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Role of Wnt/?-Catenin Signaling in the Chemoresistance Modulation of Colorectal Cancer.

ABSTRACT: Colorectal cancer (CRC) is a common malignancy with high morbidity and mortality worldwide. To date, chemotherapy plays an important role in the treatment of CRC patients. Multidrug resistance (MDR) is one of the major hurdles in chemotherapy for CRC, and the underlying mechanisms need to be explored. Studies have demonstrated that Wnt/?-catenin signaling plays a critical role in oncogenesis and tumor development, and its function in inhibiting apoptosis could facilitate tumor chemoresistance. Recent investigations have also suggested the regulatory effects of the Wnt/?-catenin signaling pathway in response to chemotherapeutic agents in CRC. Here, we particularly focus on reviewing the evidences suggesting the mechanisms of Wnt/?-catenin signaling in the chemoresistance modulation of colorectal cancer.

SUBMITTER: Yuan S

PROVIDER: S-EPMC7109575 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Role of Wnt/<i>β</i>-Catenin Signaling in the Chemoresistance Modulation of Colorectal Cancer.

Yuan Shengli S Tao Fengying F Zhang Xinglin X Zhang Yan Y Sun Xingxing X Wu Dapeng D

BioMed research international 20200318

Colorectal cancer (CRC) is a common malignancy with high morbidity and mortality worldwide. To date, chemotherapy plays an important role in the treatment of CRC patients. Multidrug resistance (MDR) is one of the major hurdles in chemotherapy for CRC, and the underlying mechanisms need to be explored. Studies have demonstrated that Wnt/<i>β</i>-catenin signaling plays a critical role in oncogenesis and tumor development, and its function in inhibiting apoptosis could facilitate tumor chemoresist ...[more]

PMID: 32258160

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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

Role of Wnt/?-Catenin Signaling in the Chemoresistance Modulation of Colorectal Cancer.

Publications

Role of Wnt/<i>β</i>-Catenin Signaling in the Chemoresistance Modulation of Colorectal Cancer.

Similar Datasets

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