靜水壓影響膀胱癌細胞之分子機制探討

以作者查詢圖書館館藏

、以作者查詢臺灣博碩士

、以作者查詢全國書目

、勘誤回報

、線上人數：39

、訪客IP：52.15.59.163

姓名

施秉玠(Ping-Chieh Shih) 查詢紙本館藏

畢業系所

生物醫學工程研究所

論文名稱

靜水壓影響膀胱癌細胞之分子機制探討

相關論文

★ 溫度調變對二元合金固液介面形態穩定的影響	★ 濃度調變對二元合金固液介面形態穩定的影響
★ 圓錐平板型生物反應器週期性流場研究	★ 圓錐平板型生物反應器二次週期流場研究
★ 圓錐平板型生物反應器脈動式流場研究	★ 濃度調變對單向固化形態穩定的影響
★ 圓錐平板型生物反應器脈動式二次流場研究	★ 模擬注流式生物反應器之流場及細胞生長
★ 週期式圓錐平板裝置之設計與量測	★ 模擬注流式生物反應器之細胞培養研究
★ 軟骨細胞在組織工程支架之培養研究	★ 細胞在組織工程支架之生長與遷移
★ 冷電漿沉積類鑽碳膜之製程模擬分析	★ 格狀自動機探討組織工程細胞體外培養研究
★ 細胞在注流式生物反應器之生長研究	★ 週期式圓錐平板裝置之流場分析

檔案

[Endnote RIS 格式]

[Bibtex 格式]

[相關文章]

[文章引用]

[完整記錄]

[館藏目錄]

[檢視]

[下載]

本電子論文使用權限為同意立即開放。
已達開放權限電子全文僅授權使用者為學術研究之目的，進行個人非營利性質之檢索、閱讀、列印。
請遵守中華民國著作權法之相關規定，切勿任意重製、散佈、改作、轉貼、播送，以免觸法。

摘要(中)

不受控制的細胞分裂為惡性腫瘤發展的根本原因，在各種人類癌症中皆發現細胞中的細胞週期素 (cyclins) 過度表達或是細胞週期素依賴性激酶抑制物 (CKIs) 的缺失以及腫瘤抑制因子的突變與缺失，導致細胞內的檢查點監控機制發生故障，癌細胞因而獲得抵抗凋亡的能力，而細胞無止盡的增生最終將發展成腫瘤。膀胱癌屬於人類泌尿系統中常見的腫瘤之一，對於初期膀胱癌之治療方案，一般採用手術後輔以膀胱灌注法之方式，將藥物直接灌注至病患膀胱中，透過藥物毒性徹底殺死癌細胞，以避免腫瘤復發。灌注藥物期間，病患膀胱內的壓力也會提高，有學者指出此種壓力刺激可能具有抑制細胞增生的效果，且配合藥物刺激有助於提升誘導膀胱癌細胞凋亡的效率，但仍不清楚此種機械刺激在細胞中所扮演的角色。因此，本研究將在符合生理情況下，探討靜水壓刺激對於膀胱癌細胞之影響。
本研究以靜水壓生物反應器系統對BFTC905膀胱癌細胞株施以靜水壓刺激，透過流式細胞儀分析與西方墨點分析證實，以10 kPa之靜水壓刺激5小時期間內並不會誘導細胞凋亡，也不會誘導p53的表現，然而處於G1期之細胞量比例卻明顯增加了，說明靜水壓刺激確實會誘導G1停滯。根據實驗結果，我們發現不論有無施加靜水壓刺激，皆不影響cyclin D (D1、D3)、CDK4與CDK6的表現，這可能是由於INK4蛋白質的缺失所致。在加壓2.5小時內，處於G2/M之細胞量比例降低，大部分細胞停留於S期，且Cdc2於Tyr15的磷酸化程度增加，但是持續加壓至5小時後，大部分細胞卻停滯於G1期，而且不僅cyclin E1與CDK2的表現下降，甚至cyclin A2與cyclin B1的表現也都降低了，加上組蛋白H3於Ser10皆維持低磷酸化的狀態，這些證據表示靜水壓刺激可能會先延遲S/G2的進展，同時誘導細胞細胞週期停滯於G1期。此外不同於p21，在BFTC905細胞株中p27的表達明顯受到抑制，然而經過靜水壓刺激後p27卻大幅地上升，而p21則僅有些微的增加，接著我們也發現Rb於Ser807/811的低磷酸化，這些證據說明了靜水壓刺激將透過p53-非依賴性路徑提高p21與p27的表現，抑制cyclin E1-CDK2並且間接影響了Rb於Ser807/811的磷酸化程度以誘導G1停滯。

摘要(英)

