Characterizing the activation of the Wnt signaling pathway in hilar cholangiocarcinoma using a tissue microarray approach

Abstract

Hilar cholangiocarcinoma (HCCA) is an invasive hepatic malignancy that is difficult to biopsy; therefore, novel markers of HCCA prognosis are needed. Here, the level of canonical Wnt activation in patients with HCCA, intrahepatic cholangiocarcinoma (IHCC), and congenital choledochal cysts (CCC) was compared to understand the role of Wnt signaling in HCCA. Pathology specimens from HCCA (n=129), IHCC (n=31), and CCC (n=45) patients were used to construct tissue microarrays. Wnt2, Wnt3, β-catenin, TCF4, c-Myc, and cyclin D1 were detected by immunohistochemistry. Parallel correlation analysis was used to analyze differences in protein levels between the HCCA, IHCC, and CCC groups. Univariate and multivariate analyses were used to determine independent predictors of successful resection and prognosis in the HCCA group. The protein levels of Wnt2, β-catenin, TCF4, c-Myc, and cyclin D1 were significantly higher in HCCA compared to IHHC or CCC. Wnt signaling activation (Wnt2+, Wnt3+, nuclear β-catenin+, nuclear TCF4+) was significantly greater in HCCA tissues than CCC tissues. Univariable analyses indicated that expression of cyclin D1 as well as Wnt signaling activation, and partial Wnt activation (Wnt2+ or Wnt3+ and nuclear β-catenin+ or nuclear TCF4+) predicted successful resection, but only cyclin D1 expression remained significant in multivariable analyses. Only partial Wnt activation was an independent predictor of survival time. Proteins in the canonical Wnt signaling pathway were present at higher levels in HCCA and correlated with tumor resecility and patient prognosis. These results suggest that Wnt pathway analysis may be a useful marker for clinical outcome in HCCA.

SRC‑like adaptor protein negatively regulates Wnt signaling in intrahepatic cholangiocarcinoma

“…The abnormal activation of Wnt signaling has been frequently exhibited in patients with IHCC (24,25). The canonical Wnt signaling results in a transcriptional response with the transcription factor β-catenin as a key mediator (26).…”

Pontin Acts as a Potential Biomarker for Poor Clinical Outcome and Promotes Tumor Invasion in Hilar Cholangiocarcinoma

“…Unexpectedly, binding sites for c-Myc were found in the promoter of Pontin; thus, c-Myc could probably regulate Pontin transcription directly [ 31 , 32 ]. Given that c-Myc is aberrantly activated in various cancers, including HC, this may provide a plausible explanation for the increased levels of Pontin in HC [ 33 ].…”

New Horizons for Precision Medicine in Biliary Tract Cancers

“…High nuclear expression with low membranous expression of β-CATENIN expression has been described in ICC (15%) (171); WNT signaling seems to be most relevant in hilar cholangiocarcinoma (172). WNT pathway activation is associated with chemo-resistance and metastatic spread in a cholangiocarcinoma xenograft tumor model (173) and WNT-inhibition has reversed chemo-resistance in cell lines (174).…”