Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/92150
標題: 探討腹腔鏡手術於胃部胃腸基質瘤之角色及Cdk5與p35蛋白於胃部胃腸基質瘤與甲狀腺癌及乳癌之表現
Investigation of the role of laparoscopic surgery in stomach gastrointestinal stromal tumor and the expression of Cdk5 and p35 proteins in stomach gastrointestinal stromal tumor, thyroid and breast cancer
作者: Yueh-Tsung Lee
李岳聰
關鍵字: 胃腸基質瘤;腹腔鏡手術;甲狀腺癌;乳癌;Cdk5 protein;p35 protein;gastrointestinal stromal tumor;laparoscopic surgery;thyroid cancer;breast cancer
引用: 1.Hwang JH, Saunders MD, Rulyak SJ, Shaw S, Nietsch H, Kimmey MB. A prospective study comparing endoscopy and EUS in the evaluation of GI subepithelial masses. Gastrointestinal endoscopy. 2005;62:202-208. 2.Furuhashi S, Takamori H, Abe S, Nakahara O, Tanaka H, Horino K et al. Solid-pseudopapillary pancreatic tumor, mimicking submucosal tumor of the stomach: A case report. World journal of gastrointestinal surgery. 2011;3:201-203. 3.Lee YT, Lin H, Guo JC, Yan SL, Hou HJ, Lai YS et al. Laparoscopy-assisted billroth I gastrectomy for ectopic pancreas in the prepyloric region. Case reports in gastroenterology 2012;6:712-719. 4.Hsu SD, Wu HS, Kuo CL, Lee YT. Robotic-assisted laparoscopic resection of ectopic pancreas in the posterior wall of gastric high body: case report and review of the literature. World journal of gastroenterology. 2005;11:7694-7696. 5.Lee MW, Kim SH, Kim YJ, Lee JM, Lee JY, Park EA et al. Gastrointestinal stromal tumor of the stomach: preliminary results of preoperative evaluation with CT gastrography. Abdominal imaging. 2008;33:255-261. 6.Kume K, Kanda K, Tabaru A, Yoshikawa I, Abe S, Otsuki M. Splenic artery aneurysm exhibiting the features of submucosal tumor in the stomach. Gastrointestinal endoscopy. 2001;53:208-209. 7.Kashyap P, Medeiros F, Levy M, Larson M. Unusual submucosal tumor in the stomach. Diagnosis. Endometriosis. Gastroenterology. 2011;140:e7-8. 8.Carboni F, Carlini M, Scardamaglia F, Santoro E, Boschetto A, Castelli M et al. Gastrointestinal stromal tumors of the stomach. A ten-year surgical experience. Journal of experimental & clinical cancer research. 2003; 22:379-384. 9.Miettinen M, Lasota J. Gastrointestinal stromal tumors--definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Archiv. 2001;438:1-12. 10.Tran T, Davila JA, El-Serag HB. The epidemiology of malignant gastrointestinal stromal tumors: an analysis of 1,458 cases from 1992 to 2000. The American journal of gastroenterology. 2005;100:162-168. 11.Yeh CN, Hwang TL, Huang CS, Lee PH, Wu CW, Ker CC et al. On behalf of Taiwan Surgical Society of G: Clinical practice guidelines for patients with gastrointestinal stromal tumor in Taiwan. World Journal of Surgical Oncology. 2012;10:246-254. 12.Tzen CY, Wang JH, Huang YJ, Wang MN, Lin PC, Lai GL et al. Incidence of gastrointestinal stromal tumor: a retrospective study based on immunohistochemical and mutational analyses. Digestive diseases and sciences. 2007;52:792-797. 13.Berindoague R, Targarona EM, Feliu X, Artigas V, Balague C, Aldeano A et al. Laparoscopic resection of clinically suspected gastric stromal tumors. Surgical Innovation. 2006;13:231-237. 14.Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Human pathology. 2008;39:1411-1419. 15.Kakeji Y, Nakanoko T, Yoshida R, Eto K, Kumashiro R, Ikeda K et al. Laparoscopic resection for gastrointestinal stromal tumors in the stomach. Surgery Today. 2012;42:554-558. 16.Molloy D, Kaloo PD, Cooper M, Nguyen TV. Laparoscopic entry: a literature review and analysis of techniques and complications of primary port entry. The Australian & New Zealand journal of obstetrics & gynaecology. 2002; 42:246-254. 17.Ahmad G, Duffy JM, Phillips K, Watson A. Laparoscopic entry techniques. The Cochrane database of systematic reviews. 2008;CD006583. 18.Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. The journal of the American Medical Association. 2006; 295:2164-2167. 19.Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid : official journal of the American Thyroid Association. 2009;19:1167-1214. 20.DM p. global cancer statistics in the year 2000. The lancet oncology. 2001;2:11. 21.Patani N, Jouhra F, Mokbel K. Changes in breast cancer incidence rates. Cancer epidemiology, biomarkers & prevention. 2008;17:742. 22.Pusztai L. Current status of prognostic profiling in breast cancer. The oncologist. 2008;13:350-360. 23.Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J et al. Molecular definition of breast tumor heterogeneity. Cancer cell. 2007;11:259-273. 24.Chia S, Bryce C, Gelmon K. The 2000 EBCTCG overview: a widening gap. Lancet. 2005;365:1665-1666. 25.Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Annals of oncology. 2007;18:1133-1144. 26.Paik S. Methods for gene expression profiling in clinical trials of adjuvant breast cancer therapy. Clinical cancer research. 