Uncontrolled cell division is the cause of malignant cell development. To date, there are large amount of literatures that investigate the cause of cancer and try to develop applicable strategies for cancer therapy. It has been well addressed that the mutation of tumor suppressor, overexpression of cyclins or loss of CKIs are common in a variety of human cancers. Those mutations, overexpressions or deletions will result in the malfunction of regulatory checkpoints mechanism of the cell, or make the cancer cells obtain abilities to resist apoptosis. At the end, unlimited cell proliferation will eventually lead tumorigenesis.
Bladder cancer is a common cancer in human urinary system. In addition to the primary surgical treatment, patients will be treated by adjuvant intravesical therapy that utilize chemotherapy agents such as mytomicin C to kill the remaining cancer cells after the surgery to prevent tumor recurrence. However not only the cytotoxic stress for cells but also the pressure effect were present in the bladder during the intravesical therapy. It is suggested that hydrostatic pressure stimulation may have the ability to inhibit cancer cell proliferation, because the drugs induced apoptosis will be enhanced by applying the hydrostatic pressure. However, the cellular mechnism of this mechanical stress still remain unclear.
This study applied the hydrostatic pressure bioreactor system to provide the hydrostatic pressure (10 kPa) on BFTC905 cells, a cell line of bladder cancer, and investigated how this mechanical stress effects the bladder cancer cells under physiological conditions. Results from flow cytometry showed most of cells stay in G1 phase, and rare cells go into apoptosis after 5 h hydrostatic pressure application. And we also found undetectable p53 expression after treated hydrostatic pressure by Western blot analysis no matter we applied hydrostatic pressure or not in BFTC905 cells. Our data shown the expression of cyclin D (D1, D3) and CDK4, CDK6 were the same as control cells after treatment, and these would be the results of loss of INK4 proteins in BFTC905 cells. However, under hydrostatic pressure stimulation, we found most of cells stayed in S phase and cells in G2/M were declined, also the phosphorylation state of Cdc2 on Tyr15 was increased within 2.5 h. But after treatment for 5 h, most of cells stayed in G1 phase and cyclin E1 and CDK2 were decreased. Not only that, but the data also shown both of cyclin A2 and cyclin B1 were down-regulated after treatement for 5 h, and Ser10 of histone H3 remained in the hypophosphorylation state. These evidences suggested hydrostatic pressure stimulation might cause cell cycle delay in G2/M transition and induce G1 arrest, simultaneously.
Futhermore, unlike p21, p27 levels were strongly inhibited in BFTC905 cells in the originated status. However, p27 levels were significantly increased by hydrostatic pressure application whether p21 levels just slightly increase. Also Ser807/811 of Rb became hypophosphorylation after treatment within 2.5 h or 5 h. These finding concluded that hydrostatic pressure stimulation induce G1 arrest by elavated p21 and p27 levels in a p53-independent manner, results cyclin E1 and CDK2 degradation, and hypophophorylation of Ser807/811 of Rb.

關鍵字(中)

★ 膀胱癌
★ 細胞週期
★ 靜水壓
★ G1停滯

關鍵字(英)

★ Bladder cancer
★ Cell cycle
★ Hydrostatic pressure
★ G1 arrest

論文目次

摘要 i
Abstract iii
誌謝 v
目錄 vi
圖目錄 viii
表目錄 ix
第一章緒論 1
1.1 前言 1
1.2 文獻回顧 3
1.2.1 細胞週期與癌症 3
1.2.2 壓力刺激對細胞的影響 10
1.2.3 膀胱癌與治療方式 13
1.3 研究目的 14
第二章實驗方法 18
2.1 細胞培養相關操作 19
2.2 壓力刺激實驗 20
2.3 流式細胞儀分析 (Flow cytometric analysis) 22
2.4 蛋白質定量分析 24
2.5 蛋白質體電泳 (SDS-PAGE) 25
2.6 西方墨點分析法 (Western Blot analysis) 27
第三章結果與討論 30
3.1 實驗前言 30
3.2 細胞週期各階段之分佈率 31
3.3 細胞凋亡測定之結果與討論 34
3.4 西方墨點分析法之結果與討論 37
3.4.1 靜水壓刺激對於cyclins與CDKs之影響 37
3.3.1 靜水壓刺激誘導組蛋白H3於Ser10的低磷酸化 40
3.3.2 靜水壓刺激對於CKIs之影響 42
3.3.3 靜水壓刺激對Rb磷酸化程度之影響 44
3.3.4 靜水壓刺激誘導p53-非依賴性之G1停滯 46
第四章結論與未來展望 48
參考文獻 51
附錄-實驗藥劑、耗材與儀器 70

