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.
Highlights
Renal neoplasms account for approximately 3% of the total human cancers
Expression of inhibitor of caspase-activated DNase” (ICAD) decreases in renal cell carcinoma (RCC) and localises to the nucleus in clear cell RCC
ICAD is a downstream molecule of the caspases, usually inhibiting nuclear DNA fragmentation induced by caspase-activated DNase (CAD) during apoptosis
Summary
Renal neoplasms account for approximately 3% of the total human cancers. Renal cell carcinomas (RCCs), the major proportion of renal neoplasms, are the tenth leading cause of cancer mortality in Western industrialised countries, including Australia [1,2,3]. RCC represents on average 90% of the renal neoplasms in adults of both sexes worldwide [3]. Surgery is a successful curative treatment for localised RCC, metastasis is common and these metastases are resistant to cancer therapies. Improving therapy-associated kidney cancer regression would be of great benefit to patients. Increased knowledge of the underlying molecular characteristics of RCC will result in the identification of molecular pathways involved in tumour growth and metastasis, and resistance to therapies, and expedite development of targeted therapies, and may identify useful markers of RCC development and progression
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