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BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Suppression of Slit3 induces tumor proliferation and chemoresistance in hepatocellular carcinoma through activation of GSK3β/β-catenin pathway

Authors: Lui Ng, Ariel K. M. Chow, Johnny H. W. Man, Thomas C. C. Yau, Timothy M. H. Wan, Deepak N. Iyer, Virginia H. T. Kwan, Ronnie T. P. Poon, Roberta W. C. Pang, Wai-Lun Law

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

It is essential to understand the mechanisms responsible for hepatocellular carcinoma (HCC) progression and chemoresistance in order to identify prognostic biomarkers as well as potential therapeutic avenues. Recent findings have shown that SLIT3 appears to function as a novel tumor suppressor gene in various types of cancers, yet its clinical correlation and role in HCC has not been understood clearly.

Methods

We determined the transcript levels of Slit3 in tumor and adjacent normal tissues within two cohorts (N = 40 and 25) of HCC patients, and correlated the gene expression with the clinicopathological data. Subsequently, the functional effects and underlying molecular mechanisms of Slit3 overexpression and/or repression were studied using cell-line and mouse models.

Results

Our results demonstrated a repression in Slit3 expression in nearly 50% of the HCC patients, while the overall expression of Slit3 inversely correlated with the size of the tumor in both cohorts of patients. Stable down-regulation of Slit3 in HCC cell-lines induced cell proliferation in vitro and tumor growth in vivo, while stable Slit3 overexpression repressed these effects. Molecular investigations showed that the stable Slit3 repression-induced cell proliferation was associated with a higher expression of β-catenin and a repressed GSK3β activity. Moreover, Slit3-repression induced chemoresistance to sorafenib, oxaliplatin and 5-FU through impairment of β-catenin degradation and induction of cyclin D3 and survivin levels. The effects induced by stable Slit3-repression were diminished by transient repression of β-catenin by siRNA approach.

Conclusion

This study suggests that Slit3 acts as a tumor suppressor in HCC by repressing the tumor growth and thus tumor progression. Low Slit3 level indicates a poor response of HCC cells to chemotherapy. Restoration or overexpression of Slit3 is a potential therapeutic approach to repress the tumor growth and enhance the efficacy of chemotherapeutic agents.
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Metadata
Title
Suppression of Slit3 induces tumor proliferation and chemoresistance in hepatocellular carcinoma through activation of GSK3β/β-catenin pathway
Authors
Lui Ng
Ariel K. M. Chow
Johnny H. W. Man
Thomas C. C. Yau
Timothy M. H. Wan
Deepak N. Iyer
Virginia H. T. Kwan
Ronnie T. P. Poon
Roberta W. C. Pang
Wai-Lun Law
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4326-5

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