臺灣博碩士論文加值系統

腎細胞癌是最普遍的腎臟癌，發生於腎臟中的近曲小管中，依照組職學型態clear cell RCC (ccRCC, 70-75%)為最常見的類型。惡性橫紋肌樣瘤是一種罕見及具有高度侵犯性的癌症，發生在嬰兒及小孩的腎臟及腦部，而其最重要的發病機制為Integrase interactor 1 (INI1/hSNF5) 腫瘤抑癌基因的突變或是表現量下降。INI1屬於BAF (hSWI/SNF) complex的成員，其為ATP依賴型染色質重塑複合體，在許多細胞核內的反應像是基因轉錄、DNA複製、修補以及細胞週期當中扮演了重要角色。此外SWI/SNF remodeling complex也參與了細胞增生、分化、抑制病毒活性以及抑制腫瘤形成。而類橫紋肌上皮腎細胞癌在整個腎細胞癌中佔了3% - 7%以及伴隨著較差的預後，然而其發病機制目前還不清楚。在分析了五對腫瘤及正常的檢體之後當中發現在轉錄及轉譯的層次上INI1的表現量下降，在另外追加8個臨床的病例當中(年齡範圍為48到79歲)，利用免疫組織染色發現這八個病例中的類橫紋肌細胞核內INI1的表現量缺失以及臨床結果當中發現從診斷到轉移之間的間隔為3至43個月，而在這八位病人當中有四位已經死亡，其中一位存活的病人也已經惡化。為了確認類橫紋肌上皮腎細胞癌中發病機制之重要性，我們利用ACHN細胞株來建立INI1穩定下降的細胞株。在INI1表現之後，伴隨的類橫紋肌特徵、增加細胞增生及EGFR及VEGF家族的表現量及分泌量增加。然而在細胞存活率的實驗當中發現在外加VEGFR的抑制劑(蕾莎瓦(Sorafenib) and紓癌特 (Sunitinib)之後發現腫瘤細胞沒有顯著專一抑制的效果，也因此確立了發展多標靶抗癌藥物治療策略的潛力。在利用microarray 技術分析後所得到的1024 上升和908 下降的基因群中，我們挑選前列腺素E受體家族做為研究目標，因為其可接收PGE2的訊號，而且參與VEGF-C所產生的癌化，以及和EGFR下游的傳導路徑有交互作用。利用RT-PCR及Western blot分析後，發現在INI1表現量下降以後，EP1及EP4的表現量上升。再更深入的探討PGE2/COX的訊息傳遞路徑之後，發現到在INI1表現量下降以後，PGE2分泌量及COX1表現量都會上升。EGFR抑制劑-得舒緩(Erlotinib)對於ACHN INI1表現量穩定下降的細胞株具有顯著的專一性抑制效果；但另一EGFR抑制劑-艾瑞莎(Gefitinib)則沒有顯著抑制效果。而mTOR抑制劑-癌伏妥(Everolimus)也對於ACHN INI1表現量穩定下降的細胞株具有顯著專一性抑制的效果。建立的ACHN INI1＆EP1表現量穩定下降的細胞株對會被EGFR抑制劑-得舒緩(Erlotinib)、艾瑞莎(Gefitinib)、以及mTOR抑制劑-癌伏妥(Everolimus)給抑制。本研究顯示得舒緩、艾瑞莎、癌伏妥、以及前列腺素E受體的組合藥物，也許是類橫紋肌上皮腎細胞癌最好的多標靶治療策略。