2006;12:1019s-1023s. 27.Ingle JN, Krook JE, Green SJ, Kubista TP, Everson LK, Ahmann DL et al. Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer. Journal of clinical oncology. 1986;4:178-185. 28.Muss HB. Endocrine therapy for advanced breast cancer: a review. Breast cancer research and treatment. 1992;21:15-26. 29.Hammond ME, Hayes DF, Wolff AC, Mangu PB, Temin S. American society of clinical oncology/college of american pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Journal of oncology practice. 2010;6:195-197. 30.Arteaga CL. Epidermal growth factor receptor dependence in human tumors: more than just expression? The oncologist. 2002; 7 Suppl 4:31-39. 31.Ross JS, Symmans WF, Pusztai L, Hortobagyi GN. Breast cancer biomarkers. Advances in clinical chemistry. 2005;40:99-125. 32.Ross JS, Linette GP, Stec J, Clark E, Ayers M, Leschly N et al. Breast cancer biomarkers and molecular medicine. Expert review of molecular diagnostics. 2003;3:573-585. 33.Bates S, Peters G. Cyclin D1 as a cellular proto-oncogene. Seminars in cancer biology. 1995;6:73-82. 34.Bland KI, Konstadoulakis MM, Vezeridis MP, Wanebo HJ. Oncogene protein co-expression. Value of Ha-ras, c-myc, c-fos, and p53 as prognostic discriminants for breast carcinoma. Annals of Surgery. 1995;221:706-718. 35.Pines J. Cyclins, CDKs and cancer. Seminars in cancer biology. 1995;6:63-72. 36.Spirin KS, Simpson JF, Takeuchi S, Kawamata N, Miller CW, Koeffler HP. p27/Kip1 mutation found in breast cancer. Cancer research. 1996;56:2400-2404. 37.Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C et al. Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nature medicine. 1997;3:227-230. 38.Porter PL, Malone KE, Heagerty PJ, Alexander GM, Gatti LA, Firpo EJ et al. Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nature medicine. 1997;3:222-225. 39.Keyomarsi K, Tucker SL, Buchholz TA, Callister M, Ding Y, Hortobagyi GN et al. Cyclin E and survival in patients with breast cancer. The New England journal of medicine. 2002;347:1566-1575. 40.Farber E. Cell proliferation is not a major risk factor for cancer. Modern pathology. 1996;9:606. 41.Mills GB, Kohn E, Lu Y, Eder A, Fang X, Wang H et al. Linking molecular diagnostics to molecular therapeutics: targeting the PI3K pathway in breast cancer. Seminars in oncology. 2003;30:93-104. 42.Ross JS, Fletcher JA, Bloom KJ, Linette GP, Stec J, Clark E et al. HER-2/neu testing in breast cancer. American journal of clinical pathology. 2003; 120:S53-71. 43.Bostrom P, Soderstrom M, Palokangas T, Vahlberg T, Collan Y, Carpen O, Hirsimaki P. Analysis of cyclins A, B1, D1 and E in breast cancer in relation to tumour grade and other prognostic factors. BMC research notes. 2009;2:140. 44.Elayat G, Selim AG, Wells CA. Alterations of the cell cycle regulators cyclin D1, cyclin A, p27, p21, p16, and pRb in apocrine metaplasia of the breast. The breast journal. 2009;15:475-482. 45.Nishimura R, Osako T, Okumura Y, Hayashi M, Arima N. Clinical significance of Ki-67 in neoadjuvant chemotherapy for primary breast cancer as a predictor for chemosensitivity and for prognosis. Breast Cancer. 2010;17:269-75. 46.Sousa-Junior EC, Alencar AP, da Silva BB. Analysis of Ki-67 and Bcl-2 protein expression in normal colorectal mucosa of women with breast cancer. Europian journal of cancer. 2009;45.3081-3086. 47.Frierson HF, Jr. Ploidy analysis and S-phase fraction determination by flow cytometry of invasive adenocarcinomas of the breast. American journal of surgical pathology. 1991;15:358-367. 48.Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Annals of oncology. 2009;20:1319-1329. 49.Konigsberg R, Rogelsperger O, Jager W, Thalhammer T, Klimpfinger M, De Santis M et al. Cell cycle dysregulation influences survival in high risk breast cancer patients. Cancer investigation. 2008;26:734-740. 50.van Nes JG, Smit VT, Putter H, Kuppen PJ, Kim SJ, Daito M et al. Validation study of the prognostic value of cyclin-dependent kinase (CDK)-based risk in Caucasian breast cancer patients. British journal of cancer. 2009;100:494-500. 51.Fleming IN, Hogben M, Frame S, McClue SJ, Green SR. Synergistic inhibition of ErbB signaling by combined treatment with seliciclib and ErbB-targeting agents. Clinical cancer research. 2008;14:4326-4335. 52.Hui AB, Yue S, Shi W, Alajez NM, Ito E, Green SR et al. Therapeutic efficacy of seliciclib in combination with ionizing radiation for human nasopharyngeal carcinoma. Clinical cancer research. 2009;15:3716-3724. 53.Valabrega G, Montemurro F, Aglietta M. Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Annals of oncology. 2007;18:977-984. 54.Allred DC, Clark GM, Molina R, Tandon AK, Schnitt SJ, Gilchrist KW et al. Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer. Human pathology. 