Increased Activation of the Wnt/β-Catenin Pathway in Spontaneous Hepatocellular Carcinoma Observed in Farnesoid X Receptor Knockout Mice

Abstract

Farnesoid X receptor (FXR), the primary bile acid-sensing nuclear receptor, also is known for its anticancer properties. It is known that FXR deficiency in mice results in spontaneous hepatocellular carcinoma (HCC), but the mechanisms are not completely understood. We report that sustained activation of the Wnt/␤-catenin pathway is associated with spontaneous HCC in FXR-knockout (KO) mice. HCC development was studied in FXR-KO mice at 3, 8, and 14 months of age. No tumors were observed at either 3 or 8 months, but the presence of HCC was observed in 100% of the FXR-KO mice at the age of 14 months. Further analysis revealed no change in ␤-catenin activation in the livers of 3-month-old FXR-KO mice, but a moderate increase was observed in 8-month-old FXR-KO mice. ␤-Catenin activation further increased significantly in 14-month-old tumor-bearing mice. Further analysis revealed that two independent mechanisms might be involved in ␤-catenin activation in the livers of FXR-KO mice. Activation of canonical Wnt signaling was evident as indicated by increased Wnt4 and dishevelled expression along with glycogen synthase kinase-3␤ inactivation. We also observed decreased expression of E-cadherin, a known regulator of ␤-catenin, in FXR-KO mice. The decrease in E-cadherin expression was accompanied by increased expression of its transcriptional repressor, Snail. Consistent with the increased HCC in FXR-KO mice, we observed a significant decrease in FXR expression and activity in human HCC samples. Taken together, these data indicate that a temporal increase in the activation of Wnt/␤-catenin is observed during spontaneous HCC development in FXR-KO mice and is potentially critical for tumor development.

P21-activated kinase 5 plays essential roles in the proliferation and tumorigenicity of human hepatocellular carcinoma

“…The tumor data are quite striking as mice injected with cells expressing the shRNA against PAK5 had no visible tumors in contrast to the control mice ( Figure 3D). Genetic evidence supports a role for Cyclin D1 and beta-catenin activation in HCC [21][22][23][24][25][26] , and our results indicated that silencing of PAK5 gene expression significantly decreased Cyclin D1 and beta-catenin mRNA and protein, although the exact mechanism requires further study. This result is consistent with the reduced tumorigenicity of HepG2 cells upon PAK5 gene silencing.…”

“…In addition, the fraction of cells in the S phase decreased upon PAK5 gene silencing. All PAK5 gene silencing suppresses hepatocellular cancer related gene expression Genes encoding Cyclin D1 and beta-catenin have been implicated in hepatocellular carcinoma [21][22][23][24][25][26] . To determine whether PAK5 gene silencing affects the expression of these genes, HepG2 cells were transfected with the Lv-PAK5-shRNAs or control Lv-scr-shRNA as before, and the expression of Cyclin D1 and beta-catenin were analyzed by qPCR and Western blotting.…”

The effect and mechanism of bufalin on regulating hepatocellular carcinoma cell invasion and metastasis via Wnt/β-catenin signaling pathway

“…Phosphorylated Tyr216 can strengthen GSK-3β activity, while phosphorylated Ser9 site will lead to GSK-3β deactivation (32). The higher phosphorylation at GSK-3β ser9 site and lower expression of E-cadherin is regarded as major causes of activation of Wnt/β-catenin pathway in HCC cells (33). In addition, epithelial-mesenchymal transition (EMT) also plays a key role in cancer metastasis process.…”

Nem alkoholos zsírmáj és hepatocellularis carcinoma – 2016

“…Az FXR a májban -mint epesavakat érzékelő nukleáris hormonreceptor -fontos a lipid-és glükózanyagcserével, gyulladással, fibrosissal és onkogenezissel kapcsolatos gének expressziójának szabá-lyozásában. HCC-ben az FXR downregulációját közöl-ték, FXR-deficiens egerekben daganatképződést írtak le [61]. Az obetikólsav az FXR szintetikus ligandja, NASH-betegek 72 hetes kezelése kapcsán a placebóval szemben csökkentette a gyulladást és a fibrosist, bár mellékhatásai is voltak, mint a pruritus, az IR fokozódása és a lipidprofil romlása [62].…”