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[Cancer Research 57, 3381-3385, August 15, 1997]
© 1997 American Association for Cancer Research
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Prognostic Role of the Cyclin-dependent Kinase Inhibitor p27 in Non-Small Cell Lung Cancer1

Vincenzo Esposito2, Alfonso Baldi2,3,, Antonio De Luca, Angela M. Groger4, Massimo Loda, Giovan Giacomo Giordano, Mario Caputi, Feliciano Baldi, Michele Pagano and Antonio Giordano5

Departments of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107 [V. E., A. B., A. D. L., A. M. G., A. G.]; Istituto di Tisiologia e Malattie Respiratorie "S. Marcatili," Seconda Università degli Studi di Napoli, Naples, Italy [V. E., M. C.]; Department of Pathology, Deaconess Hospital, Harvard Medical School, 1 Deaconess Road, Boston, Massachusetts 02215 [M. L.]; Istituto di Anatomia e Istologia Patologica, Seconda Università degli Studi di Napoli, Naples, Italy [G. G. G., F. B.]; and Department of Pathology, MSB 548, New York University Medical Center and Kaplan Comprehensive Cancer Center, New York, New York 10016 [M. P.]

Despite its potential role as a tumor suppressor, p27 gene, a member of the Cip/Kip family of cyclin-dependent kinase inhibitor genes, has never been found mutated in human tumors. We investigated p27 protein expression in a series of 108 non-small cell lung cancers (57.4% stage 1, 16.7% stage 2, and 25.9% stage 3) to determine whether the lack or altered expression of this protein correlates with neoplastic transformation and/or progression. We performed immunohistochemistry and Western blot analysis of each specimen. We found that tumors expressing low to undetectable levels of p27 contained high p27 degradation activity. When we evaluated the outcome of the patients in relationship to p27 expression, we found p27 to be a prognostic factor correlating with the overall survival times (P = 0.0012).

The possibility of a simple assay, such as the immunohistochemical analysis of p27 expression on routinely formalin-fixed, paraffin-embedded specimens, has considerable value for the prognosis of patients who undergo surgical resection. In addition, confirmation of the involvement of the proteasome-mediated proteolysis in p27 degradation should stimulate new strategies of nonsurgical treatments of non-small cell lung cancer.

1 This work was supported by Sbarro Institute for Cancer Research and Molecular Medicine. NIH Grants RO1 CA60999-01A1 and PO1 N536466, and The Council for Tobacco Research (to A. G.). M. P. is in part supported by an NIH Grant CA66229-02. V. E. is supported by a fellowship from the Second Università di Napoli (Dottorato di Ricerca in Broncopneumologia). A. D. L. is supported by an Advanced Fellowship NATO-CNR.

2 These authors have contributed equally to this work.

3 Present address: Laboratory of Neuroscience, Libero Istituto Universitario C. B. M., Rome, Italy.

4 On leave of absence from the Department of Cardio-Thoracic Surgery of the University of Vienna, Austria.

5 To whom requests for reprints should be addressed, at Department of Pathology, Anatomy & Cell Biology, Jefferson Medical College, Room 226, 1020 Locust St., Philadelphia, PA 19107. Fax: (215) 923-9626.

Received 5/15/97. Accepted 7/ 2/97.




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Clin. Cancer Res., October 1, 1999; 5(10): 2925 - 2938.
[Abstract] [Full Text] [PDF]

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 J. Thorac. Cardiovasc. Surg.Home page
A. M. Groeger, M. Caputi, V. Esposito, A. De Luca, L. Bagella, C. Pacilio, W. Klepetko, G. G. Giordano, F. Baldi, H. E. Kaiser, et al.
INDEPENDENT PROGNOSTIC ROLE OF p16 EXPRESSION IN LUNG CANCER
J. Thorac. Cardiovasc. Surg., September 1, 1999; 118(3): 529 - 535.
[Abstract] [Full Text] [PDF]

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 CarcinogenesisHome page
C. C. R. Lee, T. Ichihara, S. Yamamoto, H. Wanibuchi, K. Sugimura, S. Wada, T. Kishimoto, and S. Fukushima
Reduced expression of the CDK inhibitor p27KIP1 in rat two-stage bladder carcinogenesis and its association with expression profiles of p21WAF1/Cip1 and p53
Carcinogenesis, September 1, 1999; 20(9): 1697 - 1708.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
V. Masciullo, A. Sgambato, C. Pacilio, B. Pucci, G. Ferrandina, J. Palazzo, A. Carbone, A. Cittadini, S. Mancuso, G. Scambia, et al.
Frequent Loss of Expression of the Cyclin-dependent Kinase Inhibitor p27 in Epithelial Ovarian Cancer
Cancer Res., August 1, 1999; 59(15): 3790 - 3794.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
N. Sueoka, H.-Y. Lee, G. L. Walsh, W. K. Hong, and J. M. Kurie
Posttranslational Mechanisms Contribute to the Suppression of Specific Cyclin: CDK Complexes by All-Trans Retinoic Acid in Human Bronchial Epithelial Cells
Cancer Res., August 1, 1999; 59(15): 3838 - 3844.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
A. Sgambato, M. Migaldi, B. Faraglia, L. Garagnani, G. Romano, C. De Gaetani, P. Ferrari, G. Capelli, G. P. Trentini, and A. Cittadini
Loss of P27Kip1 Expression Correlates with Tumor Grade and with Reduced Disease-free Survival in Primary Superficial Bladder Cancers
Cancer Res., July 1, 1999; 59(13): 3245 - 3250.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
H. Yamamoto, J.-W. Soh, T. Monden, M. G. Klein, L. M. Zhang, H. Shirin, N. Arber, N. Tomita, I. Schieren, C. A. Stein, et al.
Paradoxical Increase in Retinoblastoma Protein in Colorectal Carcinomas May Protect Cells from Apoptosis
Clin. Cancer Res., July 1, 1999; 5(7): 1805 - 1815.
[Abstract] [Full Text] [PDF]

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 Cell Growth Differ.Home page
N. Baghdassarian, A. Peiretti, E. Devaux, P. André Bryon, and M. Ffrench
Involvement of p27Kip1 in the G1- and S/G2-phase Lengthening Mediated by Glucocorticoids in Normal Human Lymphocytes
Cell Growth Differ., June 1, 1999; 10(6): 405 - 412.
[Abstract] [Full Text]

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 Am. J. Pathol.Home page
E. Santoni-Rugiu, M. R. Jensen, V. M. Factor, and S. S. Thorgeirsson
Acceleration of c-myc-Induced Hepatocarcinogenesis by Co-Expression of Transforming Growth Factor (TGF)-{alpha} in Transgenic Mice Is Associated with TGF-ß1 Signaling Disruption
Am. J. Pathol., June 1, 1999; 154(6): 1693 - 1700.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
J. D. heng, B. A. Werness, J. S. Babb, and N. J. Meropol
Paradoxical Correlations of Cyclin-dependent Kinase Inhibitors p21waf1/cip1 and p27kip1 in Metastatic Colorectal Carcinoma
Clin. Cancer Res., May 1, 1999; 5(5): 1057 - 1062.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
S. Mizumatsu, T. Tamiya, Y. Ono, T. Abe, K. Matsumoto, T. Furuta, and T. Ohmoto
Expression of Cell Cycle Regulator p27Kip1 Is Correlated with Survival of Patients with Astrocytoma
Clin. Cancer Res., March 1, 1999; 5(3): 551 - 557.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
C. Catzavelos, M.-S. Tsao, G. DeBoer, N. Bhattacharya, F. A. Shepherd, and J. M. Slingerland
Reduced Expression of the Cell Cycle Inhibitor p27Kip1 in Non-Small Cell Lung Carcinoma: A Prognostic Factor Independent of Ras
Cancer Res., February 1, 1999; 59(3): 684 - 688.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
R. V. Lloyd, L. A. Erickson, L. Jin, E. Kulig, X. Qian, J. C. Cheville, and B. W. Scheithauer
p27kip1: A Multifunctional Cyclin-Dependent Kinase Inhibitor with Prognostic Significance in Human Cancers
Am. J. Pathol., February 1, 1999; 154(2): 313 - 323.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
E. W. Newcomb, M. Sosnow, R. I. Demopoulos, A. Zeleniuch-Jacquotte, J. Sorich, and J. L. Speyer
Expression of the Cell Cycle Inhibitor p27KIP1 Is a New Prognostic Marker Associated with Survival in Epithelial Ovarian Tumors
Am. J. Pathol., January 1, 1999; 154(1): 119 - 125.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
B. E. Clurman and P. Porter
New insights into the tumor suppression function of P27Kip1
PNAS, December 22, 1998; 95(26): 15158 - 15160.
[Full Text] [PDF]

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 Am. J. Pathol.Home page
X. Qian, L. Jin, E. Kulig, and R. V. Lloyd
DNA Methylation Regulates p27Kip1 Expression in Rodent Pituitary Cell Lines
Am. J. Pathol., November 1, 1998; 153(5): 1475 - 1482.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
G. V. Thomas, K. Szigeti, M. Murphy, G. Draetta, M. Pagano, and M. Loda
Down-Regulation of p27 Is Associated with Development of Colorectal Adenocarcinoma Metastases
Am. J. Pathol., September 1, 1998; 153(3): 681 - 687.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
A. M. De Marzo, A. K. Meeker, J. I. Epstein, and D. S. Coffey
Prostate Stem Cell Compartments : Expression of the Cell Cycle Inhibitor p27Kip1 inNormal, Hyperplastic, and Neoplastic Cells
Am. J. Pathol., September 1, 1998; 153(3): 911 - 919.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
H. Kawana, J.-i. Tamaru, T. Tanaka, A. Hirai, Y. Saito, M. Kitagawa, A. Mikata, K. Harigaya, and T. Kuriyama
Role of p27Kip1 and Cyclin-Dependent Kinase 2 in the Proliferation of Non-Small Cell Lung Cancer
Am. J. Pathol., August 1, 1998; 153(2): 505 - 513.
[Abstract] [Full Text] [PDF]

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 BloodHome page
M. Erlanson, C. Portin, B. Linderholm, J. Lindh, G. Roos, and G. Landberg
Expression of Cyclin E and the Cyclin-Dependent Kinase Inhibitor p27 in Malignant Lymphomas---Prognostic Implications
Blood, August 1, 1998; 92(3): 770 - 777.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
V. A. Florenes, G. M. Mælandsmo, R. S. Kerbel, J. M. Slingerland, J. M. Nesland, and R. Holm
Protein Expression of the Cell-Cycle Inhibitor p27Kip1 in Malignant Melanoma : Inverse Correlation with Disease-Free Survival
Am. J. Pathol., July 1, 1998; 153(1): 305 - 312.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
H.-Y. Yang, B. P. Zhou, M.-C. Hung, and M.-H. Lee
Oncogenic Signals of HER-2/neu in Regulating the Stability of the Cyclin-dependent Kinase Inhibitor p27
J. Biol. Chem., August 4, 2000; 275(32): 24735 - 24739.
[Abstract] [Full Text] [PDF]


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