臺灣博碩士論文加值系統

目的：分子、細胞及動物的實驗已證實過度表現的脯氨酸導引蛋白質激酶FA (PDPK FA) 被認為對於人類癌細胞的腫瘤形成、侵犯、轉移等是必備因子之一。然而，PDPK FA 在癌症病人的預後角色上所知甚少。本論文將完整地探討早期子宮頸癌病人開刀後，PDPK FA和其預後的相關性。
病人和方法：利用免疫組織染色法分析146位早期子宮頸癌病人外科切除的腫瘤切片中，PDPK FA的表現情形。腫瘤細胞核具PDPK FA高度濃染者是PDPK FA陽性表現的主要評估依據。所得資料進一步利用醫學統計進行存活分析。
結果：在早期子宮頸癌病人，PDPK FA陽性表現的比率為12% (17/146)，在統計上，這些PDPK FA陽性表現的病人有意義的呈現較差的預後狀況，如較易復發、轉移和死亡(P<0.001)。克氏多變項比例風險模式進一步建立PDPK FA在早期子官頸癌的疾病惡化和病人存活上都是最強的獨立預後預測指標(復發風險比為8.533、死亡風險比為9.678， P<0.001)。PDPK FA若同時合併臨床上已建立的預後參數(淋巴結侵犯與否)做存活分析，PDPK FA過度表現仍能相當明確預測病人將有一個不好的預後狀況。最後，線性回歸模式分析顯示已建立的PDPK FA 在預測早期子宮頸癌病人開刀後接受輔助性治療的反應是一個非常強的預測分子，PDPK FA陰性表現的病人接受輔助性治療的勝算比為34.636，統計上達到P=0.006的顯著意義。
結論：本論文建立PDPK FA在早期子宮頸癌經外科切除後預後的重要性，此結果和過去研究發現PDPK FA在促進癌快速惡化的致命性角色一致，PDPK FA是個新的訊號傳遞分子預測癌症惡化和病人存活。綜言之，PDPK FA在早期子宮頸癌病人開完刀後預後的預測與治療上是個全新、可矯正的訊號傳遞標的分子。

CHAPTER 1 Summary......4
CHAPTER 2 General Introduction......6
TABLE I The proposed potential molecular and
cellular markers associated with cervical
cancer......9
TABLE II Historic review on proline-directed
protein kinase FA (PDPK FA)......15
TABLE III PDPK FA and GSK3 are two distinct signal
transducing PDPKs......16
CHAPTER 3 Experimental Procedures......17
CHAPTER 4 The Characteristics of the 146 Patients
with Early Stage Cervical Cancer Studied
Here Represent the Current Study
Population and are Applicable to Cervical
Cancer Worldwide......22
TABLE IV The characteristics of the patients
with cervical cancer......24
TABLE V The patient characteristics of the
cervical cancer studied here were similar
to current study population......25
CHAPTER 5 The Early Stage Cervical Cancer Patients
whose Tumor Exhibited Positive PDPK FA
Had a Very Unfavorable Clinical
Outcome......26
FIGURE 1 The representative patterns of PDPK FA
expression in cervical cancer......29
FIGURE 2 The disease-free survival (A) and overall
survival (B) of the cervical cancer
patients with respect to PDPK FA
expression......30

TABLE VI Distribution of the PDPK FA expression
with respect to the disease-free survival
and overall survival in 146 patients with
cervical cancer......31
TABLE VII Relation between PDPK FA expression and
clinicopathologic factors in 146 patients
with cervical cancer......32
CHAPTER 6 PDPK FA is a Very Powerful and
Independent Prognostic Predictor for
Progression and Patient Survival of Early
Stage Cervical Cancer......33
TABLE VIII Univariate analysis of prognostic factors
for disease-free survival and overall
survival in 146 patients with cervical
cancer......35
TABLE IX Cox multivariate regression analysis of
potential prognostic factors for disease-
free survival and overall survival in 146
patients with cervical cancer......36
CHAPTER 7 PDPK FA can Resolve the Current
Prognostic Uncertainties in the Early
Stage Cervical Cancer Patients with
Negative or Positive Lymph Node Status
after Aggressive Treatments......37
FIGURE 3 The disease-free survival (A) and overall
survival (B) of the cervical cancer
patients with respect to PDPK FA
expression combination with lymph node
status......40
TABLE X Cox univariate regression qnalysis of
combined PDPK FA expression and
independent prognostic factors for
disease-free survival and overall
survival in 146 patients with cervical
cancer......41