參考文獻

Aguero M. F., Facchinetti M. M., Sheleg Z. and Senderowicz A. M., 2005. Phenoxodiol, a novel isoflavone, induces G1 arrest by specific loss in cyclin-dependent kinase 2 activity by p53-independent induction of p21WAF1/CIP1. Cancer Res. 65:3364-3373.
Alberts B., Alexander J ., Julian L., Martin R., Keith R. and Peter W., 2002. Molecular biology of the cell. Garland Science.
Alfred W. J., Hendricksen K., Gofrit O., Risi O. and Nativ O., 2009. Intravesical hyperthermia and mitomycin-C for carcinoma in situ of the urinary bladder: experience of the European Synergo working party. World J. Urol. 27 (3): 319-24.
Amato R. J., 2003. Vaccine Therapy for Renal Cell Carcinoma. Rev. Urol. 5(2): 65-71.
Androic I., Krämer A., Yan R., Rödel F., Gätje R., Kaufmann M., Strebhardt K. and Yuan J., 2008. Targeting cyclin B1 inhibits proliferation and sensitizes breast cancer cells to taxol. BMC Cancer. 8: 391.
Angele P., Yoo J. U., Smith C., Mansour J., Jepsen K .J., Nerlich M., and Johnstone B., 2003. Cyclic hydrostatic pressure enhances the chondrogenic phenotype of human mesenchymal progenitor cells differentiated in vitro. J. Orthop. Res. 21: 451-457.
Apetoh L., Tesniere A., Ghiringhelli F., Kroemer G. and Zitvogel L., 2008. Molecular interactions between dying tumor cells and the innate immune system determine the efficacy of conventional anticancer therapies. Cancer Res. 68(11): 4026-4030.
Arellano M., Moreno S., 1997. Regulation of CDK/cyclin complexes during the cell cycle. Int. J. Biochem. Cell Biol. 29: 559-573.
Avni D., Yang H., Martelli F., Hofmann F., ElShamy W. M., Ganesan S., Scully R. and Livingston D. M., 2003. Active localization of the retinoblastoma protein in chromatin and its response to S phase DNA damage. Mol. Cell. 12: 735-746.
Bai L. and Zhu W. –G., 2006. p53: Structure, Function and Therapeutic Applications. J. Cancer Mol. 2(4): 141-153.
Baker S. J., Fearon E. R., Nigro J. M., Hamilton S. R., Preisinger A. C., Jessup J. M., van Tuinen P., Ledbetter D. H., Barker D. F., Nakamura Y. et al., 1989. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 244: 217-221.
Bartek J., Lukas C. and Lukas J., 2004. Checking on DNA damage in S phase. Nat. Rev. Mol. Cell Biol. 5: 792-804.
Bartoletti R., Cai T., Gabriella Nesi G., Girardi L. R., Baroni G. and Canto M. D., 2007. Loss of p16 expression and chromosome 9p21 LOH in predicting outcome of patients affected by superficial bladder cancer. J. Surg. Res. 43: 422-427.
Blomen V. A. and Boonstra J., 2007. Cell fate determination during G1 phase progression. Cell. Mol. Life Sci. 64: 3084-3104.
Bocchia M., Bronte V., Colombo M. P., De Vincentiis A., Di Nicola M., Forni G., Lanata L., Lemoli R. M., Massaia M., Rondelli D., Zanon P. and Tura S., 2000. Antitumor vaccination: where we stand. Haematologica. 85(11): 1172-1206.
Boonstra J., 2003. Progression through the G1-phase of the on-going cell cycle. J. Cell Biochem. 90: 244-252.
Boonstra, J., 2003. Progression through the G1-phase of the on-going cell cycle. J. Cell Biochem. 90: 244-252.
Brugarolas J., Chandrasekaran C., Gordon J. I., Beach D., Jacks T. and Hannon G. J., 1995. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature. 377: 552-557.
Burke J. R, Hura G. L. and Rubin S. M., 2012. Structures of inactive retinoblastoma protein reveal multiple mechanisms for cell cycle control. Genes Dev. 26:1156-1166.
Caldas C., Hahn S. A., daCosta L. T., Redston M. S., Schutte M., Seymour A. B., Weinstein C. L., Hruban R. H., Yeo C. J., and Kern S. E., 1994. Frequent somatic mutations and homozygous deletions of the p16(MTS1) gene in pancreatic adenocarcinoma. Nature Genet. 8: 27-32.
Carver S. E., and Heath C. A., 1999. Semi-continuous perfusion system for delivering intermittent physiological pressure to regenerating cartilage. Tissue Eng. 5: 1-11.
Castedo M., Perfettini J. L., Roumier T., Andreau K., Medema R. and Kroemer G., 2004. Cell death by mitotic catastrophe: a molecular definition. Oncogene. 23: 2825-2837.
Chen L., Wei T. Q., Wang Y., Zhang J., Li H. and Wang K. J., 2012. Simulated bladder pressure stimulates human bladder smooth muscle cell proliferation via the PI3K/SGK1 signaling pathway. J. Urol. 188: 661-667.
Chen S. K., Chung C. A., Cheng Y. C., Huang C. J., Ruaan R. C., Chen W. Y., Li C., Tsao C. W., Hu W. W. and Chien C. C., 2013. Hydrostatic pressure enhances mitomycin C induced apoptosis in urothelial carcinomacells. Urol. Oncol. pii: S1078-1439(12)00336-5. doi: 10.1016/j.urolonc.2012.09.004.
Chen X., Chang C. H. and Goldenberg D. M., 2009. Novel strategies for improved cancer vaccines. Expert. Rev. Vaccines. 8(5): 567-76.
Chinnam M. and Goodrich D. W., 2011. RB1, development, and cancer. Curr. Top. Dev. Biol. 94: 129-169.
