塊生長。這個新的發現對GPC3在未來肝癌的癌症治療發展可能是很重要的。 | zh_TW |
| dc.description.abstract | Glypican-3 (gpc3) belongs to the glycosylphosphatidylinositol (GPI)-anchored glypican family and responsible for Simpson-Golabi-Behmel overgrowth syndrome, an X-linked condition characterized by pre-and postnatal overgrowth with visceral and skeletal anomalies. Previously, we have shown that GPC3 is overexpressed in more than 70% hepatocellular carcinoma (HCC) by Northern Blot analysis. In addition to HCC, GPC3 overexpression was also reported in certain types of human cancers, including Wilms' tumor, hepatoblastoma, melanoma, and choriocarcinoma. GPC3 can promote the growth of cancer cells. GPC3 has been linked to Wnt, Hedgehog, BMPs and insulin-like growth factor (IGF) pathway, but the molecular mechanism remains unclear. In this study, we attempted to elucidate the mechanisms for GPC3-mediated oncogenesis.
We demonstrated that ectopic overexpression of GPC3 in NIH3T3 cells led to cancer cell phenotypes including growth in serum-free medium, forming colonies in soft agar, and formation of in vivo malignant tumors in nude mice. GPC3-expressing PLC-PRF-5 cells enhanced cell growth in low serum. On the other hand, GPC3 knockdown decreased the oncogenic capability of HuH-7 cells. GPC3 stimulated the phosphorylation of IGF-1R and the downstream signaling molecule ERK in an IGF2-dependent fashion. Also, GPC3 knockdown in HCC HuH-7 cells decreased the phosphorylation of IGF-1R, IRS-1 and ERK. Therefore, we conclude that GPC3 confers oncogenecity through the interaction between IGF2 and its receptor, and the subsequent activation of the IGF-signaling pathway. We further demonstrated that GPC3 bound specifically through its N-terminal proline-rich region to both insulin-like growth factor (IGF)-II and IGF-1R. This proline-rich region was also important for the downstream ERK activation and AP-1 activity. GPC3 is a secretory protein. We demonstrated that the conditioned medium of MCF7 cells after transient transfection with GPC3 promoted colony growth of MCF7 and HA22T/VGH cells in soft agar. These findings are novel in the current understanding of the role of GPC3 in HCC and can be important in future developments of cancer therapy. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T03:53:09Z (GMT). No. of bitstreams: 1 ntu-99-D97444002-1.pdf: 3094171 bytes, checksum: 981400efda318f13c265172b2f4a99a0 (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 1. 中文摘要- 1
2. ABSTRACT- 3 3. INTRODUCTION- 5 3.1 Glypican-3 (GPC3) and human cancers and hepatocellular carcinoma (HCC)-----5 3.2 Glypican family-6 3.3 Structure of GPCs-7 3.4 Subcellular localization and function of GPCs-8 3.5 Processing of GPC3-9 3.6 GPC3 in Development-10 3.7 Signal Pathways associated with GPC3-11 3.7.1 GPC3 and Insulin-like growth factor (IGF) -11 3.7.2 GPC3 and Wnt signaling pathway-13 3.7.3 GPC3 and Hedgehog pathway-15 3.7.4 GPC3 and BMPs -15 3.8 GPC3 in Immunotherapy -16 Text-Table 1 -18 Text-Figure 1 Schematic representation of GPCs -19 Text-Figure 2 Alignment of the predicted amino acid sequences of the members of the glypican family. -21 Text-Figure 3 GPC3 in IGFs signaling in development -23 Text-Figure 4 GPC3 activates non-canonical pathway and leads to the inhibition of canonical Wnt signaling in II14, MCF7 and LM3 cells -24 Text- Figure 5 GPC3 stimulates Wnt signaling by facilitating/stabilizing Wnt-Frizzled interaction in HCC -25 Text-Figure 6 The role of glypican3 in Hh signaling -26 Text-Figure 7 GPC3 in BMPs signaling in development -27 4. MATERIALS AND METHODS -28 4.1 Cell lines used -28 4.2 Plasmids -28 4.3 Transfection and selection for stable lines -29 4.4 Reverse transcription-polymerase chain reaction (RT-PCR) -29 4.5 Antibodies used respectively -29 4.6 Generation and purification of anti-GPC3 (anti-CC3) antibody -30 4.7 Western blot analysis-30 4.8 Immunoprecipitation -31 4.9 Intact cell IGF-1R phosphorylation and IRS-1 phosphorylation - 31 4.10 Heparitinase digestion -31 4.11 RNA interference -32 4.12 Determination of cell growth and colony formation -32 4.13 Soft agar assay -33 4.14 Soft agar assay with conditioned medium of GPC3 transfected MCF7 -33 4.15 GST pull-down assay -34 4.16 Coimmunoprecipitation detection of the GPC3/IGF-1R complex -34 4.17 Tumorigenicity in nude mice -34 4.18 Luciferase assays for AP-1 reporter activities -35 II 5. RESULTS -36 5.1 Localization and Identification of GPC3 -36 5.2 Establishment of GPC3 expressing cells -38 5.3 Oncogenic property of stable GPC3 cell lines derived from NIH3T3 cells -38 5.4 Role of GPC3 in HCC cells-39 5.5 GPC3 associates