27-Hydroxycholesterol in bile duct tissue promotes cholangiocarcinoma progression through estrogen receptor signaling.

BACKGROUND

The oxysterol 27-hydroxycholesterol (27-HC) is widely produced in human tissues, functions as a selective estrogen receptor modulator (SERM), is implicated in the progression of estrogen receptor (ER)-positive cancers. While 27-HC is abundant in bile, its SERM role in extrahepatic cholangiocarcinoma (eCCA) remains unclear. Therefore, this study aims to test the hypothesis that 27-HC promotes eCCA cell proliferation via ER activation.

METHODS

Oxysterol levels and the expression of ERs and proliferation-related genes were compared between eCCA tissues (N = 17) and noncancerous extrahepatic bile ducts (N = 6). The effects of 27-HC on cell proliferation were evaluated in two human cholangiocarcinoma cell lines: ERα-expressing intrahepatic CCA-1 and ERβ-expressing extrahepatic TFK-1 cells.

RESULTS

27-HC and mRNA expression levels of ERα and ERβ were significantly higher in eCCA tissues than in noncancerous tissues. Expression levels of cMYC, HIF-1α, and VEGFα expression levels were elevated in eCCA tissues with high ERα and/or ERβ expression. In both cell lines, 27-HC (1-1,000 nM) dose-dependently enhanced cell proliferation for 48 h, similar to that of 17β-estradiol; these effects were blocked by ER inhibitors ICI-182,780 and PHTPP.

CONCLUSIONS

These findings indicate that 27-HC promotes eCCA cell proliferation through ERα- and ERβ-mediated SERM-like effects, highlighting that 27-HC and ERs as potential therapeutic targets in eCCA.