Hypermethylation-modulated downregulation of claudin-7 expression promotes the progression of colorectal carcinoma.
OBJECTIVE
The expression of tight junction-related transmembrane protein claudin-7 (CLDN7) and its regulatory mechanism were investigated in colorectal carcinomas (CRCs).


METHODS
Methylation-specific polymerase chain reaction and treatment with the demethylating agent 5-aza-2'-deoxycytidine were conducted to analyze the methylation status at the CLDN7 promoter region in the Colo320 CRC cell line. We used a total of 26 stage 0 CRCs with an adenoma component and 90 invasive CRCs (stage I-IV), as well as their corresponding lymph node metastases, in an immunohistochemical study.


RESULTS
In Colo320 (CLDN7-negative) cells, hypermethylation at the CLDN7 promoter was detected and treatment with 5-aza-2'-deoxycytidine restored CLDN7 expression. In CRC tissues, decreased CLDN7 expression was detected in 62% of stage 0 CRCs and 80% of stage I-IV CRCs, compared with their adjacent adenoma lesions and nonneoplastic epithelia, which had a close correlation with the incidence of vessel infiltration and clinicopathologic stage. Hypermethylation at the CLDN7 promoter was detected in 20% of CRCs with low CLDN7 expression. However, CLDN7 expression tended to be re-expressed in their corresponding lymph node metastases.


CONCLUSIONS
These findings suggest that the CLDN7 gene silencing by promoter hypermethylation and the resultant reduction of CLDN7 expression may play an important role in the progression of CRCs.
Division of Pathology, Department of Pathology and Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan.
Fumihito
F
Nakayama
Shuho
S
Semba
Yu
Y
Usami
Hideki
H
Chiba
Norimasa
N
Sawada
Hiroshi
H
Yokozaki
D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D057167:Claudins; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D019175:DNA Methylation; D000077209:Decitabine; D018450:Disease Progression; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic
C473255:CLDN7 protein, human; D057167:Claudins; D008565:Membrane Proteins; D000077209:Decitabine; D001374:Azacitidine