CHAPTER 8 PDPK FA is a Novel Prognostic Indicator
of Response to Adjuvant Therapy in the
Early Stage Cervical Cancer Patients
......42
FIGURE 4 The overall survival of the cervical
cancer patients with received adjuvant
therapy with respect to PDPK FA
expression......45
TABLE XI Logistic regression analysis of potential
prognostic factors and PDPK FA as
predictors of response to adjuvant
therapy in 59 patients with cervical
cancer......46
CHAPTER 9 Concluding Remarks......47
FIGURE 5 The essential and critical roles of the
multisubstrate/multifunctional signaling
molecule PDPK FA in the regulation of the
malignant phenotype and disease
progression of early stage cervical cancer ......50
FIGURE 6 The proposed molecular action mechanisms
for PDPK FA in the regulation of diverse
malignant phenotypes and rapid
progression of human cancers......51
FIGURE 7 Potential applications of the
multisubstrate/ multifunctional signaling
molecule PDPK FA in the management of
various types of human cancers......52
REFERENCES........53
APPENDIX..........62

Aoki, Y., Sasaki, M., Watanabe, M., Sato, T., Tsuneki, I., Aida, H. & Tanaka, K. (2000). High-risk group in node-positive patients with stage IB, IIA, and IIB cervical carcinoma after radical hysterectomy and postoperative pelvic irradiation. Gynecol Oncol, 77, 305-9.

Baykal, C., Ayhan, A., Al, A. & Yuce, K. (2003).
Overexpression of the c-Met/HGF receptor and its prognostic significance in uterine cervix carcinomas. Gynecol Oncol, 88, 123-9.

Benedet, J.L., Odicino, F., Maisonneuve, P., Beller, U., Creasman, W.T., Heintz, A.P., Ngan, H.Y. & Pecorelli, S. (2003). Carcinoma of the cervix uteri. Int J Gynaecol Obstet, 83 Suppl 1, 41-78.

Benedet, J.L., Odicino, F., Maisonneuve, P., Beller, U., Creasman, W.T., Heintz, A.P., Ngan, H.Y., Sideri, M. & Pecorelli, S. (2001). Carcinoma of the cervix uteri. J Epidemiol Biostat, 6, 7-43.

Bureau of Health Promotion, Department of Health, ROC. (2005)
http://www. bhp.doh.gov.tw/BHP/do/chinese/home

Cheng, W.F., Chen, C.A., Lee, C.N., Wei, L.H., Hsieh, F.J. & Hsieh, C.Y. (2000). Vascular endothelial growth factor and prognosis of cervical carcinoma. Obstet Gynecol, 96, 721-6.

Chernofsky, M.R., Felix, J.C., Muderspach, L.I., Morrow, C.P., Ye, W., Groshen, S.G. & Roman, L.D. (2006). Influence of quantity of lymph vascular space invasion on time to recurrence in women with early-stage squamous cancer of the cervix. Gynecol Oncol, 100, 288-93.

Chung, Y.C., Chang, K.J., Yang, C.C., Lai, M.T., Hsu, C.P., Hsueh, S.F., Peng, C.C., Fu, H.H., Chang, Y.F. & Yang, S.D. (2002). Association of proline-directed protein kinase FA with tumorigenesis, invasion, and poor prognosis of human colon carcinoma. Cancer, 95, 1840-7.

Cohen, P. & Frame, S. (2001). The renaissance of GSK3. Nat Rev Mol Cell Biol, 2, 769-76.

Ellenson, L.H. & Wu, T.C. (2004). Focus on endometrial and cervical cancer. Cancer Cell, 5, 533-8.

Frame, S. & Cohen, P. (2001). GSK3 takes centre stage more than 20 years after its discovery. Biochem J, 359, 1-16.

Fu, H.H. & Yang, S.D. (2004). Suppression of proline-directed protein kinase FA inhibits the malignant growth of human pancreatic ductal adenocarcinoma. Anticancer Res, 24, 1489-94.

Geisler, J.P. & Geisler, H.E. (2001). Tumor markers and molecular biological markers in gynecologic malignancies. Curr Opin Obstet Gynecol, 13, 31-9.

