Loss of claudin-3 expression induces IL6/gp130/Stat3 signaling to promote colon cancer malignancy by hyperactivating Wnt/β-catenin signaling

Abstract

The hyperactivated Wnt/β-catenin signaling acts as a switch to induce epithelial to mesenchymal transition and promote colorectal cancer. However, due to its essential role in gut homeostasis, therapeutic targeting of this pathway has proven challenging. Additionally, IL-6/Stat-3 signaling, activated by microbial translocation through the dysregulated mucosal barrier in colon adenomas, facilitates the adenoma to adenocarcinomas transition. However, inter-dependence between these signaling pathways and key mucosal barrier components in regulating colon tumorigenesis and cancer progression remains unclear. In current study, we have discovered, using a comprehensive investigative regimen, a novel and tissue-specific role of claudin-3, a tight junction integral protein, in inhibiting colon cancer progression by serving as the common rheostat of Stat-3 and Wnt-signaling activation. Loss of claudin-3 also predicted poor patient survival. These findings however contrasted an upregulated claudin-3 expression in other cancer types and implicated role of the epigenetic regulation. Claudin-3-/- mice revealed dedifferentiated and leaky colonic epithelium, and developed invasive adenocarcinoma when subjected to colon cancer. Wnt-signaling hyperactivation, albeit in GSK-3β independent manner, differentiated colon cancer in claudin-3-/- mice versus WT-mice. Claudin-3 loss also upregulated the gp130/IL6/Stat3 signaling in colonic epithelium potentially assisted by infiltrating immune components. Genetic and pharmacological studies confirmed that claudin-3 loss induces Wnt/β-catenin activation, which is further exacerbated by Stat-3-activation and help promote colon cancer. Overall, these novel findings identify claudin-3 as a therapeutic target for inhibiting overactivation of Wnt-signaling to prevent CRC malignancy.

A SUMOylation-dependent HIF-1α/CLDN6 negative feedback mitigates hypoxia-induced breast cancer metastasis

“…There has been increasing evidence suggesting that CLDNs can affect β-catenin. The loss of CLDN3 induces Wnt/β-catenin activation in colon cancer [42], while downregulation of CLDN4 results in E-cadherin loss and increased β-catenin signalling [43]. Our study showed the role of SENP1 in the inhibition of HIF-1α by CLDN6, but the contribution of other factors such as βcatenin should not be ignored.…”

Frizzled-7 Is Required for Wnt Signaling in Gastric Tumors with and Without Apc Mutations

“…Gastric adenomas in gp130 FF mice do not harbor any Wnt-activating mutations (41); however, they display high levels of Wnt signaling. Stat-3 has been shown to activate Wnt signaling, which would allow pathway activation in the absence of Wnt mutations in gp130 FF adenomas (46,47). Indeed, Wnt and gp130/Stat3 signaling operate in parallel during gastric tumorigenesis as active p-Stat3 levels remain high in Fzd7-deleted adenomas, demonstrating that Wnt/Fzd7 Scale bars, 100 mm.…”

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

“…Mucosal barrier disruption by loss of CLDN-3 promotes CRC malignancy through induction of the Wnt/β-catenin signaling by activation of IL-6/JAK/STAT3 signaling. In contrast, the upregulation of CLDN-17 activates Tyk2/STAT3 signaling to promote malignancy in HCC [155,156]. In particular, the androgen receptor (AR) decreases macrophage recruitment by reduction of CCL2.…”