with IGF2 and IGF-1R through its proline-rich region, and requires the convertase cleavage for the interaction with IGF2 -40 5.6 GPC3 induces and activates IGF-1R and IRS-1 -41 5.7 Phosphorylation of ERK by GPC3 -42 5.8 GPC3 modulates AP-1 activity -44 5.9 Promotion of MCF7 and HA22T growth by conditioned medium (CM) of GPC3 positive cells -44 5.10 The Internal-tagged HA-GPC3 expressing NIH3T3 cells exhibit no significant phenotypic changes -45 6. DISCUSSION -47 6.1 GPC3 increases oncogenicity in NIH3T3 cells, promotes PLC/PRF/5 cell growth, and GPC3 knockdown decreases oncogenicity inHuH-7 cells -47 6.2 Glypican-3 is involved in the activation of insulin-like growth factors axis-48 6.3 Proline-rich region of GPC3 is important for protein-protein interaction, ERK activation and AP-1 activity -50 6.4 Processing by convertase is required for the function of GPC3 -52 6.5 GPC3 may possess paracrine activity -53 6.6 GPC3 exerts dual function in cell growth and cell death at least in part pending upon cell context, growth factors, or construct difference -54 7. REFERENCES -58 8. TABLES -78 Table 1 Anchorage independent growth of GPC3-expressing NIH3T3 cells -78 Table 2 Tumorigenicity of NIH3T3 and GPC3-EGFP expressing NIH3T3 cells in nude mice -79 Table 3A Growth of MCF7 cells in soft agar supplemented with conditioned medium of transfected MCF7 cells -80 Table 3B Growth of HA22T/VGH cells in soft agar supplemented with conditioned medium of transfected MCF7 cells -80 Table 4 Summary of GPC3 constructs used in this study and HA-GPC3 with internal HA tag and their effects on cells -81 9. FIGURES -82 Figure 1 Schematic representation of expression vectors WT-GPC3, GPC3-myc, GPC3-EGFP, pHA-GPC3, P26-30A, and RRAA -82 Figure 2 Schematic diagram of the primary structure of GPC3 -83 Figure 3 Expression of GPC3 in HEK293T cells -84 Figure 4 Confocal microscopy images for the expression of GPC3 mutants in HeLa Cells-85 Figure 5 Secretory GPC3 in the conditioned media -86 Figure 6 GPC3 expression in NIH3T3 cells -87 Figure 7 Morphology of the GPC3 expressing NIH3T3 cells -88 Figure 8 Growth of the GPC3-expressing NIH3T3 cells in serum-free medium -89 Figure 9 Colony formation of GPC3 expressing NIH3T3 cells -90 Figure 10 Tumorigenicity of GPC3 expressing NIH3T3 cells -91 Figure 11 Microscopic appearance of tumors stained with hematoxylin and eosin –92 Figure 12 GPC3 expression in PLC/PRF/5 cells -93 Figure 13 Knockdown of GPC3 in HuH-7 cells-94 Figure 14 Reverse transcription–polymerase chain reaction analysis of IGF1 and IGF2gene expressions in different cell lines-95 Figure 15 Interaction of overexpressed GPC3 proteins with IGF2 -96 Figure 16 Interaction between GPC3 and IGF-1R -97 Figure 17 IGF-1R phosphorylation in GPC3-expressing lines -98 Figure 18 IGF2-triggered IGF-1R phosphorylation in HEK293 cells -99 Figure 19 IRS-1 phosphorylation in GPC3-expressing cell lines -100 Figure 20 GPC3 activates ERK phosphorylation -101 Figure 21 ERK phosphorylation in HA22T/VGH cells -102 Figure 22 IGF2 knockdown by siRNA (siIGF2) -103 Figure 23 GPC3 modulates AP-1 activity -104 Figure 24 GPC3 containing conditioned media promotes MCF7 and HA22T growth in soft agar -105 Figure 25 Phenotypes of HA-GPC3 expressing cells -106 Figure 26 Comparison of different constructs and their properties -108 Figure 27 Schematic diagram of the possible ways that GPC3 activates ERK -109 10. PUBLICATION-110 | |
| dc.language.iso | en | |
| dc.subject | 類胰島素生長激素一型受器 | zh_TW |
| dc.subject | 磷脂肌醇聚糖3 | zh_TW |
| dc.subject | 第二型類胰島素生長激素 | zh_TW |
| dc.subject | 肝細胞癌 | zh_TW |
| dc.subject | glypican-3 (GPC3) | en |
| dc.subject | hepatocellular carcinoma (HCC) | en |
| dc.subject | insulin-like growth factor I receptor (IGF-1R) | en |
| dc.subject | insulin-like growth factor II (IGF2) | en |
| dc.title | 肝細胞癌過度表現磷脂肌醇聚糖3之致癌性與類胰島素生長激素訊息傳導路徑研究 | zh_TW |
| dc.title | Hepatocellular carcinoma overexpressed Glypican-3-Mediated Oncogenesis Involves the Insulin-like Growth Factor Signaling Pathway | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.coadvisor | 李玉梅 | |
| dc.contributor.oralexamcommittee | 周成功,陳培哲,陳瑞華,鐘邦柱 | |
| dc.subject.keyword | 磷脂肌醇聚糖3,第二型類胰島素生長激素,類胰島素生長激素一型受器,肝細胞癌, | zh_TW |
| dc.subject.keyword | glypican-3 (GPC3),insulin-like growth factor II (IGF2),insulin-like growth factor I receptor (IGF-1R),hepatocellular carcinoma (HCC), | en |
| dc.relation.page | 109 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2010-07-05 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 病理學研究所 | zh_TW |
| 顯示於系所單位： | 病理學科所 | |
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