Loss of PL6 protein expression in renal clear cell carcinomas and other VHL-deficient tumours.
Mutations in the von Hippel-Lindau tumour suppressor gene (VHL) cause the VHL hereditary cancer syndrome and occur in most sporadic clear cell renal cell cancers (CC-RCCs). The mechanisms by which VHL loss of function promotes tumour development in the kidney are not fully elucidated. Here, we analyse expression of PL6, one of the potential tumour suppressor genes from the critical 3p21.3 region involved in multiple common cancers. We classify PL6 as a Golgi-resident protein based on its perinuclear co-localization with GPP130 in all cells and tissues analysed. We show that PL6 RNA and protein expression is completely or partially lost in all analysed CC-RCCs and other VHL-deficient tumours studied, including the early precancerous lesions in VHL disease. The restoration of VHL function in vitro in the VHL-deficient CC-RCC cell lines was found to reinstate PL6 expression, thus establishing a direct link between VHL and PL6. Insensitivity of PL6 to hypoxia suggested that PL6 is regulated by VHL via a HIF-1-independent pathway. We ruled out mutations and promoter methylation as possible causes of PL6 down-regulation in CC-RCC. We hypothesize that loss of a putative PL6 secretory function due to VHL deficiency is an early and important event that may promote tumour initiation and growth.
Ivanova
A V
AV
Laboratory of Immunobiology, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA. alla.ivanova@med.nyu.edu
Vortmeyer
A
A
Ivanov
S V
SV
Nickerson
M L
ML
Maher
E R
ER
Lerman
M I
MI
D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism*; D011230:Precancerous Conditions / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000502:physiology*
D004273:DNA, Neoplasm; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C526513:TMEM115 protein, human; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human