Cicchillitti L., Fasanaro P., Biglioli P., Capogrossi M. C. and Martelli F., 2003. Oxidative stress induces protein phosphatase 2A-dependent dephosphorylation of the pocket proteins pRb, p107, and p130. J. Biol. Chem. 278: 19509-19517.
Coverley D., Laman H. and Laskey R. A., 2002. Distinct roles for cyclins E and A during DNA replication complex assembly and activation. Nat. Cell Biol. 4 (7): 523-528.
Cuadrado M., Gutierrez-Martinez P., Swat A., Nebreda A. R. and Fernandez-Capetillo O., 2009. P27Kip1 stabilization is essential for the maintenance of cell ccle arrest in response to DNA damage. Cancer Res. 69(22):8726-8732.
Davidson I. F., Li A. and Blow J. J., 2006. Deregulated replication licensing causes DNA fragmentation consistent with head-to-tail fork collision. Mol. Cell. 24: 433-443.
de Rozieres S., Maya R., Oren M. and Lozano G., 2000. The loss of mdm2 induces p53-mediated apoptosis. Oncogene. 19: 1691-1697.
Deng C., Zhang P., Harper J. W., Elledge S. J. and Leder P., 1995. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell. 82: 675-684.
Dimova D. K. and Dyson N., 2005. The E2F transcriptional network: old acquaintances with new faces. Oncogene. 24: 2810-2826.
Dimova D. K., Stevaux O., Frolov M. V. and Dyson N. J., 2003. Cell cycle-dependent and cell cycle-independent control of transcription by the Drosophila E2F/RB pathway. Genes Dev. 17: 2308-2320.
Dyson N., Bernards R., Friend S. H., Gooding L. R., Hassell J. A., Major E. O. Pipas J. M., Vandyke T. and Harlow T., 1990. Large T antigens of many polyomaviruses are able to form complexes with the retinoblastoma protein. J. Virol. 64: 1353-1356.
Dyson N., Howley P. M., Munger K. and Harlow E., 1989. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science. 243: 934-937.
el-Deiry W. S., Harper J. W., O’Connor P. M., et al., 1994. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 54:1169-1174.
Ekholm S. V. and Reed S. I., 2000. Regulation of G(1) cyclin-dependent kinases in the mammalian cell cycle. Curr. Opin. Cell Biol. 12: 676-684.
Eyers P. A., Erikson E., Chen L. G. and Maller J. L., 2003. A novel mechanism for activation of the protein kinase aurora-A. Curr. Biol. 13: 691-697.
Ferreira R., Naguibneva I., Mathieu M., Ait-Si-Ali S., Robin P., Pritchard L. L. and Harel-Bellan A., 2001. Cell cycle-dependent recruitment of HDAC-1 correlates with deacetylation of histone H4 on an Rb-E2F target promoter. EMBO Rep. 2: 794-799.
Finn O. J., 2003. Premalignant lesions as targets for cancer vaccines. J. Exp. Med. 198: 1623-1626.
Frederick A. D., 2007. Structure-function analysis of the retinoblastoma tumor suppressor protein - is the whole a sum of its parts? Cell div. 2: 26.
Frescas D. and Pagano M., 2008. Deregulated proteolysis by the F box proteins SKP2 and β TrCP: tipping the scales of cancer. Nat. Rev. Cancer. 8(6): 438-49.
Frolov M. V. and Dyson N. J., 2004. Molecular mechanisms of E2F-dependent activation and pRb-mediated repression. J. Cell Sci. 117: 2173-2181.
Furukawa Y., Terui Y., Sakoe K., Ohta M. and Saito M., 1994. The role of cellular transcription factor E2F in the regulation of Cdc2 mRNA expression and cell cycle control of human hematopoietic cells. J. Biol. Chem. 269: 26249-26258.
George V. T., Brooks G. and Humphrey T. C., 2007. Regulation of cell cycle and stress responses to hydrostatic pressure in fission yeast. Mol. Biol. Cell. 18: 4168-4179.
Green D. R. and Kroemer G., 2009. Cytoplasmic functions of the tumour suppressor p53. Nature. 458: 1127-1130.
Hall P. A. and Watt F.M., 1989. Stem cells: the generation and maintenance of cellular diversity. Development. 106: 619-633.
Hanahan D. and Weinberg R. A., 2011. Hallmarks of cancer: the next generation. Cell. 144: 646-674.
Hans F. and Dimitrov S., 2001. Histone H3 phosphorylation and cell division. Oncogene. 20: 3021-3027.
Hartwell L. H. and Weinert T. A., 1989. Checkpoints: controls that ensure the order of cell cycle events. Science. 246: 629-634.
Hauf S., Cole R. W., LaTerra S., Zimmer C., Schnapp G., Walter R., Heckel A., van Meel J., Rieder C. L. and Peters J. M., 2003. The small molecule Hesperidin reveals a role for Aurora-B in correcting kinetochoremicrotubule attachment and in maintaining the spindle assembly checkpoint. J. Cell Biol. 161: 281-294.
Heyland J., Wiegandt K., Goepfert C., Nagel-Heyer S., Ilinich E., Schumacher U. and Pörtner R., 2006. Redifferentiation of chondrocytes and cartilage formation under intermittent hydrostatic preesure. Biotech. Lett. 28: 1641-1648.
Hirsch C. L. and Bonham K., 2004 Histone deacetylase inhibitors regulate p21WAF1 gene expression at the post-transcriptional level in HepG2 cells. FEBS Lett. 70:37-40.
Hollstein M. C., Metcalf R. A., Welsh J. A., Montesano R. and Harris C. C., 1990. Frequent mutation of the p53 gene in human esophageal cancer. Proc. Natl. Acad. Sci. 87: 9958-9961.
