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- Title
Interleukin-4 receptor alpha overexpression in human bladder cancer correlates with the pathological grade and stage of the disease.
- Authors
Joshi, Bharat H.; Leland, Pamela; Lababidi, Samir; Varrichio, Frederick; Puri, Raj K.
- Abstract
Previously, we have demonstrated that interleukin-4 receptor α ( IL-4R α) is overexpressed on a variety of human cancers and can serve as target for IL-4 immunotoxin comprised of IL-4 and a mutated Pseudomonas exotoxin. However, its expression and association with grade and clinical stage of bladder cancer has not been studied. IL-4R α expression was examined in human bladder cancer cell lines, mouse xenografts, and biopsy specimens at mRNA and protein levels by real-time RT-PCR and IHC/ ISH techniques. We also examined the effect of IL-4 on proliferation and invasion of bladder carcinoma cell lines. For tissue microarray ( TMA) results, we analyzed the precision data using exact binomial proportion with exact two-sided P-values. We used Cochran-Armitage Statistics with exact two-sided P-values to examine the trend analysis of IL-4R α over grade or stage of the bladder cancer specimens. The influence of age and gender covariates was also analyzed using multiple logistic regression models. IL-4R α is overexpressed in five bladder cancer cell lines, while normal bladder and human umbilical vein cell lines ( HUVEC) expressed at low levels. Two other chains of IL-4 receptor complex, IL-2R γC and IL-13R α1, were absent or weakly expressed. IL-4 modestly inhibited the cell proliferation, but enhanced cell invasion of bladder cancer cell lines in a concentration-dependent manner. Bladder cancer xenografts in immunodeficient mice also maintained IL-4R α overexpression in vivo. Analysis of tumor biopsy specimens in TMAs revealed significantly higher IL-4R α immunostaining (≥2+) in Grade 2 (85%) and Grade 3 (97%) compared to Grade 1 tumors (0%) ( P ≤ 0.0001). Similarly, 9% stage I tumors were positive for IL-4R α (≥2+) compared to 84% stage II ( P ≤ 0.0001) and 100% stages III-IV tumors ( P ≤ 0.0001). IL-13R α1 was also expressed in tumor tissues but at low levels and it did not show any correlation with the grade and stage of disease. However, the IL-2R γC was not expressed. Ten normal bladder specimens demonstrated ≤1+ staining for IL-4Rα and IL-13Rα1 and no staining for IL-2R γC. These results demonstrate that IL-4R α is overexpressed in human bladder cancer, which correlates with advanced grade and stage of the disease. Thus, IL-4R α may be a bladder tumor-associated protein and a prognostic biomarker.
- Subjects
GENETIC overexpression; INTERLEUKIN-4 receptors; BLADDER cancer genetics; DISEASE progression; PSEUDOMONAS
- Publication
Cancer Medicine, 2014, Vol 3, Issue 6, p1615
- ISSN
2045-7634
- Publication type
Article
- DOI
10.1002/cam4.330