1992; 23:974-979. 55.Mojarad S, Venturini B, Fulgenzi P, Papaleo R, Brisigotti M, Monti F et al. Prediction of nodal metastasis and prognosis of breast cancer by ANN-based assessment of tumour size and p53, Ki-67 and steroid receptor expression. Anticancer research. 2013; 33:3925-3933. 56.Lee YT, Lin H, Lai MT, Guo ZC, Chen CT. Ki-67 expression correlated with lymphovascular invasion in breast cancer. The Journal of physiological sciences. 2009;59(Suppl 1):1. 57.Gottwald L, Kubiak R, Sek P, Piekarski J, Szwalski J, Pasz-Walczak G et al. The value of Ki-67 antigen expression in tissue microarray method in prediction prognosis of patients with endometrioid endometrial cancer. Ginekologia polska. 2013;84:444-449. 58.Trivers KF, Lund MJ, Porter PL, Liff JM, Flagg EW, Coates RJ et al. The epidemiology of triple-negative breast cancer, including race. Cancer causes & control. Cancer causes control. 2009;20:1071-1082. 59.Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clinical cancer research. 2007; 13:4429-4434. 60.Walentinsson A, Helou K, Levan G. A dual-color FISH gene map of the proximal region of rat Chromosome 4 and comparative analysis in human and mouse. Mammalian genome. 2001;12:900-908. 61.Weishaupt JH, Neusch C, Bahr M. Cyclin-dependent kinase 5 (CDK5) and neuronal cell death. Cell and tissue research. 2003;312:1-8. 62.Hellmich MR, Pant HC, Wada E, Battey JF. Neuronal cdc2-like kinase: a cdc2-related protein kinase with predominantly neuronal expression. Proceedings of the National Academy of Sciences of the United States of America. 1992;89:10867-10871. 63.Tsai LH, Takahashi T, Caviness VS, Jr., Harlow E. Activity and expression pattern of cyclin-dependent kinase 5 in the embryonic mouse nervous system. Development. 1993;119:1029-1040. 64.Tsai LH, Delalle I, Caviness VS, Jr., Chae T, Harlow E. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature. 1994;371:419-423. 65.Mao D, Hinds PW. p35 is required for CDK5 activation in cellular senescence. The Journal of biological chemistry. 2010;285:14671-14680 66.Dhavan R, Tsai LH. A decade of CDK5. Nature reviews. Molecular cell biology. 2001; 2:749-759. 67.Weishaupt JH, Kussmaul L, Grotsch P, Heckel A, Rohde G, Romig H et al. Inhibition of CDK5 is protective in necrotic and apoptotic paradigms of neuronal cell death and prevents mitochondrial dysfunction. Molecular and cellular neurosciences. 2003;24:489-502. 68.Chen F, Wang Q, Wang X, Studzinski GP. Up-regulation of Egr1 by 1,25-dihydroxyvitamin D3 contributes to increased expression of p35 activator of cyclin-dependent kinase 5 and consequent onset of the terminal phase of HL60 cell differentiation. Cancer research. 2004;64:5425-5433. 69.Liu JL, Wang XY, Huang BX, Zhu F, Zhang RG, Wu G. Expression of CDK5/p35 in resected patients with non-small cell lung cancer: relation to prognosis. Medical oncology. 2011;28:673-678. 70.Lin H, Chen MC, Ku CT. Cyclin-dependent kinase 5 regulates steroidogenic acute regulatory protein and androgen production in mouse Leydig cells. Endocrinology. 2009;150:396-403. 71.Goodyear S, Sharma MC. Roscovitine regulates invasive breast cancer cell (MDA-MB231) proliferation and survival through cell cycle regulatory protein cdk5. Experimental and molecular pathology. 2007;82:25-32. 72.Upadhyay AK, Ajay AK, Singh S, Bhat MK. Cell cycle regulatory protein 5 (Cdk5) is a novel downstream target of ERK in carboplatin induced death of breast cancer cells. Current cancer drug targets. 2008;8:741-752. 73.Ye Y, Tinari A, Malorni W, Lockshin RA, Zakeri Z. Activation of cyclin-dependent kinase 5 is a consequence of cell death. Journal of biomedicine & biotechnology. 2009;2009:805709. 74.Lin H, Juang JL, Wang PS. Involvement of Cdk5/p25 in digoxin-triggered prostate cancer cell apoptosis. The Journal of biological chemistry. 2004;279:29302-29307. 75.Lin H, Chen MC, Chiu CY, Song YM, Lin SY. Cdk5 regulates STAT3 activation and cell proliferation in medullary thyroid carcinoma cells. The Journal of biological chemistry. 2007;282:2776-2784. 76.Kuo HS, Hsu FN, Chiang MC, You SC, Chen MC, Lo MJ et al. The role of Cdk5 in retinoic acid-induced apoptosis of cervical cancer cell line. The Chinese journal of physiology. 2009;52:23-30. 77.Choi HS, Lee Y, Park KH, Sung JS, Lee JE, Shin ES et al. Single-nucleotide polymorphisms in the promoter of the CDK5 gene and lung cancer risk in a Korean population. Journal of human genetics. 2009;54:298-303. 78.Strock CJ, Park JI, Nakakura EK, Bova GS, Isaacs JT, Ball DW et al. Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. Cancer research. 2006;66:7509-7515. 79.Sandal T, Stapnes C, Kleivdal H, Hedin L, Doskeland SO. A novel, extraneuronal role for cyclin-dependent protein kinase 5 (CDK5): modulation of cAMP-induced apoptosis in rat leukemia cells. The Journal of biological chemistry. 