Hollstein M., Sidransky D., Vogelstei, B. and Harris C. C., 1991. p53 mutations in human cancers. Science. 253: 49-53.
Horowitz J. M., Park, S. H., Bogenmann E., Cheng J. C., Yandell D. W., Kaye F. J., Minna J. D., Dryja T. P., and Weinberg R. A., 1990. Frequent inactivation of the retinoblastoma antioncogene is restricted to a subset of human tumor cells. Proc. Natl. Acad. Sci. 87: 2775-2779.
Hussussian C. J., Struewing J. P., Goldstein A. M., Higgins P. A. T., Ally D. S., Sheahan M. D., Clark W. H. Jr., Tucker M. A., and Dracopoli N. C., 1994. Germline p16 mutations in familial melanoma. Nature Genet. 8: 15-21.
Ikenoue T., Trindade M. C. D., Lee M. S., Lin Eric Y., schurman D. J., Goodman S. B., and Smith L. R., 2003. Mechanoregulation of human articular chondrodyte aggrecan and type II collagen expression by intermittent hydrostatic pressure in vitro. J. Orthop. Res. 21: 110-116.
Ishida S., Huang E., Zuzan H., Spang R., Leone G., West M. and Nevins J. R., 2001. Role for E2F in control of both DNA replication and mitotic functions as revealed from DNA microarray analysis. Mol. Cell Biol. 21: 4684-4699.
Islam N. Haqqi T. M., Jepsen K. J., Kraay M., Welter J. F., Goldberg V. M. and Malemud C. J., 2002. Hydrostatic pressure induces apoptosis in human chondrocytes from osteoarthritic cartilage through up-regulation of tumor necrosis factor-α, inducible nitric oxide synthase, p53, c-myc, and bax-α, and suppression of bcl-2. J. Cell Biochem. 87: 266-278.
Janeway C. A., Travers P., Walport M. and Shlomchik M., 2001. Immunobiology; The Immune System in Health ad Disease. 6th ed. Elsevier Science.
Jen J., Harper J. W., Bigner S. H., Bigner D. D., Papadaopouios N., Markowitz S., Willson J. K. V., Kinzler K. W., and Vogelstein B., 1994. Deletion of p15 and p16 genes in brain tumors. Cancer Res. 54: 6353-6358.
Jiang W., Kahan S., Tomita N., Zhang Y., Lu S., and Weinstein B., 1992. Amplification and expression of the human cyclin D gene in esophageal cancer. Cancer Res. 52: 2980-2983.
Johnson D. G. and Walker C. L., 1999. Cyclins and cell cycle checkpoints. Annu. Rev. Pharmacol. Toxicol. 39: 295-312.
Ju W. K., Kim K. Y., Lindsey J. D., Angert M., Patel A., Scott R. T., Liu Q., Crowston J. G., Ellisman M. H., Perkins G. A. and Weinreb R. N., 2009. Elevated hydrostatic pressure triggers release of OPA1 and cytochrome C, and induces apoptotic cell death in differentiated RGC-5 cells. Mol. Vision. 15: 120-134
Jung J. U., Stager M., and Desrosiers R. C., 1994. Virus-encoded cyclin. Mol. Cell. Biol. 14: 7235-7244.
Kaelin W. G., 1997. Recent insights into the functions of the retinoblastoma gene product. Cancer Invest. 15:243-254.
Kamb A., Gruis N. A., Weaver-Feldhaus J., Liu Q., Harshman K., Tavitian S. V., Stockert E., Day R., III., Johnson B. E., and Skolnik, M H., 1994a. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 264: 436-440.
Kamb A., Shattuck-Erdens D., Eeles R., Liu Q., Gruis N. A., Ding W., Hussey C., Tran T., Miki Y., Feldhaus J. et al., 1994b. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nature Genet. 8: 23-26.
Kao H., Marto J. A., Hoffmann T. K., Shabanowitz J., Finkelstein S. D., Whiteside T. L., Hunt D. F. and Finn O. J., 2001. Identification of cyclin B1 as a shared human epithelial tumor-associated antigen recognized by T cells. J. Exp. Med. 194: 1313-1323.
Kawamoto H., Koizumi H. and Uchikoshi T., 1997. Expression of the G2-M checkpoint regulators cyclin B1 and Cdc2 in nonmalignant and malignant breast lesions. Am. J. Pathol. 150: 15-23.
Kelman Z., Prokocimer M., Peller S., Kahn Y., Rechavi G., Manor Y., Cohen A., Rotter V. et al., 1989. Rearrangements in the p53 gene in Philadelphia chromosome positive chronic myelogenous leukemia. Blood. 74: 2318-2324.
Knudsen E. S. and Knudsen K. E., 2006. Retinoblastoma tumor suppressor: Where cancer meets the cell cycle. Exp. Biol. Med. 231:1271-1281.
Knudsen E. S. and Wang J. Y. J., 1997. Dual mechanisms for the inhibition of E2F binding to RB by cyclin-dependent kinase mediated RB phosphorylation. Mol. Cell Biol. 17:5771-5783.
Krucher N. A., Rubin E., Tedesco V. C., Roberts M. H., Sherry T. C. and Leon G. D., 2006. Dephosphorylation of Rb (Thr-821) in response to cell stress. Exp. Cell Res. 312:2757-2763.
Lammie G., Fantl V., Smith R., Schuuring E., Brookes S., Michalides R., Dickson C., Arnold A., and Peter G., 1991. D11S287, a putative oncogene on chromosome 1 lq13, is amplified and expressed in squamous cell and mammary carcinomas and linked to BCL-1. Oncogene. 6: 439-444.
Lau E., Tsuji T., Guo L. Lu S. H. and Jiang W., 2007. The role of pre-replicative complex (pre-RC) components in oncogenesis. FASEB J. 21: 3786-3794.

