Wnt/β-catenin activation and macrophage induction during liver cancer development following steatosis

Abstract

Obesity confers an independent risk for carcinogenesis. In the liver, steatosis often proceeds cancer formation; however, the mechanisms by which steatosis promotes carcinogenesis is unknown. We hypothesize that steatosis alters the microenvironment to promote proliferation of tumor initiating cells (TICs) and carcinogenesis. We used several liver cancer models to address the mechanisms underlying the role of obesity in cancer and verified these findings in patient populations. Using bioinformatics analysis and verified by biochemical assays, we identified that hepatosteatosis resulting from either Pten deletion or transgenic expression of HCV core/NS5A proteins, promotes the activation of Wnt/β-catenin. We verified that high fat diet lipid accumulation is also capable of inducing Wnt/β-catenin. Caloric restriction inhibits hepatosteatosis, reduces Wnt/β-catenin activation and blocks the expansion of TICs leading to complete inhibition of tumorigenesis without affecting the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) loss regulated protein kinase B (AKT) activation. Pharmacological inhibition or loss of the Wnt/β-catenin signal represses TIC growth in vitro, and decreases the accumulation of TICs in vivo. In human liver cancers, ontology analysis of gene set enrichment analysis (GSEA)-defined Wnt signature genes indicates that Wnt signaling is significantly induced in tumor samples compared with healthy livers. Indeed, Wnt signature genes predict 90% of tumors in a cohort of 558 patient samples. Selective depletion of macrophages leads to reduction of Wnt and suppresses tumor development, suggesting infiltrating macrophages as a key source for steatosis-induced Wnt expression. These data established Wnt/β-catenin as a novel signal produced by infiltrating macrophages induced by steatosis that promotes growth of tumor progenitor cells, underlying the increased risk of liver tumor development in obese individuals.

BARX2 expression is downregulated by CpG island hypermethylation and is associated with suppressed cell proliferation and invasion of gastric cancer cells

“…Despite the major exciting findings presented here, we were not able to fully explain the effects of the epigenetic modification on BARX2 transcription and, more importantly, to determine the interactive effects between BARX2 and the Wnt/β-catenin signaling pathway. We are currently planning to establish a GC transplantation model to explore the regulatory effects of BARX2 on the Wnt/β-catenin pathway or vice versa, using techniques such as RNA-Seq and ChIP-Seq (36)(37)(38)(39). In addition, our preliminary immunohistochemical experiments on the expression pattern of BARX2 in colorectal cancer, surprisingly, indicate that BARX2 protein expression is higher in colorectal cancer compared to normal colon mucosa (data not shown).…”

RNF43 and PWWP2B inhibit cancer cell proliferation and are predictive or prognostic biomarker for FDA-approved drugs in patients with advanced gastric cancer

“…Aberrant regulation of Wnt/β-catenin signaling is observed in colon, ovarian, lung, prostate, liver, breast, and gastric cancers [12,[15][16][17][18][19][20]. Wnt/β-catenin signaling mediates the epithelial-to-mesenchymal transition in gastric cancer [21], a process whereby epithelial cells are converted into migratory and invasive cells [22,23].…”

Wnt/?-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

“…Debebe and colleagues demonstrated recently that hepatic steatosis experimentally induced by feeding of a high fat diet, deletion of phosphatase and tensin homologue deleted on chromosome 10 (Pten) or transgenic expression of HCV core/NS5A protein, all resulted in macrophage-secreted Wnt activating CD133 + CD49f + tumour-initiating cells. These data strongly suggested a Wnt/β-catenin-mediated link between obesity and cancer (50). In addition, β-catenin was shown to regulate hepatic gluconeogenesis during starvation and insulinresistant conditions via interaction with the transcription factor forkhead box protein O 1 (FoxO1).…”