Silencing of the candidate tumor suppressor gene solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer.
OBJECTIVE
Few genetic mutations have been identified in pancreatic adenocarcinoma, whereas epigenetic changes that lead to gene silencing are known in several genes. Because SLC5A8 is regarded as a potential tumor suppressor gene that is down-regulated by epigenetic changes in several other cancers, we sought to characterize promoter methylation status and its relationship to SLC5A8 expression in pancreatic cancer.


METHODS
Promoter methylation and expression of SLC5A8 were evaluated in pancreatic cancer cell lines, tumor, and adjacent nontumor tissues from pancreatic cancer patients using methylation-specific polymerase chain reaction analysis, quantitative real-time and semiquantitative reverse transcriptase-polymerase chain reaction, and bisulfate-modified sequencing.


RESULTS
Complete or partial loss of SLC5A8 expression was observed in all tumor tissues. Bisulfite sequencing analysis on pancreatic cancer cell lines that did not express SLC5A8 detected dense methylation of the promoter region. SLC5A8 expression was reactivated by treatment with aza-deoxycytidine or trichostatin A. Methylation-specific polymerase chain reaction detected methylation in 7 of 10 pancreatic tumor tissues, whereas in only 3 of 28 adjacent nontumor tissues (P < 0.001).


CONCLUSIONS
Our findings indicate loss of SLC5A8 expression as a result of aberrant promoter methylation in pancreatic adenocarcinoma. We suggest that SLC5A8 may function as a tumor suppressor gene whose silencing by epigenetic changes may contribute to carcinogenesis and progression of pancreatic cancer.
Park
Jong Y
JY
Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Jong.Park@moffitt.org
Helm
James F
JF
Zheng
Weipeng
W
Ly
Quan P
QP
Hodul
Pamela J
PJ
Centeno
Barbara A
BA
Malafa
Mokenge P
MP
D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D001483:Base Sequence; D027682:Cation Transport Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D027501:Monocarboxylic Acid Transporters; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction
D027682:Cation Transport Proteins; D027501:Monocarboxylic Acid Transporters; D012334:RNA, Neoplasm; C476760:SLC5A8 protein, human