DNA copy-number loss on 1p36.1 harboring RUNX3 with promoter hypermethylation and associated loss of RUNX3 expression in liver fluke-associated intrahepatic cholangiocarcinoma.
Runt-related transcription factor 3 (RUNX3) is a candidate tumor suppressor gene, localized on 1p36, involved in TGF-beta-Smads signaling. To assess its role in liver fluke-associated intrahepatic cholangiocarcinoma (ICC), the promoter methylation status was investigated in 53 ICCs by methylation-specific PCR, with determination of loss of 1p36.1 by microarray comparative genomic hybridization and RUNX3 protein expression by immunohistochemistry. Loss at 1p36.1 was found 41.5% of ICCs (22/53). In addition, DNA hypermethylation of the RUNX3 promoter was found in 49.1% (26/53) of cancers and 57.1% (4/7) of ICC cell lines. The protein was highly expressed in normal bile ducts but mostly decreased in ICCs, 67.9% (n= 36) being negative for immunohistochemical staining. Promoter hypermethylation of RUNX3 was associated with reversible decrease or absence of RUNX3 protein expression (p<0.001), but this was not found to differ with the ICC subtype. In contrast, loss of 1p36.1 demonstrated a significant link (p= 0.020). In conclusion, RUNX3 promoter hypermethylation and loss of 1p36.1 are causal mechanisms for loss of RUNX3 function in liver fluke-associated ICC carcinogenesis.
Dachrut
Somkid
S
Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
Banthaisong
S
S
Sripa
M
M
Paeyao
A
A
Ho
C
C
Lee
S A
SA
Kosinski
C
C
Patil
M A
MA
Zhang
J
J
Chen
X
X
Sripa
Banchob
B
Pairojkul
Chawalit
C
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000469:parasitology / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000469:parasitology / Q000473:pathology; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics*; D019175:DNA Methylation; D005210:Fasciola hepatica / Q000302:isolation & purification; D005211:Fascioliasis / Q000235:genetics* / Q000469:parasitology / Q000473:pathology; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D050677:Core Binding Factor Alpha 3 Subunit; C493729:Runx3 protein, human; D001374:Azacitidine