Wntless Is Highly Expressed in Advanced-Stage Intrahepatic Cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the bile duct, representing the second most common primary liver cancer. Wntless (Wls) is a highly conserved transmembrane protein that shuttles palmitoylated Wnt proteins from the endoplasmic reticulum to the plasma membrane. Wls is highly expressed in various types of cancers and is essential for cell proliferation, anti-apoptotic activity, and survival. The profile of Wls expression and its clinical significance has not been well clarified in ICC. In the present study, we analyzed Wls expression in a set of ICC tissues (n = 44) by immunohistochemistry and the relationship between Wls expression and clinicopathological parameters. Immunoreactive Wls was detected in normal cholangiocytes, but was undetectable in normal hepatocytes. The intensity for immunoreactive Wls was varied, depending on ICC specimens. The degree of Wls expression was scored as 0 or 1+ in 8 specimens (18.2%), 2+ in 24 (54.5%), and 3+ in 12 (27.3%) out of the 44 ICC specimens, based on the staining intensity and percentage of Wls-positive cells. In normal cholangiocytes, the scores were varied from 0 to 2+. The intensity of Wls expression was positively associated with tumor stage (T stage, P = 0.005, r = 0.413), tumor-node-metastasis stage (TNM stage, P = 0.000, r = 0.548), and lymphatic invasion (P = 0.000, r = 0.548). Our results show that Wls is differentially expressed in ICC tissues and positively related to tumor stage and lymphatic invasion. Wls is a potential marker for advanced tumor stage and metastasis in ICC.

Wnt Signaling in the Regulation of Immune Cell and Cancer Therapeutics

“…The activation of Wnt signaling has been detected in cholangiocarcinoma, and the validated mutations identified so far are an inhibitory ring finger protein 43 (RNF43) mutation, overexpression of Wntless, and hypermethylation of secreted frizzled-related protein 2 ( SFRP2 ) [176,177,178]. Furthermore, osteopontin, a chemokine-like glycoprotein, has been found to enhance Wnt signaling in cholangiocarcinoma upon activation of the MEK–MAPK1 pathway via Ser675 phosphorylation and nuclear localization of β-catenin [179].…”

The Wnt signaling pathway: a potential therapeutic target against cancer

“…Other factors involved in cholangiocarcinoma include the inhibitory mutation of RNF43 , hypermethylation of SFRP2 , and high expression of Wntless . Recently, osteopontin, a chemokine‐like glycoprotein, has been reported to elevate Wnt signaling in cholangiocarcinoma through activated MEK/MAPK1 pathway–mediated Ser675 phosphorylation and nuclear accumulation of β‐catenin …”

Wnt Signaling Pathway Is among the Drivers of Liver Metastasis

“…Wls is highly expressed in advanced-stage ICC. The intensity of Wls expression was positively associated with tumor stage, tumor-nodemetastasis stage, and lymphatic invasion in ICC [22]. These studies indicate that metastatic progression of HCC and ICC include higher expression of some of the components that positively regulate the Wnt signaling pathway.…”