Disturbed balance of expression between XIAP and Smac/DIABLO during tumour progression in renal cell carcinomas.
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.
Institute of Pathology, University Hospital, Duesseldorf, Germany.
Y
Y
Yan
C
C
Mahotka
S
S
Heikaus
T
T
Shibata
N
N
Wethkamp
J
J
Liebmann
C V
CV
Suschek
Y
Y
Guo
H E
HE
Gabbert
C D
CD
Gerharz
U
U
Ramp
D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology*; D002352:Carrier Proteins / Q000096:biosynthesis*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D016335:Zinc Fingers
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human