Genetic alterations of Wnt signaling pathway-associated genes in hepatocellular carcinoma.
OBJECTIVE
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Recently, abnormal activation of the Wnt pathway has been found to be involved in the carcinogenesis of HCC. However, the relationship between genetic changes in the Wnt pathway-associated genes and its protein expression has not been studied in patients with HCC and cirrhotic nodules. The purpose of this study is to explore the contribution of inappropriate activation of the Wnt pathway in liver carcinogenesis.


METHODS
Somatic mutation in exons 3-5 of AXIN1 and exon 3 of beta-catenin were analyzed by direct sequencing and expression of axin and beta-catenin proteins by immunohistochemistry in a series of 36 patients with HCC and cirrhosis.


RESULTS
The AXIN1 and beta-catenin gene mutations were observed in 25% (9/36) and 2.8% (1/36) of HCCs, respectively. All mutations detected in AXIN1 and beta-catenin genes were missense point mutations. Abnormal nuclear expression of beta-catenin was observed in 11 of 36 cases of HCCs (30.6%), but not in cirrhotic nodules. Reduced or absent expression of axin was seen in 24 of 36 HCCs (66.7%). The abnormal expression of beta-catenin and axin proteins was closely correlated with mutations of AXIN1 and beta-catenin (P < 0.0001 and P = 0.008, respectively).


CONCLUSIONS
These data suggest that mutation of AXIN1 gene is a frequent and late event for HCC associated with cirrhosis, and is correlated significantly with abnormal expression of axin and beta-catenin. Therefore, activation of Wnt signaling through AXIN1 rather than beta-catenin mutation might play an important role in liver carcinogenesis.
Kim
Young-Dae
YD
Department of Internal Medicine, College of Medicine, Chosun University, Gwangju, Korea.
Park
Chang-Hwan
CH
Kim
Hyun-Soo
HS
Choi
Sung-Kyu
SK
Rew
Jong-Sun
JS
Kim
Dong-Yi
DY
Koh
Yang-Suk
YS
Jeung
Kyung-Woon
KW
Lee
Kyung-Hwa
KH
Lee
Ji-Shin
JS
Juhng
Sang-Woo
SW
Lee
Jae-Hyuk
JH
D000328:Adult; D000368:Aged; D060466:Axin Protein; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D017354:Point Mutation; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics
C555451:AXIN1 protein, human; D060466:Axin Protein; D012097:Repressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin