The PTEN regulator DJ-1 is associated with hTERT expression in clear cell renal cell carcinoma.
DJ-1 is as a novel regulator of the tumor suppressor PTEN with stimulatory effects on PI3K-AKT/PKB signaling, one possible target of which is cMyc. The catalytic unit of the telomerase complex, hTERT, can be activated at different levels, including transcriptionally by cMyc and through phosphorylation by AKT/PKB. The aim of the study was to analyze the putative signaling pathway encompassing DJ-1, cMyc and hTERT in a series of 176 renal cell carcinomas (RCC) and experimentally in cell lines. DJ-1 mRNA expression was significantly elevated in clear cell RCC (ccRCC) compared with in papillary RCC (pRCC; p = 0.005) and kidney cortex tissue (p < 0.001). ccRCC and pRCC demonstrated higher cMyc RNA levels than in kidney cortex (p < 0.001 for both) as well as increased levels of hTERT RNA (p < 0.001 and p = 0.011, respectively). DJ-1 was positively correlated to cMyc and hTERT in ccRCC (p < 0.001 and p = 0.019, respectively), but not in pRCC, indicating that this pathway could have a functional significance in ccRCC. siRNA knock down of DJ-1 induced downregulation of cMyc and hTERT mRNA associated with decreased expression of pAKT and cMyc protein levels. hTERT promoter activity was upregulated after DJ-1 transfection and this upregulation was inhibited after mutation of the cMyc binding sites. These experimental data support the functional link among DJ-1, cMyc and hTERT expression as indicated in the tumor material. Neither DJ-1, cMyc nor hTERT mRNA levels were associated with proliferation (S-phase fraction), telomere length or prognosis in ccRCC.
Sitaram
Raviprakash T
RT
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Cairney
Claire J
CJ
Grabowski
Pawel
P
Keith
W Nicol
WN
Hallberg
Bengt
B
Ljungberg
Börje
B
Roos
Göran
G
D015153:Blotting, Western; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011003:Ploidies; D011401:Promoter Regions, Genetic; D000071617:Protein Deglycase DJ-1; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase; D015996:Survival Rate; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D016615:Telomere
D047908:Intracellular Signaling Peptides and Proteins; C489427:MYC protein, human; D015513:Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C509186:TERT protein, human; D019098:Telomerase; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human