Abstract
BackgroundIt 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.MethodsWe 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.ResultsOur 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.ConclusionThis 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.
Highlights
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
No significant difference was seen in Slit3 gene expression between Hepatocellular carcinoma (HCC) and adjacent non-tumorous livers, we observed that 42.5% (N = 17) of the HCC patients showed Slit3 down-regulation, suggesting that Slit3 repression was a frequent event associated with HCC
In conjuncture with the previous studies that demonstrated that the activation of β-catenin pathway enhanced the chemotherapeutic resistance of HCC cells [40, 41], results from the current study suggested that Slit3 repression contributed to the chemoresistance in HCC cells, through its inhibitory effect on β-catenin degradation
Summary
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. The Slit family of guidance cues interacts with the Robo family of transmembrane receptors in a wide variety of physiological processes requiring cell migration [2]. They were first identified as an important regulator in axon guidance and cell migration in Drosophila and vertebrates [3]. Slit has been shown to suppress tumor growth of breast cancer in a mouse model [33] and impair cancer cell invasion and migration [24, 28, 34] through modulation of the expressions of E-cadherin, Vimentin, MMP2 and MMP9 [28].These findings demonstrate the tumor suppressive role of Slit in multiple types of tumor, a comprehensive analysis addressing the clinicopathological and functional significances of Slit is still lacking
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