The genetic locus NRC-1 within chromosome 3p12 mediates tumor suppression in renal cell carcinoma independently of histological type, tumor microenvironment, and VHL mutation.
Human chromosome 3p cytogenetic abnormalities and loss of heterozygosity have been observed at high frequency in the nonpapillary form of sporadic renal cell carcinoma (RCC). The von Hippel-Lindau (VHL) gene has been identified as a tumor suppressor gene for RCC at 3p25, and functional studies as well as molecular genetic and cytogenetic analyses have suggested as many as two or three additional regions of 3p that could harbor tumor suppressor genes for sporadic RCC. We have previously functionally defined a novel genetic locus nonpapillary renal carcinoma-1 (NRC-1) within chromosome 3p12, distinct from the VHL gene, that mediates tumor suppression and rapid cell death of RCC cells in vivo. We now report the suppression of tumorigenicity of RCC cells in vivo after the transfer of a defined centric 3p fragment into different histological types of RCC. Results document the functional involvement of NRC-1 in not only different cell types of RCC (i.e., clear cell, mixed granular cell/clear cell, and sarcomatoid types) but also in papillary RCC, a less frequent histological type of RCC for which chromosome 3p LOH and genetic aberrations have only rarely been observed. We also report that the tumor suppression observed in functional genetic screens was independent of the microenvironment of the tumor, further supporting a role for NRC-1 as a more general mediator of in vivo growth control. Furthermore, this report demonstrates the first functional evidence for a VHL-independent pathway to tumorigenesis in the kidney via the genetic locus NRC-1.
Lovell
M
M
Department of Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston 77030-4095, USA.
Lott
S T
ST
Wong
P
P
El-Naggar
A
A
Tucker
S
S
Killary
A M
AM
D000818:Animals; D002291:Carcinoma, Papillary / Q000235:genetics / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D005816:Genetic Complementation Test; D006801:Humans; D006822:Hybrid Cells / Q000637:transplantation; D007680:Kidney Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D008025:Ligases; D051379:Mice; D008819:Mice, Nude; D018895:Microsatellite Repeats; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000637:transplantation; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D011506:Proteins; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D011494:Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D008025:Ligases; C497446:VHL protein, human