Gombos, Z., Xu, X., Chu, C.S., Zhang, P.J. & Acs, G. (2005). Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix. Clin Cancer Res, 11, 8364-71.

Grisaru, D.A., Covens, A., Franssen, E., Chapman, W., Shaw, P., Colgan, T., Murphy, J., DePetrillo, D., Lickrish, G., Laframboise, S. & Rosen, B. (2003). Histopathologic score predicts recurrence free survival after radical surgery in patients with stage IA2-IB1-2 cervical carcinoma. Cancer, 97, 1904-8.

Hazelbag, S., Kenter, G.G., Gorter, A. & Fleuren, G.J. (2004). Prognostic relevance of TGF-beta1 and PAI-1 in cervical cancer. Int J Cancer, 112, 1020-8.

He, X., Saint-Jeannet, J.P., Woodgett, J.R., Varmus, H.E. & Dawid, I.B. (1995). Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos. Nature, 374, 617-22.

Hsu, C.P., Hsueh, S.F., Yang, C.C. & Yang, S.D. (2000a). Suppression of proline-directed protein kinase FA expression inhibits the growth of human chronic myeloid leukaemia cells. Br J Cancer, 82, 1480-4.

Hsu, C.P., Yang, C.C., Hsueh, S.F., Peng, C.C., Fu, H.H. & Yang, S.D. (2001a). Suppression of proline-directed protein kinase FA potentiates apoptotic induction and greatly enhances chemosensitivity in human acute lymphoblastic leukemia cells. Cancer, 92, 1753-8.

Hsu, C.P., Yang, C.C. & Yang, S.D. (2000b). Suppression of proline-directed protein kinase FA expression potentiates erythroid differentiation of human myeloid leukemia cells. Cancer, 89, 1004-11.

Hsu, C.P., Yang, C.C. & Yang, S.D. (2001b). Suppression of proline-directed protein kinase FA systemically inhibits the growth of human acute leukemia cells. Int J Cancer, 91, 650-53.

Hsueh, S.F., Lai, M.T., Yang, C.C., Chung, Y.C., Hsu, C.P., Peng, C.C., Fu, H.H., Cheng, Y.M., Chang, K.J. & Yang, S.D. (2002). Association of overexpressed proline-directed protein kinase FA with chemoresistance, invasion, and recurrence in patients with bladder carcinoma. Cancer, 95, 775-83.

Hsu, Y.C., Fu, H.H., Jeng, Y.M., Lee, P.H., & Yang, S.D. (2006) Proline-directed protein kinase FA is a very powerful and independent prognostic predictor for progression and patient survival of Hepatocellular carcinoma. J Clin Oncol In press

Jordan, L.B. & Monaghan, H. (2004). Pathology of the cervix: recent developments. Clin Oncol (R Coll Radiol), 16, 248-54.

Kim, Y.B., Kim, G.E., Cho, N.H., Pyo, H.R., Shim, S.J., Chang, S.K., Park, H.C., Suh, C.O., Park, T.K. & Kim, B.S. (2002). Overexpression of cyclooxygenase-2 is associated with a poor prognosis in patients with squamous cell carcinoma of the uterine cervix treated with radiation and concurrent chemotherapy. Cancer, 95, 531-9.

Kristensen, G.B., Abeler, V.M., Risberg, B., Trop, C. & Bryne, M. (1999). Tumor size, depth of invasion, and grading of the invasive tumor front are the main prognostic factors in early squamous cell cervical carcinoma. Gynecol Oncol, 74, 245-51.

Kuzuya, K. (2004). Chemoradiotherapy for uterine cancer: current status and perspectives. Int J Clin Oncol, 9, 458-70.

Lau, K.F., Miller, C.C., Anderton, B.H. & Shaw, P.C. (1999a). Expression analysis of glycogen synthase kinase-3 in human tissues. J Pept Res, 54, 85-91.

Lau, K.F., Miller, C.C., Anderton, B.H. & Shaw, P.C. (1999b). Molecular cloning and characterization of the human glycogen synthase kinase-3beta promoter. Genomics, 60, 121-8.

