Dataset Information

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.

SUBMITTER: Ahmad R

PROVIDER: S-EPMC6512312 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Ahmad R R Kumar B B Chen Z Z Chen X X Müller D D Lele S M SM Washington M K MK Batra S K SK Dhawan P P Singh A B AB

Oncogene 20170807 47

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 pathwa ...[more]

PMID: 28783170

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Project description:Statins are first-line drugs used to control patient lipid levels, but there is recent evidence that statin treatment can lower colorectal cancer (CRC) incidence by 50% and prolong CRC patient survival through mechanisms that are poorly understood. In this study, we found that the treatment of APCmin mice by the mevalonate pathway inhibitor lovastatin significantly reduced the number of colonic masses and improved hypersplenism and peripheral anemia. Furthermore, reverse transcription polymerase chain reaction (RT-PCR) analysis of colonic mass tissues showed a potent inhibitory effect in both Wnt/β-catenin signaling and YAP/TAZ signaling in the lovastatin treatment group. The results of our transcriptomic analyses in RKO indicated that lovastatin regulated several proliferation-related signaling pathways. Moreover, lovastatin suppressed important genes and proteins related to the canonical Wnt/β-catenin and alternative Wnt-YAP/TAZ signaling pathways in RKO and SW480 cells, and these effects were rescued by mevalonic acid (MVA), as confirmed through a series of Western blotting, RT-PCR, and reporter assays. Given that statins suppress oncogenic processes primarily through the inhibition of Rho GTPase in the mevalonate pathway, we speculate that lovastatin can inhibit certain Rho GTPases to suppress both canonical Wnt/β-catenin signaling and alternative Wnt-YAP/TAZ signaling. In RKO cells, lovastatin showed similar inhibitory properties as the RhoA inhibitor CCG1423, being able to inhibit β-catenin, TAZ, and p-LATS1 protein activity. Our results revealed that lovastatin inhibited RhoA activity, thereby suppressing the downstream canonical Wnt/β-catenin and alternative Wnt-YAP/TAZ pathways in colon cancer cells. These inhibitory properties suggest the promise of statins as a treatment for CRC. Altogether, the present findings support the potential clinical use of statins in non-cardiovascular contexts and highlight novel targets for anticancer treatments.

Project description:BackgroundChemotherapeutic agents that modulate cell cycle checkpoints and/or tumor-specific pathways have shown immense promise in preclinical and clinical studies aimed at anti-cancer therapy. MASTL (Greatwall in Xenopus and Drosophila), a serine/threonine kinase controls the final G2/M checkpoint and prevents premature entry of cells into mitosis. Recent studies suggest that MASTL expression is highly upregulated in cancer and confers resistance against chemotherapy. However, the role and mechanism/s of MASTL mediated regulation of tumorigenesis remains poorly understood.MethodsWe utilized a large patient cohort and mouse models of colon cancer as well as colon cancer cells to determine the role of Mastl and associated mechanism in colon cancer.ResultsHere, we show that MASTL expression increases in colon cancer across all cancer stages compared with normal colon tissue (P < 0.001). Also, increased levels of MASTL associated with high-risk of the disease and poor prognosis. Further, the shRNA silencing of MASTL expression in colon cancer cells induced cell cycle arrest and apoptosis in vitro and inhibited xenograft-tumor growth in vivo. Mechanistic analysis revealed that MASTL expression facilitates colon cancer progression by promoting the β-catenin/Wnt signaling, the key signaling pathway implicated in colon carcinogenesis, and up-regulating anti-apoptotic proteins, Bcl-xL and Survivin. Further studies where colorectal cancer (CRC) cells were subjected to 5-fluorouracil (5FU) treatment revealed a sharp increase in MASTL expression upon chemotherapy, along with increases in Bcl-xL and Survivin expression. Most notably, inhibition of MASTL in these cells induced chemosensitivity to 5FU with downregulation of Survivin and Bcl-xL expression.ConclusionOverall, our data shed light on the heretofore-undescribed mechanistic role of MASTL in key oncogenic signaling pathway/s to regulate colon cancer progression and chemo-resistance that would tremendously help to overcome drug resistance in colon cancer treatment.

Dataset Information

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

Publications

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

Similar Datasets

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