TY - JOUR
T1 - Dual role of RASSF1 as a tumor suppressor and an oncogene in neuroendocrine tumors of the lung
AU - Pelosi, Giuseppe
AU - Fumagalli, Caterina
AU - Trubia, Maurizio
AU - Sonzogni, Angelica
AU - Rekhtman, Natasha
AU - Maisonneuve, Patrick
AU - Galetta, Domenico
AU - Spaggiari, Lorenzo
AU - Veronesi, Giulia
AU - Scarpa, Aldo
AU - Malpeli, Giorgio
AU - Viale, Giuseppe
PY - 2010/10
Y1 - 2010/10
N2 - Background: Little is known about the dual role of RAS-association domain family 1 (RASSF1) gene at 3p21.3 in neuroendocrine tumors (NET) of the lung. Materials and Methods: Twenty typical carcinoids (TC), 11 atypical carcinoids (ATC), 11 large cell neuroendocrine carcinomas (LCNEC) and 16 small cell lung carcinomas (SCLC) were analyzed for RASSF1 promoter methylation, mRNA and protein expression, and loss of 3p21.3 locus. Results: Promoter 1 was hypermethylated in NET but not in paired non-neoplastic lung tissues nor in 20 control NSCLC, with the degree of hypermethylation paralleling tumor grade. RASSF1 A/E isoform mRNA but not protein expression was lost in most NET compared to NSCLC or non-neoplastic tissues. The relationship between methylation level and mRNA or protein loss varied by NET type, with significant correlation for decreasing RASSF1 A protein in ACT, and marginal correlation for down-regulated RASSF 1 A/E mRNA in TC, this suggesting a non linear regulation by methylation in NET. No promoter 2 methylation was detected in NET; however, up-regulation of its RASSF1 C transcript emerged as an adverse prognostic factor in the LCNEC/SCLC group. A correlation was found between 3p21.3 allelic loss and decrease of RASSF1 A/E mRNA (p=0.023) and protein (p=0.043) expression in ATC, suggesting that 3p21.3 allelic loss contributed to the loss of gene expression. Conclusion: RASSF1 A/E is likely to act as a tumor suppressor gene in most pulmonary NET, and RASSF1 C as an oncogene in high-grade tumors.
AB - Background: Little is known about the dual role of RAS-association domain family 1 (RASSF1) gene at 3p21.3 in neuroendocrine tumors (NET) of the lung. Materials and Methods: Twenty typical carcinoids (TC), 11 atypical carcinoids (ATC), 11 large cell neuroendocrine carcinomas (LCNEC) and 16 small cell lung carcinomas (SCLC) were analyzed for RASSF1 promoter methylation, mRNA and protein expression, and loss of 3p21.3 locus. Results: Promoter 1 was hypermethylated in NET but not in paired non-neoplastic lung tissues nor in 20 control NSCLC, with the degree of hypermethylation paralleling tumor grade. RASSF1 A/E isoform mRNA but not protein expression was lost in most NET compared to NSCLC or non-neoplastic tissues. The relationship between methylation level and mRNA or protein loss varied by NET type, with significant correlation for decreasing RASSF1 A protein in ACT, and marginal correlation for down-regulated RASSF 1 A/E mRNA in TC, this suggesting a non linear regulation by methylation in NET. No promoter 2 methylation was detected in NET; however, up-regulation of its RASSF1 C transcript emerged as an adverse prognostic factor in the LCNEC/SCLC group. A correlation was found between 3p21.3 allelic loss and decrease of RASSF1 A/E mRNA (p=0.023) and protein (p=0.043) expression in ATC, suggesting that 3p21.3 allelic loss contributed to the loss of gene expression. Conclusion: RASSF1 A/E is likely to act as a tumor suppressor gene in most pulmonary NET, and RASSF1 C as an oncogene in high-grade tumors.
KW - Carcinoid
KW - Carcinoma
KW - Immunofluorescence
KW - Large cell neuroendocrine carcinoma
KW - Methylation
KW - Small cell carcinoma
KW - Survival
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M3 - Article
C2 - 21036752
AN - SCOPUS:78650254808
VL - 30
SP - 4269
EP - 4281
JO - Anticancer Research
JF - Anticancer Research
SN - 0250-7005
IS - 10
ER -