2002;277:20783-20793. 80.Liu R, Tian B, Gearing M, Hunter S, Ye K, Mao Z. Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:7570-7575. 81.Kim E, Chen F, Wang CC, Harrison LE. CDK5 is a novel regulatory protein in PPARgamma ligand-induced antiproliferation. International journal of oncology. 2006;28:191-194. 82.Feldmann G, Mishra A, Hong SM, Bisht S, Strock CJ, Ball DW et al. Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling. Cancer research. 2010;70:4460-4469. 83.Hsu FN, Chen MC, Chiang MC, Lin E, Lee YT, Huang PH et al. Regulation of androgen receptor and prostate cancer growth by cyclin-dependent kinase 5. The Journal of biological chemistry. 2011;286:33141-33149. 84.Lee YT, Hsu SD, Kuo CL, Chou DA, Lin MS, Huang MH et al. Squamous cell carcinoma arising from longstanding colocutaneous fistula: a case report. World journal of gastroenterology. 2005;11:5251-5253. 85.Lee YT, Wu HS, Hung MC, Lin ST, Hwang YS, Huang MH. Ruptured appendiceal cystadenoma presenting as right inguinal hernia in a patient with left colon cancer: a case report and review of literature. BMC gastroenterology 2006; 6:32. 86.Yan SL, Wu HS, Chou DA, Kuo CL, Huang HT, Lee YT et al. Pseudoaneurysm of superior mesentery artery branch after renal extracorporeal shock wave lithotripsy: case report and review. The Journal of trauma. 2007;62:770-773. 87.Han Y, Yang L, Suarez-Saiz F, San-Marina S, Cui J, Minden MD. Wilms' tumor 1 suppressor gene mediates antiestrogen resistance via down-regulation of estrogen receptor-alpha expression in breast cancer cells. Molecular cancer research. 2008;6:1347-1355. 88.Lee YT, Lin H, Chen KY, Wu HS, Hwang MH, Yan SL. Life-threatening hemobilia caused by hepatic pseudoaneurysm after T-tube choledochostomy: report of a case. BMC gastroenterology. 2010; 10:81. 89.Lai HW, Tseng SH, Lee YT, Hsu CH, Chou DA, Wu HS et al. Impact of AITS laparoscopic training center on surgeons' preference for appendectomy. Surgical endoscopy. 2010; 24:2210-2215. 90.Wu HS, Lai HW, Kuo SJ, Lee YT, Chen DR, Chi CW et al. Competitive edge of laparoscopic appendectomy versus open appendectomy: a subgroup comparison analysis. Journal of laparoendoscopic & advanced surgical techniques: Part A. 2011;21:197-202. 91.Lin H, Lin TY, Juang JL. Abl deregulates Cdk5 kinase activity and subcellular localization in Drosophila neurodegeneration. Cell death and differentiation. 2007;14:607-615. 92.Hsu FN, Chen MC, Lin KC, Peng YT, Li PC, Lin E et al. Cyclin-dependent kinase 5 modulates STAT3 and androgen receptor activation through phosphorylation of Ser727 on STAT3 in prostate cancer cells. American journal of physiology Endocrinology and metabolism. 2013;305:E975-986. 93.Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Modern pathology. 1998;11:155-168. 94.Hu TH, Lin JW, Changchien CS, Liu SY, Chiou SS, Chuang JH. Immunohistochemical analyses of gastric stromal tumors in Taiwanese. Journal of the Formosan Medical Association. 2003;102:707-714. 95.Iwahashi M, Takifuji K, Ojima T, Nakamura M, Nakamori M, Nakatani Y et al. Surgical management of small gastrointestinal stromal tumors of the stomach. World journal of surgery. 2006;30:28-35. 96.Lai IR, Lee WJ, Yu SC. Minimally invasive surgery for gastric stromal cell tumors: intermediate follow-up results. Journal of gastrointestinal surgery. 2006;10:563-566. 97.Melstrom LG, Phillips JD, Bentrem DJ, Wayne JD. Laparoscopic versus open resection of gastric gastrointestinal stromal tumors. American journal of clinical oncology. 2012;35:451-454. 98.Hindmarsh A, Koo B, Lewis MP, Rhodes M. Laparoscopic resection of gastric gastrointestinal stromal tumors. Surgical endoscopy. 2005;19:1109-1112. 99.Jeong IH, Kim JH, Lee SR, Kim JH, Hwang JC, Shin SJ et al. Minimally invasive treatment of gastric gastrointestinal stromal tumors: laparoscopic and endoscopic approach. Surgical laparoscopy, endoscopy & percutaneous techniques. 2012;22:244-250. 100.Kim KH, Kim MC, Jung GJ, Kim SJ, Jang JS, Kwon HC. Long term survival results for gastric GIST: is laparoscopic surgery for large gastric GIST feasible? World journal of surgical oncology. 2012; 10:230. 101.Thakkar DV, Wani SV, Shetty V, Patankar RV. Laparoscopic sleeve gastrectomy for a large gastrointestinal stromal tumor. Surgical laparoscopy, endoscopy & percutaneous techniques. 2012;22:e61-62. 102.Yano H, Kimura Y, Iwazawa T, Takemoto H, Imasato M, Monden T et al. Hand-assisted laparoscopic surgery for a large gastrointestinal stromal tumor of the stomach. Gastric Cancer. 2005;8:186-192. 103.Hyung WJ, Lim JS, Cheong JH, Kim J, Choi SH, Noh SH. Laparoscopic resection of a huge intraluminal gastric submucosal tumor located in the anterior wall: eversion method. Journal of surgical oncology. 