Bile acids repress E-cadherin through the induction of Snail and increase cancer invasiveness in human hepatobiliary carcinoma.
Although some kinds of bile acids have been implicated in colorectal cancer development, the mechanism of cancer progression remains unexplored in hepatobiliary cancer. From our personal results using complementary DNA microarray, we found that chenodeoxycholic acid (CDCA) induced Snail expression in human carcinoma cell lines derived from hepatocellular carcinoma and cholangiocarcinoma. Snail expression plays an important role in the regulation of E-cadherin and in the acquisition of invasive potential in many types of human cancers including hepatocellular carcinoma. We found that CDCA and lithocholic acid (LCA) induced Snail expression in a concentration-dependent manner and down-regulated E-cadherin expression in hepatocellular carcinoma and cholangiocarcinoma cell lines. Moreover, Snail short interference RNA (siRNA) treatment reduced the down-regulation of E-cadherin by CDCA or LCA. Luciferase analysis demonstrated that the promoter region from -111 to -24 relative to the transcriptional start site was necessary for this induction and, at least in part, nuclear factor Y (NF-Y) and stimulating protein 1 (Sp1) might be an inducer of Snail expression in response to bile acids. In addition, using an in vitro wound healing assay and invasion assay, we observed that CDCA and LCA induced cell migration and invasion. These results suggest that bile acids repress E-cadherin through the induction of transcription factor Snail and increase cancer invasiveness in human hepatocellular carcinoma and cholangiocarcinoma. Inhibition of this bile acid-stimulated pathway may prove useful as an adjuvant in the therapy of hepatocellular carcinoma.
Fukase
Koji
K
Department of Surgery, Tohoku University Graduate School of Medical Science, Sendai 980-8574, Japan.
Ohtsuka
Hideo
H
Onogawa
Tohru
T
Oshio
Hiroshi
H
Ii
Takayuki
T
Mutoh
Mitsuhisa
M
Katayose
Yu
Y
Rikiyama
Toshiki
T
Oikawa
Masaya
M
Motoi
Fuyuhiko
F
Egawa
Shinichi
S
Abe
Takaaki
T
Unno
Michiaki
M
D001650:Bile Duct Neoplasms / Q000378:metabolism*; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D018281:Cholangiocarcinoma / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology; D006801:Humans; D008095:Lithocholic Acid / Q000494:pharmacology; D008113:Liver Neoplasms / Q000378:metabolism; D008297:Male; D009361:Neoplasm Invasiveness; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*
D015820:Cadherins; D005765:Gastrointestinal Agents; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D002635:Chenodeoxycholic Acid; D008095:Lithocholic Acid