Localization of nuclear cathepsin L and its association with disease progression and poor outcome in colorectal cancer.
Sullivan, Shane Tosetto, Miriam Kevans, David Coss, Alan Wang, Laimun O'Donoghue, Diarmuid Hyland, John Sheahan, Kieran Mulcahy, Hugh O'Sullivan, Jacintha
Sullivan, Shane
Tosetto, Miriam
Kevans, David
Coss, Alan
Wang, Laimun
O'Donoghue, Diarmuid
Hyland, John
Sheahan, Kieran
Mulcahy, Hugh
O'Sullivan, Jacintha
Advisors
Editors
Other Contributors
Date
2012-02-01T10:34:51Z
Date Submitted
Keywords
Other Subjects
Subject Mesh
Adult
Aged
Aged, 80 and over
Blotting, Western
Cathepsin L
Cathepsins/*metabolism
Cell Nucleus/*metabolism/pathology
Colorectal Neoplasms/*metabolism/pathology
Cysteine Endopeptidases/*metabolism
Cytoplasm/*metabolism/pathology
Disease Progression
Female
Humans
Immunoenzyme Techniques
Male
Middle Aged
Neoplasm Staging
Prognosis
Survival Rate
Tissue Array Analysis
Tumor Cells, Cultured
Tumor Markers, Biological/*metabolism
Aged
Aged, 80 and over
Blotting, Western
Cathepsin L
Cathepsins/*metabolism
Cell Nucleus/*metabolism/pathology
Colorectal Neoplasms/*metabolism/pathology
Cysteine Endopeptidases/*metabolism
Cytoplasm/*metabolism/pathology
Disease Progression
Female
Humans
Immunoenzyme Techniques
Male
Middle Aged
Neoplasm Staging
Prognosis
Survival Rate
Tissue Array Analysis
Tumor Cells, Cultured
Tumor Markers, Biological/*metabolism
Planned Date
Start Date
Collaborators
Principal Investigators
Alternative Titles
Publisher
Abstract
Previous in vitro studies have identified a nuclear isoform of Cathepsin L. The aim of this study was to examine if nuclear Cathepsin L exists in vivo and examine its association with clinical, pathological and patient outcome data. Cellular localization (nuclear and cytoplasmic) and expression levels v of Cathespin L in 186 colorectal cancer cases using immunohistochemistry. The molecular weight and activity of nuclear and cytoplasmic Cathepsin L in vivo and in vitro were assessed by Western blotting and ELISA, respectively. Epithelial nuclear staining percentage (p = 0.04) and intensity (p = 0.006) increased with advancing tumor stage, whereas stromal cytoplasmic staining decreased (p = 0.02). Using multivariate statistical analysis, survival was inversely associated with staining intensity in the epithelial cytoplasm (p = 0.01) and stromal nuclei (p = 0.007). In different colorectal cell lines and in vivo tumors, pro- and active Cathepsin L isoforms were present in both the cytoplasm and nuclear samples, with pro-Cathepsin L at 50 kDa and active Cathepsin L at 25 kDa. Purified nuclear and cytoplasmic fractions from cell lines and tumors showed active Cathepsin L activity. The identification of nuclear Cathepsin L may play an important prognostic role in colorectal disease progression and patient outcome. Moreover, these findings suggest that altering active nuclear Cathepsin L may significantly influence disease progression.
Language
eng
ISSN
1097-0215 (Electronic)
0020-7136 (Linking)
0020-7136 (Linking)
eISSN
ISBN
DOI
10.1002/ijc.24275
PMID
19291794