The Ras effector NORE1A is suppressed in follicular thyroid carcinomas with a PAX8-PPARgamma fusion.
BACKGROUND
The Ras effector NORE1A (RASSF5A) is a putative tumor suppressor and is inactivated in several human cancers. NORE1A has not been studied in thyroid cancer.


OBJECTIVE
The objective of this study was to investigate whether NORE1A is involved in follicular thyroid cancer (FTC) development.


METHODS
We analyzed NORE1A expression in 25 FTCs, eight follicular thyroid adenomas, and seven normal thyroid tissues by TaqMan quantitative RT-PCR. The results were evaluated in relation to RASSF1A expression, RAS mutations, and PAX8-PPARgamma fusions assessed in the same material. NORE1A promoter methylation was assessed by the combined bisulfite restriction endonuclease assay.


RESULTS
Although the NORE1A mRNA levels of the majority of the tumors were similar to those in the normal controls, the cases harboring a PAX8-PPARgamma translocation (n = 6) exhibited dramatically reduced NORE1A expression (P < 0.001). In contrast, RAS mutations (n = 5) and NORE1A down-regulation were mutually exclusive. A significant reduction in the expression of the NORE1A homolog and the bona fide tumor suppressor gene RASSF1A was observed, but with weak correlation to the respective NORE1A values. No NORE1A promoter methylation was detected in the 32 thyroid tumors analyzed.


CONCLUSIONS
Our experiments demonstrate the suppression of NORE1A, a known Ras effector, in PAX8-PPARgamma carrying FTCs.
Foukakis
Theodoros
T
Department of Molecular Medicine and Surgery, Karolinska University Hospital, CMM L8:01, SE-171 76 Stockholm, Sweden. theodoros.foukakis@ki.se
Au
Amy Y M
AY
Wallin
Göran
G
Geli
Janos
J
Forsberg
Lars
L
Clifton-Bligh
Roderick
R
Robinson
Bruce G
BG
Lui
Weng-Onn
WO
Zedenius
Jan
J
Larsson
Catharina
C
D048868:Adaptor Proteins, Signal Transducing; D018263:Adenocarcinoma, Follicular / Q000235:genetics* / Q000601:surgery; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D000072636:PAX8 Transcription Factor; D047495:PPAR gamma / Q000235:genetics*; D051761:Paired Box Transcription Factors / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics*; D011995:Recombination, Genetic; D015183:Restriction Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013489:Suppression, Genetic / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000601:surgery; D013965:Thyroidectomy
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D004273:DNA, Neoplasm; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D047495:PPAR gamma; D051761:Paired Box Transcription Factors; C454042:RASSF5 protein, human; D012333:RNA, Messenger; D020559:Monomeric GTP-Binding Proteins