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Published on: November 30, 2013
Decreased Expression of Inhibitor of Caspase-Activated DNase (ICAD) in Renal Cell Carcinoma - Tissue Microarray of
Retnagowri Rajandram1, Azad H A Razack1, Keng Lim Ng1
1Department of Surgery, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia; University Malaya Cancer Research Institute (UMCRI), and University Malaya Medical Centre, Kuala Lumpur, Malaysia; Centre for Kidney Disease Research, School of Medicine, The University of Queensland, Translational Research Institute, Brisbane, Australia.
Abstract:
Although primary localised tumours of renal cell carcinoma (RCC) can be treated relatively successfully with surgery, metastatic RCC has poor prognosis because of late diagnosis and resistance to therapies. In the present study, we were interested in profiling the protein expression of "inhibitor of caspase-activated DNase" (ICAD), an apoptosis inhibitor, in kidney cancer and its paired normal kidney. Immunohistochemistry with automated batch staining and morphometry using digital pathology were used to compare ICAD in 121 RCC specimens with their paired normal kidney tissue. Tissue microarray of formalin-fixed, paraffin-embedded archival tissue was used. Intensity and localisation of ICAD were compared between normal and cancer samples, and against grading within the cancers. The results demonstrated that, in this cohort, ICAD was highly expressed in the proximal tubular epithelium of normal kidney, and significantly decreased in clear cell RCC tissue (p < 0.05) as well as other subtypes of RCC (p < 0.01) compared with normal kidney. There was a tendency towards nuclear localisation of ICAD in clear cell RCC, but not in other subtypes of RCC. No significant association was found between ICAD intensity and grade of RCC. In summary, down-regulation of ICAD occurs in RCC. ICAD normally inhibits DNA fragmentation and apoptosis; thus, its down-regulation was unexpected in a cancer known for its resistance to apoptosis. However, these RCC samples were from primary, not metastatic, RCC sites, and down-regulated ICAD may be part of a progressive pathway that promotes RCC metastasis.
Insights
Inhibitor of caspase-activated DNase (ICAD) protein is significantly decreased in kidney cancer tissues compared to normal kidney. This down-regulation of ICAD in renal cell carcinoma may promote cancer metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Pathology
Background:
- Metastatic renal cell carcinoma (RCC) presents a poor prognosis due to late diagnosis and therapeutic resistance.
- Understanding molecular mechanisms underlying RCC progression is crucial for improving patient outcomes.
Purpose of the Study:
- To profile the protein expression of inhibitor of caspase-activated DNase (ICAD) in primary renal cell carcinoma (RCC) and paired normal kidney tissues.
- To investigate the correlation between ICAD expression levels, localization, and RCC subtypes and grades.
Main Methods:
- Immunohistochemistry was employed for protein expression analysis.
- Automated batch staining and digital pathology with morphometry were utilized for quantitative comparison.
- Tissue microarray from 121 RCC specimens and matched normal kidney tissues was analyzed.
Main Results:
- ICAD protein was highly expressed in the proximal tubular epithelium of normal kidney tissue.
- Significantly decreased ICAD expression was observed in clear cell RCC (p < 0.05) and other RCC subtypes (p < 0.01) compared to normal kidney.
- A trend towards nuclear localization of ICAD was noted in clear cell RCC, but not in other subtypes. No significant association between ICAD intensity and RCC grade was found.
Conclusions:
- Down-regulation of ICAD, an apoptosis inhibitor, occurs in primary renal cell carcinoma.
- The observed down-regulation of ICAD, contrary to its anti-apoptotic function, might be implicated in the progression pathway promoting RCC metastasis.
- Further research is warranted to elucidate the role of ICAD in RCC pathogenesis and its potential as a therapeutic target.