Renal cell carcinoma (RCC) arises from proximal convoluted tubules and is the most common type of kidney cancer. The common histologic subtypes include clear cell RCC (ccRCC, 70-75%), papillary RCC (16%), chromophobe RCC (7%), translocation carcinoma (1%), collecting duct carcinoma (〈0.5%), and renal medullary carcinoma (〈0.5%). Malignant rhabdoid tumor is a rare and aggressive malignant tumor that mostly occurs in the kidney and brain of infants and young children. The important pathogenic mechanism of this entity is truncating mutation of a tumor suppressor gene- Integrase interactor 1 (INI1/hSNF5) gene. The INI1, core member of BAF (hSWI/SNF) complex, is an ATP-dependent chromatin-remodeling complex and plays an essential role in multiple nuclear processes, such as transcription, DNA replication and repair and negative regulator of cell cycle. In addition, the SWI/SNF remodeling complex also involves in cell proliferation, differentiation, antiviral activity, and inhibition of tumor formation. RCC with rhabdoid features (RCC-RF) occur in around 3% to 7% of RCC and is associated with a poor prognosis. However, its pathogenesis remains elusive. Analysis of paired tumor and non-neoplastic kidney specimens (n = 5) revealed down-regulation of INI1 at both transcriptional and translational levels. A total of 8 cases (age ranged from 48 to 79) were retrieved from archive and analyzed for INI1 immunohistochemistry and clinical outcome. Loss of nuclear INI1 expression was demonstrated in the rhabdoid cells in all 8 cases compared with adjacent ccRCC. The interval between diagnosis and metastasis ranged from 3 to 43 months. Four of them died of cancer and one patient is alive with progressive disease despite of treatment with targeted therapies. To identify molecular pathogenesis of RCC-RF, an INI1 stable knock-down cell line was established from ACHN ccRCC. Suppression of INI1 was significantly associated with rhabdoid changes, enhanced cell proliferation, up-regulated EGFR, and VEGF expression/secretion in vitro. However, only Everolimus and Erlotinib were effective in suppression the growth of INI1 stable knock-down cell line, whereas treatment with VEGFR inhibitors (sorafenib or sunitinib) did not inhibit the growth of tumor cells. To identify potential co-targeting molecules, EP family, which receives PGE2 signal, was chosen from microarray profiling for investigation because of its involvement in VEGF-C-mediated pulmonary carcinogenesis and a crosstalk with EGFR. RT-PCR screening revealed an up-regulated EP1 and EP4 in ACHN INI1 knock-down stable cells compared with control. We also demonstrated that PGE2 synthase-COX1 is up-regulated by knocking down the INI1. Erlotinib (EGFR inhibitor) effectively inhibited the growth of ACHN INI1 knock-down cells compared with vector control; whereas Gefitinib had no inhibitory effect. The Everolimus (mTOR inhibitor) also inhibited the growth of ACHN INI1 knock-down cells. Both Everolimus and EGFR inhibitors (Erlotinib and Gefitinib) effectively suppressed the growth of ACHN INI1 and EP1 double knockdown cells. Using this model experiment, a cocktail of PGE2/EP1 pathway inhibitor together with Everolimus and EGFR inhibitor (Erlotinib or Gefitinib) is preferred for patients with RCC-RF.

中文摘要 I
Abstract III
Acknowledgement V
Content VI
Index of Tables VIII
Index of Figure IX
Introduction 1
Renal cell carcinoma (RCC) 1
Malignant rhabdoid tumor (MRT) 1
INI1(Integrase interactor 1) 2
Prostaglandin/cyclooxygenase (COX) pathway 3
Crosstalk of PGE/COX signalling with epidermal growth factor receptor (EGFR) pathway 4
Angiogenesis, lymphangiogenesis and prostaglandin/COX pathway 5
Targeted cancer therapy 6
Materials and methods 8
Cell culture 8
Microarray array 8
Chemical 9
Transient Transfection 9
RT-PCR 9
Western blotting 12
3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay 13
Detection of secreted VEGF-A and C in medium 13
Cell viability assay 14
Cell migration assay 15
Cell invasion assay 15
Measurement of PGE2 by enzyme linked immunosorbent assay (ELISA) 16
Immunohistochemical staining 16
Ki-67 proliferative index 16
Data Analysis and Statistics 17
Results 18
Discussion 24
References 27

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