Lee, J.W., Kim, B.G., Lee, S.J., Lee, S.H., Park, C.S., Lee, J.H., Huh, S.J. & Bae, D.S. (2005). Preliminary results of consolidation chemotherapy following concurrent chemoradiation after radical surgery in high-risk early-stage carcinoma of the uterine cervix. Clin Oncol (R Coll Radiol), 17, 412-7.

Lee, K.F., Chan, J.Y., Lau, K.F., Lee, W.C., Miller, C.C., Anderton, B.H. & Shaw, P.C. (2000). Molecular cloning and expression analysis of human glycogen synthase kinase-3 alpha promoter. Brain Res Mol Brain Res, 84, 150-7.

Lee, T.T., Ho, Y.S., Yu, J.S. & Yang, S.D. (1995). Overexpression of cellular activity and protein level of protein kinase FA/GSK-3 alpha correlates with human thyroid tumor cell dedifferentiation. J Cell Biochem, 58, 474-80.

Liu, S.S., Leung, R.C., Chan, K.Y., Chiu, P.M., Cheung, A.N., Tam, K.F., Ng, T.Y., Wong, L.C. & Ngan, H.Y. (2004). p73 expression is associated with the cellular radiosensitivity in cervical cancer after radiotherapy. Clin Cancer Res, 10, 3309-16.

Manoukian, A.S. & Woodgett, J.R. (2002). Role of glycogen synthase kinase-3 in cancer: regulation by Wnts and other signaling pathways. Adv Cancer Res, 84, 203-29.

Martinez, A., Castro, A., Dorronsoro, I. & Alonso, M. (2002). Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation. Med Res Rev, 22, 373-84.

Morice, P. & Castaigne, D. (2005). Advances in the surgical management of invasive cervical cancer. Curr Opin Obstet Gynecol, 17, 5-12.

Novina, C.D. & Roy, A.L. (1996). Core promoters and transcriptional control. Trends Genet, 12, 351-5.

Reichlin, M. (1980). Use of glutaraldehyde as a coupling agent for proteins and peptides. Methods Enzymol, 70, 159-65.

Rein, D.T. & Kurbacher, C.M. (2001). The role of chemotherapy in invasive cancer of the cervix uteri: current standards and future prospects. Anticancer Drugs, 12, 787-95.

Shaw, P.C., Davies, A.F., Lau, K.F., Garcia-Barcelo, M., Waye, M.M., Lovestone, S., Miller, C.C. & Anderton, B.H. (1998). Isolation and chromosomal mapping of human glycogen synthase kinase-3 alpha and -3 beta encoding genes. Genome, 41, 720-7.

Shiohara, S., Shiozawa, T., Miyamoto, T., Feng, Y.Z., Kashima, H., Kurai, M., Suzuki, A. & Konishi, I. (2005). Expression of cyclins, p53, and Ki-67 in cervical squamous cell carcinomas: overexpression of cyclin A is a poor prognostic factor in stage Ib and II disease. Virchows Arch, 446, 626-33.

Singh, N. & Arif, S. (2004). Histopathologic parameters of prognosis in cervical cancer--a review. Int J Gynecol Cancer, 14, 741-50.

Suzuki, M. (1989). SPXX, a frequent sequence motif in gene regulatory proteins. J Mol Biol, 207, 61-84.

Unger, E.R., Steinau, M., Rajeevan, M.S., Swan, D., Lee, D.R. & Vernon, S.D. (2004). Molecular markers for early detection of cervical neoplasia. Dis Markers, 20, 103-16.

Van de Putte, G., Holm, R., Lie, A.K., Trope, C.G. & Kristensen, G.B. (2003). Expression of p27, p21, and p16 protein in early squamous cervical cancer and its relation to prognosis. Gynecol Oncol, 89, 140-7.

Van de Putte, G., Kristensen, G.B., Baekelandt, M., Lie, A.K. & Holm, R. (2004). E-cadherin and catenins in early squamous cervical carcinoma. Gynecol Oncol, 94, 521-7.

Vandenheede, J.R., Yang, S.D., Goris, J. & Merlevede, W. (1980). ATP x Mg-dependent protein phosphatase from rabbit skeletal muscle. II. Purification of the activating factor and its characterization as a bifunctional protein also displaying synthase kinase activity. J Biol Chem, 255, 11768-74.

Waggoner, S.E. (2003). Cervical cancer. Lancet, 361, 2217-25.