2005;89:95-98. 104.Park JY, Eom BW, Yoon H, Ryu KW, Kim YW, Lee JH. Transumbilical single-incision laparoscopic wedge resection for gastric submucosal tumors: technical challenges encountered in initial experience. Journal of gastric cancer. 2012;12:173-178. 105.Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674. 106.Lin H, Wang SW, Wang RY, Wang PS. Stimulatory effect of lactate on testosterone production by rat Leydig cells. Journal of cellular biochemistry. 2001;83:147-154. 107.Arif A. Extraneuronal activities and regulatory mechanisms of the atypical cyclin-dependent kinase Cdk5. Biochemical pharmacology. 2012;84:985-993. 108.Turner NC, Lord CJ, Iorns E, Brough R, Swift S, Elliott R et al. A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. Journal of European Molecular Biology Organization. 2008;27:1368-1377. 109.Liu JL, Wang XY, Huang BX, Zhu F, Zhang RG, Wu G. Expression of CDK5/p35 in resected patients with non-small cell lung cancer: relation to prognosis. Medical oncology. 2011;28:673-678. 110.Yang S. Gene amplifications at chromosome 7 of the human gastric cancer genome. International journal of molecular medicine. 2007;20:225-231. 111.Liu NN, Ohkouchi M, Hashikura Y, Kajimoto N, Matsuda I, Isozaki K et al. Extracellular domain c-kit mutation with duplication of Ser501Ala502 found in gastrointestinal stromal tumors is more imatinib- and nilotinib-sensitive than that with duplication of Ala502Tyr503. Laboratory investigation. 2013;93:502-507. 112.Chang Q, Yan L, Wang CZ, Zhang WH, Hu YZ, Wu BY. In vivo transplantation of bone marrow mesenchymal stem cells accelerates repair of injured gastric mucosa in rats. Chinese medical journal. 2012;125:1169-1174. 113.Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nature reviews. Cancer. 2013;13:184-199. 114.Aokage K, Ishii G, Ohtaki Y, Yamaguchi Y, Hishida T, Yoshida J et al. Dynamic molecular changes associated with epithelial-mesenchymal transition and subsequent mesenchymal-epithelial transition in the early phase of metastatic tumor formation. International journal of cancer. 2011;128:1585-1595. 115.Lim IK. TIS21 (/BTG2/PC3) as a link between ageing and cancer: cell cycle regulator and endogenous cell death molecule. Journal of cancer research and clinical oncology. 2006;132:417-426. 116.Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. Journal of clinical oncology. 2007;25:5287-5312. 117.Chin K, DeVries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo WL et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer cell. 2006;10:529-541. 118.Chen MC, Lin H, Hsu FN, Huang PH, Lee GS, Wang PS. Involvement of cAMP in nerve growth factor-triggered p35/Cdk5 activation and differentiation in PC12 cells. American journal of physiology. Cell physiology. 2010; 299:C516-527. 119.Courapied S, Sellier H, de Carne Trecesson S, Vigneron A, Bernard AC et al. The cdk5 kinase regulates the STAT3 transcription factor to prevent DNA damage upon topoisomerase I inhibition. The Journal of biological chemistry. 2010;285:26765-26778. 120.Sharma P, Veeranna, Sharma M, Amin ND, Sihag RK, Grant P et al. Phosphorylation of MEK1 by cdk5/p35 down-regulates the mitogen-activated protein kinase pathway. The Journal of biological chemistry. 2002;277:528-534. 121.Yeh YT, Ou-Yang F, Chen IF, Yang SF, Wang YY, Chuang HY et al. STAT3 ser727 phosphorylation and its association with negative estrogen receptor status in breast infiltrating ductal carcinoma. International journal of cancer. 2006;118:2943-2947. 122.Fu AK, Fu WY, Ng AK, Chien WW, Ng YP, Wang JH et al. Cyclin-dependent kinase 5 phosphorylates signal transducer and activator of transcription 3 and regulates its transcriptional activity. Proceedings of the National Academy of Sciences of the United States of America. 2004;101:6728-6733.
摘要: 
Part I:
The Role of Laparoscopic Surgery in Gastrointestinal Stromal Tumor of Stomach
Gastrointestinal stromal tumors (GISTs) often occur in the alimentary tract and less common, originating from omentum, mesentery and peritoneum. They usually present as subepithelial masses in the gastrointestinal tract or intraabdominal component and possess malignant potential. The tumors might cause abdominal pain, gastrointestinal tract bleeding, obstruction and intraabdominal hemorrhage but might also be disclosed as incidental findings. Gastroscopy, ultrasonography and computed tomography scan are employed for detection and evaluation. GISTs are differential diagnosis with other mesenchymal tumors by pathological target specially. The surgical principles are to excise the tumor with margin free of tumor microscopically. GISTs are one kind of submucosal tumor. Based on our published documents, we investigated the feasibility and security of laparoscopic surgery for stomach GISTs.