Lee K. H., 2001. Proteomics: a technology-driven and technology-limited discovery science. Trends. Biotechnol. 19(6): 217-222.
Liu F., Rothblum-Oviatt C., Ryan C. E., and Piwnica-Worms H., 1999. Overproduction of human Myt1 kinase induces a G2 cell cycle delay by interfering with the intracellular traf.cking of Cdc2-cyclin B1 complexes. Mol. Cell Biol. 19: 5113-5123.
Leung-Pineda V., Pan Y., Chen H. and Kilberg M. S., 2004. Induction of p21 and p27 expression by amino acid deprivation of HepG2 human hepatoma cells involves mRNA stabilization. Biochem. J. 379:79-88.
Makoto W., Mark A. A., Joseph R. and Bauer E. S., 1997. Effect of pressure on cultured smooth muscle cells. J. Life Sci. 61: 987-996
Malumbres M. and Barbacid M., 2009. Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer. 9: 153-166.
Markey M. P., Angus S. P., Strobeck M. W., Williams S. L., Gunawardena R. W., Aronow B. J. and Knudsen E. S., 2002. Unbiased analysis of RB-mediated transcriptional repression identifies novel targets and distinctions from E2F action. Cancer Res. 62: 6587-6597.
Mashal R. D., Lester S., Corless C., Richie J. P., Chandra R., Propert K. J. and Dutta A., 1996. Expression of cell cycle-regulated proteins in prostate cancer. Cancer Res. 56: 4159-4163.
Mayol X. and Grana X., 1998. The p130 pocket protein: keeping order at cell cycle exit/re-entrance transitions. Front. Biosci. 3: 11-24.
Mittnacht S., 1998. Control of pRB phosphorylation. Curr Opin Genet Dev. 8: 21-27.
Miyanishi K., Trindade M. C. D., Lindsey D. P., Beaupre G. S., Carter D. R., Goodman S. B., Schurman D. J. and Smith R. L., 2006. Effects of hydrostatic pressure and transforming growth factor-ß3 on adult human mesenchymal stem cell chondrogenesis in vitro. Tissue Eng. 12: 1419-1428.
Montes de Oca Luna R., Wagner D. S. and Lozano G., 1995. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature. 378: 203-206.
Mori T., Miura K., Aoki T., Nishihara T., Mori S., and Nakamura Y.. 1994. Frequent somatic mutation of the MTSI/CDK41 (multiple tumor suppressor/cyclin-dependent kinase 4 inhibitor) gene in esophageal squamous cell carcinoma. Cancer Res. 54: 3396-3397.
Morrison A. J., Sardet C. and Herrera R. E., 2002. Retinoblastoma protein transcriptional repression through histone deacetylation of a single nucleosome. Mol. Cell Biol. 22: 856-865.
Motokura T., Bloom T., Kim G., JLippner H., Ruderman J. V., Kronenberg H. M., and Arnold A., 1991. A novel cyclin encoded by a bcll-linked candidate oncogene. Nature. 350: 512-515.
Muller H., Bracken A. P., Vernell R., Moroni M. C., Christians F., Grassilli E., Prosperini E., Vigo E., Oliner J. D. and Helin K., 2001. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis.Genes Dev., 15, 267-285.
Murray A. and Hunt T., 1993. The Cell Cycle: An Introduction. Oxford University Press.
Musacchio A. and Salmon E. D., 2007. The spindle-assembly checkpoint in space and time. Nat. Rev. Mol. Cell Biol. 8: 379-393.
Nagatomi J., Arulanadam B. P., Metzger D. W., Meunier A. and Bizios R., 2003. Cyclic pressure affects osteoblast functions pertinent to osteogensis. Ann. Biomed. Eng. 31: 917-923.
Nigg E. A., 1995. Cyclin-dependent protein kinases: Key regulators of the eukaryotic cell cycle. Bioessays. 17: 471-480.
Nigro J. M., Baker S. J., Preisinger A. C., Jessup J. M., Hostetter R., Cleary K., Bigner S. H., Davidson N., Baylin S., Devilee P. et al., 1989. Mutations in the p53 gene occur in diverse human tumour types. Nature. 342: 705-708.
Nobori T., Miura K., Wu D. J., Lois A., Takbayashi K., and Carson D. A., 1994. Deletion of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature. 368: 753-756.
Onishi T., Zhang W., Cao X. and Hruska K., 1997. The mitogenic effect of parathyroid hormone is associated with E2F-dependent activation of cyclin-dependent kinase 1 (Cdc2) in osteoblast precursors. J. Bone Miner. Res. 12: 1596-1605.
Orlow I., LaRue H., Osman I., Lacombe L., Moore L.,Rabbani F., ois Meyer F., Fradet Y. and Cordon-Cardo C., 1999. Deletions of the INK4A gene in superficial bladder tumors. Am. J. Pathol. 155:105-113.
Ory S., Zhou M., Conrads T. P., Veenstra T. D. and Morrison D. K., 2003. Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites. Curr. Biol. 13(16): 1356-64.
Ott O. J., Rodel C., Wittlinger M., St Krause F., Dunst J., Fietkau R. and Sauer R., 2009. Radiochemotherapy for bladder cancer. Clin. Oncol. (R. Coll. Radiol.) 21: 557-565.
Pardee A. B., 1974. A restriction point for control of normal animal proliferation. Proc. Natl. Acad. Sci. 71: 286-1290.
Park J. S., Qiao L., Gilfor D. et al., 2000. A role for both Ets and C/EBP transcription factors and mRNA stabilization in the MAPK-dependent increase in p21 (Cip-1/WAF1/mda6) protein levels in primary hepatocytes. Mol. Biol. Cell. 11:2915-2932.