Wolf, J.K. & Ramirez, P.T. (2001). The molecular biology of cervical cancer. Cancer Invest, 19, 621-9.

Woodgett, J.R. (1990). Molecular cloning and expression of glycogen synthase kinase-3/factor A. Embo J, 9, 2431-8.

Woodgett, J.R. (2003). Physiological roles of glycogen synthase kinase-3: potential as a therapeutic target for diabetes and other disorders. Curr Drug Targets Immune Endocr Metabol Disord, 3, 281-90.

Wootipoom, V., Lekhyananda, N., Phungrassami, T., Boonyaphiphat, P. & Thongsuksai, P. (2004). Prognostic significance of Bax, Bcl-2, and p53 expressions in cervical squamous cell carcinoma treated by radiotherapy. Gynecol Oncol, 94, 636-42.

Yang, C.C., Hsu, C.P. & Yang, S.D. (2000). Antisense suppression of proline-directed protein kinase FA enhances chemosensitivity in human prostate cancer cells. Clin Cancer Res, 6, 1024-30.

Yang, S.D. (1986). Identification of the ATP.Mg-dependent protein phosphatase activator (FA) as a myelin basic protein kinase in the brain. J Biol Chem, 261, 11786-91.

Yang, S.D. (1991). Characteristics and regulation of the ATP.Mg-dependent protein phosphatase activating factor (protein kinase FA). Adv Prot Phosphatase, 6, 133-157. (EMBO-FEBS Invited Review)

Yang, S.D. (1994). Signal transduction and biological functions of protein phosphatase activating factor (protein kinase FA/ GSK-3 alpha). J Chin Biochem Soc, 23, 123-134. (Invited Review)

Yang, S.D. (2004). Proline-directed protein kinase FA as a potential target for diagnosis and therapy of human cancers. Curr Cancer Drug Targets, 4, 591-6.

Yang, S.D. (2005). Proline-directed protein kinase FA as a new signal transducing target for lethal cancer treatment. Drug News Perspect, 18, 432-6.

Yang, S.D., Huang, J.J. & Huang, T.J. (1995a). Protein kinase FA/glycogen synthase kinase 3 alpha predominantly phosphorylates the in vivo sites of Ser502, Ser506, Ser603, and Ser666 in neurofilament. J Neurochem, 64, 1848-54.

Yang, S.D., Song, J.S., Yu, J.S. & Shiah, S.G. (1993). Protein kinase FA/GSK-3 phosphorylates tau on Ser235-Pro and Ser404-Pro that are abnormally phosphorylated in Alzheimer's disease brain. J Neurochem, 61, 1742-7.

Yang, S.D., Vandenheede, J.R., Goris, J. & Merlevede, W. (1980). ATP x Mg-dependent protein phosphatase from rabbit skeletal muscle. I. Purification of the enzyme and its regulation by the interaction with an activating protein factor. J Biol Chem, 255, 11759-67.

Yang, S.D., Yu, J.S., Lee, T.T., Ni, M.H., Yang, C.C., Ho, Y.S. & Tsen, T.Z. (1995b). Association of protein kinase FA/GSK-3alpha (a proline-directed kinase and a regulator of protooncogenes) with human cervical carcinoma dedifferentiation/progression. J Cell Biochem, 59, 143-50.

Yang, S.D., Yu, J.S., Shiah, S.G. & Huang, J.J. (1994). Protein kinase FA/glycogen synthase kinase-3 alpha after heparin potentiation phosphorylates tau on sites abnormally phosphorylated in Alzheimer's disease brain. J Neurochem, 63, 1416-25.

Yang, S.D., Yu, J.S., Yang, C.C., Lee, S.C., Lee, T.T., Ni, M.H., Kuan, C.Y. & Chen, H.C. (1996). Overexpression of protein kinase FA/GSK-3 alpha (a proline-directed protein kinase) correlates with human hepatoma dedifferentiation/progression. J Cell Biochem, 61, 238-45.

Yu, J.S. & Yang, S.D. (1994). Protein kinase FA/glycogen synthase kinase-3 predominantly phosphorylates the in vivo site Thr97-Pro in brain myelin basic protein: evidence for Thr-Pro and Ser-Arg-X-X-Ser as consensus sequence motifs. J Neurochem, 62, 1596-603