We retrospectively analyzed twenty four patients who was diagnosed as primary stomach GISTs and operated at our institutes during 2008 to 2012. The patients were divided to laparoscopy group (18 patients) and laparotomy group (6 patients) depending on the surgical methods. The patients' age, gender, hospital stay, operative time, blood loss, tumor size and complication rate were compared in the two groups. The role of laparoscopic surgery in the indication and safety for the primary gastrointestinal stromal tumor of stomach was explored and investigated. Tumor size and operative blood loss were significantly different in the two groups. The patients' age, gender, hospital stay, operative time and complication rate were not statistically different in both groups. However, there was a trend of shorter hospital stay in the laparoscopic group. In the past 4 years, 75% of primary gastric GISTs in our hospital were managed by laparoscopic surgery safely and efficiently. Our experience showed that laparoscopic surgery is feasible for primary stomach GISTs in selective patients with small tumors.

Part II:
Expression of cyclin-dependent kinase 5 (Cdk5) in the gastrointestinal stromal tumor, thyroid cancer and breast cancer
In the past, Cdk5 protein was usually recognized as the decisive roles in neuromuscular development. Recent reports demonstrated the roles not only in cell cycle but also in cancer biology. Its new findings on tumor proliferation such as prostate cancer, thyroid cancer, breast cancer and lung cancer highlight Cdk5 as a potential therapeutic target. We have published the effect of expressed Cdk5 protein in the prostate and thyroid cancer cell growth. Furthermore, we investigated the expression of Cdk5 protein and its activator, p35 protein in gastrointestinal stromal tumor, thyroid cancer and breast cancer. The studies focused on three kinds of tumors, GISTs, thyroid cancer and breast cancer. The paraffin-embedded specimens were stained by hematoxylin & eosin staining method to differ the tumor portion and non-tumor portion by optic microscopy. The immunohistochemical staining method was performed by interaction of Cdk5 and p35 antibody (purchased from Upstate Biotechnology, Inc. Lake Placid, New York, 12946, USA) with antigen on the paraffin-embedded specimens. The results were observed and recorded by Allred semi-quantitative method. The results were recorded as scores 0, 2-8 and 0 %, 20 %, 50 %, 75 % respectively.
Twenty two patients with primary stomach GISTs who underwent surgery in the past four years were enrolled. The results were compared with prognostic factors such as tumor size and tumor cell mitosis. By analyzing thirty four clinical cancerous specimens from differentiated thyroid cancer (papillary and follicular), we investigated the expression of Cdk5 and p35 proteins in both tumor tissue and adjacent normal tissue by immunohistochemistry method. The results were compared with patients' age, gender, tumor characteristics, whether nuchal lymph nodes metastases or not. In breast cancer study, we collected fifty six clinical specimens and forty commercial tissue array. We surveyed the expression of Cdk5 and p35 proteins in both tumor tissue and adjacent normal tissue by Western blotting methods in 28 specimens. Thirty nine clinical specimens and thirty eight commercial specimens were studied by anti-Cdk5 and anti-p35 IHC staining. The expression of Cdk5 and p35 proteins were analyzed with the parameters of breast cancer pathology such as patients' age, tumor size, nodal status in axillae, distal metastasis, tumor grade, hormone receptor, Her-2/neu receptor, and Ki-67 proliferating factor, etc. Commercial tissue microarray chips were purchased from US Biomax, Inc. (Rockville, MD 20850, USA). They consisted of forty breast cancer tissues and neighboring normal tissue from 40 patients abroad. Data was quantified and analyzed by Chi square-test, independent T test, paired T-test and Pearson correlation methods according to the variables. Partial research work was supported by research fund of Show Chwan Health System with approval of the Institutional Review Board.
Compared with normal tissue, overexpression of Cdk5 and p35 proteins were noted in 86.4 % and 81.8 % of twenty two GIST specimens respectively. The statistical trend was obvious in larger tumor and tumor with higher mitosis, up to 100 % of specimens. In the thyroid cancer study, overexpression of Cdk5 and p35 were noted in the tumor portion compared with non-tumor portion significantly (Chi-square test, p<0.05). In 24 papillary carcinoma patients, both Cdk5 and p35 proteins overexpressed in 23 patients (95.8 %). In ten follicular carcinoma patients, Cdk5 overexpressed in six (60.0 %) and p35 overexpressed in seven (70 %) patients. The studies in thyroid demonstrated overexpression of Cdk5 protein in 29 specimens (85.3 %) and p35 protein in 30 specimens (88.2 %). For five patients with neck lymph nodes metastases, all the primary tumors presented overexpression of Cdk5 and p35 protein (100.0 %). In breast cancer clinical results, we found that Cdk5 and p35 proteins overexpressed in 61.0 % (47/77) and 55.8 % (43/77) of clinical and commercial specimens. Co-overexpression of Cdk5 and p35 was noted in 42.9 % (33/77) of specimens. There was difference in pathological parameters between in clinical (Taiwanese) and commercial (Foreigners). Cdk5 and p35 proteins expressed differently in both groups also (71.8 % for Cdk5, 61. 5% for p35 and co-expression in 48.7 % in clinical specimens compared with 47.5 % for Cdk5, 47.5 % for p35 and co-expression in 35 % in commercial specimens). We found Cdk5 and p35 overexpression in 29.0 % and 32.1 % of breast cancer patients respectively with co-expression in 21.4 % of patients by Western blotting experiments. By in vitro kinase assay, we proved higher activity of Cdk5 in tumor than that in normal tissue. However, we noted that Cdk5 and pr35 proteins overexpression negatively correlated with axillary lymph nodes metastasis in breast cancer patients with statistical significance. According to the studies on our patients, Cdk5 and its activator p35 might play an important role in GISTs, thyroid cancer and breast cancer cells.