Paukovits P., Himmler G., Loibner H., 2004. Immunotherapy of malignant disease –developments and prospects. Wien. Med. Wochenschr. 154: 235-241.
Peng J., Elias J. E., Thoreen C. C., Licklider L. J. and Gygi S. P., 2003. Evaluation of Multidimensional Chromatography Coupled with Tandem Mass Spectrometry (LC/LC−MS/MS) for Large-Scale Protein Analysis: The Yeast Proteome. J. Proteome Res. 2(1): 43-50.
Pines J., 1995. Cyclins and cyclin-dependent kinase: Theme and Variations. Adv. Cancer Res. 66: 181-212.
Planas-Silva M. D. and Weinberg R. A., 1997. The restriction point and control of cell proliferation. Curr. Opin. Cell Biol. 9: 768-772.
Polager S., Kalma Y., Berkovich E. and Ginsberg D., 2002. E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis. Oncogene. 21: 437-446.
Potten C. S. and Loeffler M., 1990. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Development. 110: 1001-1020.
Prigent C. and Dimitrov S., 2003. Phosphorylation of serine 10 in histone H3, what for? J. Cell Sci. 116: 3677-3685.
Reed S. I., 1997. Control of G1/S transition. Cancer Surv. 29: 7-23.
Reed S. I., Bailly E., Dulic V., Hengst L., Resnitzky D. and Slingerland J., 1994. G1 control in mammalian cells. J. Cell Sci. 18: 69-73.
Ren B., Cam H., Takahashi Y., Volkert T., Terragni J., Young R. A. and Dynlacht B. D., 2002. E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev. 16: 245-256.
Reulen R. C. and Zeegers M. P., 2008. A meta-analysis on the association between bladder cancer and occupation. Scand. J. Urol. Nephrol. Suppl. 42 (218): 64-78.
Riley T., Sontag E., Chen P. and Levine A., 2008. Transcriptional control of human p53-regulated genes. Nat. Rev. Mol. Cell Biol. 9: 402–412.
Riley T., Sontag E., Chen P., and Levine A., 2008. Transcriptional control of human p53-regulated genes. Nat. Rev. Mol. Cell Biol. 9: 402–412.
Robert W., 2007. The biology of cancer. Garland Science.
Roninson I. B., 2003. Tumor cell senescence in cancer treatment. Cancer Res. 63: 2705-2715.
Rosenberg S. A., Yang J. C. and Restifo N. P., 2004. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10(9): 909-915.
Roussel M. F.,1998. Key effectors of signal transduction and G1 progression. Adv. Cancer Res. 69: 1-24.
Rubin S. M., Gall A. L., Zheng N. and Pavletich N. P., 2005. Structure of the Rb C-terminal domain bound to E2F1-DP1: a mechanism for phosphorylation-induced E2F release. Cell. 123:1093-1106.
Roy S., Kaur M., Agarwal C., Tecklenburg M., Sclafani R. A. and Agarwal R., 2007. p21 and p27 induction by silibinin is essential for its cell cycle arrest effect in prostate carcinoma cells. Cancer Ther. 6(10): 2696-2707.
Sarafan-Vasseur N., Lamy A., Bourguignon J., Pessot F. L., Hieter P., Sesboue R., Bastard C., Frebourg T. and Flaman J. M., 2002. Overexpression of B-type cyclins alters chromosomal segregation. Oncogene. 21: 2051-2057.
Schafer K. A., 1998. The cell cycle: A review. Vet. Pathol. 35: 461-478.
Schmidt E. E., Ichimura K., Reifenberger G., and Collins V. P., 1994. CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res. 54: 6321-6324.
Schmitt C. A., Fridman J. S., Yang M., Lee S., Baranov E., Hoffman R. M. and Lowe S. W., 2002b. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell. 109: 335–346.
Sherr C. J., 2000. The Pezcoller lecture: cancer cell cycles revisited. Cancer Res. 60: 3689-3695.
Smith E. J., Leone G., DeGregori J., Jakoi L. and Nevins J. R., 1996. The accumulation of an E2F-p130 transcriptional repressor distinguishes a G0 cell state from a G1 cell state. Mol. Cell Biol. 16: 6965-6976.
Soria J. C., Jang S. J., Khuri F. R., Hassan K., Liu D., Hong W. K. and Mao L., 2000. Over-expression of cyclin B1 in early-stage non small cell lung cancer and its clinical implication. Cancer Res. 60: 4000-4004.
Stevaux O. and Dyson N. J., 2002. A revised picture of the E2F transcriptional network and RB function. Curr. Opin. Cell Biol. 14: 684-691.
Sugiyama K., Sugiura K., Hara T., Sugimoto K., Shima H., Honda K., Furukawa K., Yamashita S. and Urano T., 2002. Aurora-B associated protein phosphatases as negative regulators of kinase activation. Oncogene. 21: 3103-3111.
Takahashi T., Nau M. M., Chiba I., Birrer M. J., Rosenberg R. K., Vinocour M., Levitt M., Pass H., Gazdar A. F., Minna J. D. et al., 1989. p53: A frequent target for genetic abnormalities in lung cancer. Science. 246: 491-494.
Takahashi Y., Rayman J. B. and Dynlacht B. D., 2000. Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes Dev. 14: 804-816.
Tatsumi Y., Sugimoto N., Yugawa T., Narisawa-Saito M., Kiyono T. and Fujita M., 2006. Deregulation of Cdt1 induces chromosomal damage without rereplication and leads to chromosomal instability. J. Cell Sci. 119: 3128-3140.
Temin H., 1971. Stimulation by serum of multiplication of stationary chicken cells. J. Cell Physiol. 78: 161-170.
