Disturbed balance of expression between XIAP and Smac/DIABLO during tumour progression in renal cell carcinomas

Br J Cancer. 2004 Oct 4;91(7):1349-57. doi: 10.1038/sj.bjc.6602127.


Dysregulation of apoptosis plays an important role in tumour progression and resistance to chemotherapy. The X-linked inhibitor of apoptosis (XIAP) is considered to be the most potent caspase inhibitor of all known inhibitor of apoptosis-family members. Only recently, an antagonist of XIAP has been identified, termed Smac/DIABLO. To explore the relevance of antiapoptotic XIAP and proapoptotic Smac/DIABLO for tumour progression in renal cell carcinomas (RCCs), we analysed XIAP and Smac/DIABLO mRNA and protein expression in the primary tumour tissue from 66 RCCs of all major histological types by quantitative real-time PCR, Western blot and ELISA. X-linked inhibitor of apoptosis and Smac/DIABLO mRNA expression was found in all RCCs. Importantly, the relative XIAP mRNA expression levels significantly increased from early (pT1) to advanced (pT3) tumour stages (P=0.0002) and also with tumour dedifferentiation (P=0.04). Western blot analysis confirmed the tumour stage-dependent increase of XIAP expression on the protein level. In contrast, mRNA and protein expression levels of Smac/DIABLO did not significantly change between early and advanced tumour stages or between low and high tumour grades. Consequently, the mRNA expression ratio between antiapoptotic XIAP and proapoptotic Smac/DIABLO markedly increased during progression from early (pT1) to advanced (pT3) tumour stages. Moreover, RCCs confined within the organ capsule (pT1 and pT2) exhibited a significantly lower XIAP to Smac/DIABLO expression ratio when compared with RCCs infiltrating beyond the kidney (pT3; P=0.01). Thus, our investigation demonstrates that the delicate balance between XIAP and Smac/DIABLO expression is gradually disturbed during progression of RCCs, resulting in a relative increase of antiapoptotic XIAP over proapoptotic Smac/DIABLO, thereby probably contributing to the marked apoptosis resistance of RCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics*
  • Apoptosis Regulatory Proteins
  • Blotting, Western
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / pathology*
  • Carrier Proteins / biosynthesis*
  • Disease Progression
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Profiling*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / pathology*
  • Mitochondrial Proteins / biosynthesis*
  • Polymerase Chain Reaction
  • Protein Biosynthesis*
  • Proteins*
  • X-Linked Inhibitor of Apoptosis Protein
  • Zinc Fingers


  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • DIABLO protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Proteins
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human