To sum up the conclusion of part I and part II, we confirm the role of laparoscopic surgery in the management of primary gastric GISTs. By investigating on the expression of Cdk5 and p35 proteins, we explored the roles of Cdk5 and p35 proteins in the GISTs, thyroid cancer and breast cancer. We are looking forward the further cell lines studies to identify the mechanism of Cdk5 and p35 proteins in tumors of epithelial and non-epithelial origination.

第一部份: 腹腔鏡手術在胃腸基質瘤之研究
台灣胃腸基質瘤(gastrointestinal stromal tumor)的年發生率約每百萬人口13.7人。這種源自間葉組織的腫瘤好發於胃、十二指腸及近端小腸,其他部位包括下端腸道、大網膜、腸系膜及腹膜。胃腸基質瘤有其特別的病理特性及免疫組織診斷方式,有惡性變化的可能,包括復發及轉移。手術切除是標準治療,手術切除時必須切除到微觀下無殘留細胞。對於腫瘤有c-kit(CD-117)標靶表現者可給與標靶藥物治療。近年來文獻認為對於胃部原發性的胃腸基質瘤腹腔鏡手術是可行及安全的。胃部的胃腸基質瘤屬於胃部黏膜下層腫瘤之一,我們基於之前以腹腔鏡針對胃部黏膜下層腫瘤之經驗,以4年的時間研究胃部原發性的胃腸基質瘤接受手術的患者。比較腹腔鏡手術及傳統開腹手術在手術時間、出血量、住院日、腫瘤大小及併發症之關係。共有24名罹患胃部原發性的胃腸基質瘤接受手術的患者。平均年紀為64.3±15.7歲(43~91歲)。男性8名,女性16名。依病患手術種類分類為腹腔鏡手術有18位,傳統開腹手術有6位。我們以卡方檢定比較兩組病人在手術時間、出血量、住院日、腫瘤大小及併發症之關係並探討腹腔鏡對於胃原發性的胃腸基質瘤患者接受手術的適應症與安全性。
平均住院日為腹腔鏡手術10.9±7.2日,傳統開腹手術19.0±3.1日。手術時間為腹腔鏡手術96.7±61.2分鐘,傳統開腹手術124.2±61.8分鐘。出血量為腹腔鏡手術平均55.6±16.2cc,傳統開腹手術平均196.7±146.5cc。腫瘤大小為腹腔鏡手術平均3.9±2.3公分(1~8.5公分),傳統開腹手術平均8.7±3.1公分(4.5~12公分)。兩組病人各有兩例併發症,皆在保守治療後改善。無手術相關死亡案例。統計學上兩組病人在腫瘤大小及出血量有明顯差異(獨立T檢定,p值<0.05)。在秀傳體系醫院,過去四年胃部原發性的胃腸基質瘤有七成五是採取腹腔鏡手術的。出血量及手術時間和相關文獻類似。腹腔鏡手術組的病人並無術中轉換成傳統開腹手術的,腹腔鏡手術組併發症亦屬可接受範圍。我們的經驗支持在較小型腫瘤的情況下,腹腔鏡手術於胃部原發性的胃腸基質瘤是安全有效率的。
第二部份: Cdk5和p35蛋白質在胃腸基質瘤之表現與在甲狀腺癌、乳癌之研究
Cdk5蛋白質是一種 cyclin-dependent kinase,p35蛋白質為其致活蛋白質。Cdk5原本被認為和神經與肌肉的生長和發育有關。近年來被發現與細胞生長、分化、凋亡甚至於細胞癌化有關。胃腸基質瘤是屬於非上皮性的間葉組織來源的腫瘤,而甲狀腺癌及乳癌均屬於上皮性的腫瘤。林赫教授實驗室之前陸續發表了Cdk5蛋白對攝護腺癌、甲狀腺癌細胞生長的影響。本部份研究探討Cdk5及p35蛋白質在甲狀腺癌及乳癌等上皮性腫瘤與胃腸基質瘤此類非上皮性的腫瘤之表現。針對所研究之三項腫瘤,將手術取得之標本以石蠟包埋切片,厚度為4μm。先以蘇木精和嗜伊紅(hematoxylin & eosin)染劑來將病理玻片染色並用顯微鏡觀察標本的腫瘤和非腫瘤部分的細胞。用Cdk5及p35的抗體來進行免疫組織化學染色,使用光學顯微鏡觀察腫瘤細胞和非腫瘤細胞之Cdk5及p35蛋白的表現。並且以Allred半定量的方法,以染色細胞的比例和染色的深度判讀並且定量紀錄。所得結果以分數及百分比兩種結果呈現,分別是0、2至8分八個等級以及0、20%、50%、75%四種等級。