Tezel G. and Wax M. B., 2000. Increased production of tumor Necrosis factor-α by glial cells exposed to simulated ischemia or elevated hydrostatic pressure induces apoptosis in cocultured retinal ganglion cells. J. Neuro. 20(23): 8693-8700.
Tzeng C. C., Liu H. S., Li C., Jin Y. T., Chen R. M., Yang W. H. and Lin J. S., 1996. Characterization of two urothelium cancer cell lines derived from a blackfoot disease endemic area in Taiwan. Anticancer Res. 16(4A):1797-804.
Umansky V., Malyguine A. and Shurin M., 2009. New perspectives in cancer immunotherapy and immunomonitoring. Future Oncol. 5(7): 941-944.
Ute H., Michael S., Christian D., Niki I., Joachim H., Thorsten G. and Bodo K., 2001. Combination of reduced oxygen tension and intermittent hydrostatic pressure: useful tool in articular cartilage tissure engineering. J. Biomech. 34: 941-949.
Vermeulen K., Van Bockstaele D. R. and Berneman Z. N., 2003. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 36: 131-149.
Vernell R., Helin K. and Muller H., 2003. Identification of target genes of the p16INK4A-pRB-E2F pathway. J. Biol. Chem. 278: 46124-46137.
Vidal A. and Koff A., 2000. Cell-cycle inhibitors: three families united by a common cause. Gene. 247: 1-15.
Vietri M., Bianchi M, Ludlow J. W., Mittnacht S. and Villa-Moruzzi E., 2006. Direct interaction between the catalytic subunit of Protein Phosphatase 1 and pRb. Cancer Cell Int. 6:3.
Vigo E., Muller H., Prosperini E., Hateboer G., Cartwright P., Moroni M. C. and Helin K., 1999. CDC25A phosphatase is a target of E2F and is required for efficient E2F-induced S phase. Mol. Cell Biol. 1999:6379-6395.
Vogan K., Bernstein M., Leclerc J. M., Brisson L., Brossard J., Brodeur G. M., Pelletier J. and Gros P., 1993. Absence of p53 gene mutations in primary neuroblastomas. Cancer Res. 53: 5269-5273.
Vogelstein B., 1990. Cancer. A deadly inheritance. Nature. 348: 681-682.
Wang A., Yoshimi N., Ino N., Tanaka T. and Mori H., 1997. Overexpression of cyclin B1 in human colorectal cancers. J. Cancer Res. Clin. Oncol. 123: 124-127.
Wang T. H., Wang H. S. and Soong Y. K., 2000. Paclitaxel-induced cell death: where the cell cycle and apoptosis come together. Cancer. 88: 2619-2628.
Weinmann A. S., Yan P. S., Oberley M. J., Huang T. H. and Farnham P. J., 2002. Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis. Genes Dev. 16: 235-244.
Welch P. and Wang J. Y., 1995. Disruption of retinoblastoma protein function by coexpression of its C pocket fragment. Genes Dev. 9:31-46.
Whyte P., Buchkovich K. J., Horowitz J. M., Friend S. H., Raybuck M., Weinberg R. A. and Harlow E., 1988. Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Nature. 334: 124-129.
Williams G. H. and Stoeber K., 2007. Cell cycle markers in clinical oncology. Curr. Opin. Cell Biol. 19: 672-679.
Witjes J. A., 2006. Management of BCG Failures in Superficial Bladder Cancer: A Review. Eur. Urol. 49:790-797.
Xiao Z., Chen J., Levine A. J., Modjtahedi N., Xing J., Sellers W. R. and Livingston D. M., 1995. Interaction between the retinoblastoma protein and the oncoprotein mdm2. Nature. 375: 694-698.
Xie X. H., An H. J., Suki Kang, Hong S., Choi Y. P., Kim Y. T., Choi Y. D. and Cho N. H., 2005. Loss of Cyclin B1 followed by downregulation of Cyclin A/Cdk2, apoptosis and antiproliferation in Hela cell line. Int. J. Cancer. 116: 520-525.
Yam C. H., Fung T. K. and Poon R. Y., 2002. Cyclin A in cell cycle control and cancer. Cell. Mol. Life Sci. 59 (8): 1317-1326.
Yee K. S. and Vousden K. H., 2005. Complicating the complexity of p53. Carcinogenesis. 26: 1317-1322.
Yin X. Y., Grove L., Datta N. S., Katula K., Long M. W. and Prochownik E. V., 2001. Inverse regulation of cyclin B1 by c-Myc and p53 and induction of tetraploidy by cyclin B1 overexpression. Cancer Res. 61: 6487-6493.
Zarkowska T. and Mittnacht S., 1997. Differential phosphorylation of the retinoblastoma protein by G1/S cyclin-dependent kinases. J. Biol. Chem. 272: 12738-12746.
Zeegers M. P., Tan F. E., Dorant E. and Van Den Brandt P. A., 2000. The impact of characteristics of cigarette smoking on urinary tract cancer risk: a meta-analysis of epidemiologic studies. Cancer. 89 (3): 630-9.
Zetterberg A., Larsson O. and Wiman K. G., 1995. What is the restriction point? Curr. Opin. Cell Biol. 7: 835-842.

Zhou X., Tarmin L., Yin J., Jiang H.-Y., Suzuki H., Rhyu M.-G., Abraham J., and Meltzer S. J., 1994. The MTSl gene is frequently mutated in primary human esophageal tumors. Oncogene. 9: 3737-3741.
zur Hausen H., 1991. Viruses in human cancer. Science. 254: 1167-1173.
Clinical Tools, Inc. http://www.clinicaltools.com/
廖士慶，2009，設計與製作回授控制壓力式生物反應器以探討壓力對骨髓幹細胞增生與型態之影響，中央大學機械工程學系碩士論文
余明翰，2012，靜水壓對細胞分化及增生影響的實驗研究，中央大學機械工程學系碩士論文
行政院衛生署2012年成果報告

指導教授

鍾志昂(Chih-Ang Chung)

審核日期

2013-10-23

推文