有22名胃部原發性的胃腸基質瘤的樣本,比較了Cdk5及p35蛋白在腫瘤和非腫瘤部分的表現。也比較了Cdk5及p35蛋白表現和腫瘤大小(tumor size)及腫瘤細胞有絲分裂(mitosis)等兩項惡性程度的指標。對於胃腸基質瘤這類非上皮性腫瘤,我們除了比較同樣屬中胚層之腫瘤細胞和非腫瘤細胞的Cdk5及p35蛋白表現,也比較手術標本上屬於正常上皮之胃黏膜細胞之Cdk5及p35蛋白表現。甲狀腺癌部分有34份進行Cdk5及p35蛋白的免疫組織化學染色。也比較了Cdk5及p35蛋白表現和病人年紀、性別、腫瘤特性(乳突癌或濾泡癌)及淋巴結之轉移情形等預後指標之相關性。乳癌部分則由53位患者取得了56件標本,加上40位國外商用標本(tumor array)。同樣有腫瘤部分及腫瘤旁的非腫瘤部分。28件標本使用西方墨點法,39份標本以免疫組織化學染色法來比較同一位患者腫瘤部分及非腫瘤部分Cdk5與p35表現之差異。同時也比較了Cdk5與p35和乳癌病理組織特性諸如病人年紀、腫瘤大小、罹癌乳房同側腋下淋巴結之轉移情形、是否有遠處器官轉移、癌細胞分裂等級、癌細胞賀爾蒙接受器、細胞膜上Her-2/neu接受器、細胞核Ki-67指數等之相關性。數值依變項之特質以卡方檢定(Chi square-test)、獨立T檢定(independent T test) 、配對T檢定(paired T test)或皮爾森相關(Pearson correlation)分析。在22名胃部原發性的胃腸基質瘤的患者的石蠟包埋切片以免疫組織學染色發現,腫瘤細胞相對於非腫瘤細胞有過度的Cdk5及p35蛋白質表現,在22位病人中有19位(86.4%)有Cdk5過度表現,p35則有18位(81.8%)有過度表現。其中Cdk5的過度表現在有絲分裂高的腫瘤及腫瘤較大者更明顯。值得一提的是Cdk5及p35蛋白質表現在正常之胃黏膜細胞並不下於腫瘤細胞,同樣比正常的間葉組織明顯,意味著Cdk5在像胃粘膜這類經常細胞更新的上皮細胞比中胚層組織細胞有較高的表現。在得自32名甲狀腺癌患者的38份石蠟包埋切片中有34份以免疫組織化學染色實驗。我們發現,腫瘤細胞相對於非腫瘤細胞有過度的Cdk5及p35蛋白質表現,在甲狀腺乳突癌患者24人中有23人(95.8%)有Cdk5蛋白質過度的表現,p35蛋白質同樣在24人中有23人(95.8%)有過度的表現。在甲狀腺濾泡癌患者10人中有6人(60.0%)有Cdk5蛋白質過度的表現,p35蛋白質同樣在10人中有7人(70.0%)有過度的表現。在8位有頸部淋巴結轉移的患者,其中5人進行Cdk5及p35的免疫組織化學染色研究。結果相較於正常組織,5人(100%)在原發的腫瘤Cdk5及p35蛋白質均有過度的表現。以上結果均達到統計學上的意義。乳癌部分由53位患者取得了56件標本染色實驗同樣發現,對同一位病人而言,腫瘤組織之Cdk5及p35蛋白質表現相對於非腫瘤組織有明顯之過度表現。在國內患者部分,Cdk5蛋白質在39人中的28人(71.8%)有過度之表現,p35蛋白質則在39人中的24人(61.5%)有過度之表現。國外商用標本40份中Cdk5及p35蛋白質均為40份中的19份(47.5%)有過度之表現。將國內外標本合併統計共有77件有效以免疫組織化學染色的實驗標本,其中Cdk5蛋白有47件(61.0%)過度表現,p35蛋白則有43件(55.8%)過度表現。國內的標本使用西方墨點法的實驗發現Cdk5蛋白質有29.0%、p35蛋白質有32.1%相對於正常組織的過度表現。兩者同時有蛋白質的過度表現則可見於21.4%的乳癌病人。使用體外激酶分析(in vitro kinase assay),也可見Cdk5活性在腫瘤表現較正常細胞高。然而,臨床統計分析乳癌腫瘤Cdk5及p35蛋白過度表現與乳癌患者腋下淋巴結轉移有統計學上的負相關。我們的實驗結果顯示Cdk5和p35蛋白在胃腸基質瘤、甲狀腺癌與乳癌細胞有過度之表現。希望此研究結果能解答Cdk5蛋白在胃腸基質瘤、甲狀腺癌與乳癌中的重要性,並開啟後續相關研究。
綜合第一及第二部份的研究結論,在臨床技術上,我們確立了腹腔鏡手術在處理胃部原發性的胃腸基質瘤的角色。在腫瘤研究上,我們以胃腸基質瘤、甲狀腺癌及乳癌來探討Cdk5及p35蛋白在上皮性及非上皮性腫瘤之表現,期待後續進一步之細胞學研究能解答其機轉並確立其在腫瘤細胞之標的角色。
URI: http://hdl.handle.net/11455/92150
Rights: 同意授權瀏覽/列印電子全文服務,2017-01-10起公開。
Appears in Collections:生命科學系所

Files in This Item:
File Description SizeFormat Existing users please Login
nchu-103-8096052206-1.pdf2.98 MBAdobe PDFThis file is only available in the university internal network    Request a copy
Show full item record
 

Google ScholarTM

Check


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.