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

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.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4326-5) contains supplementary material, which is available to authorized users.

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“…The regulation of noncoding RNAs, such as miR-125 [32], miR-31 [34], H19 [35], and NR2F1 [36], has been shown to be involved in the development and progression of HCC and is involved in tumor resistance. The NF-κB, PI3K/Akt, GSK3β/β-catenin and HIF-1α signaling pathways have been reported to be involved in HCC chemoresistance [37][38][39][40]. In our study, as shown in Fig.…”

Analysis of Genetic Host Response Risk Factors in Severe COVID-19 Patients

“…Downregulation of RRM2 suppresses the activity of β-catenin and the Wnt signaling pathway SLC9A9 55 Solute carrier family 9 Upregulates beta-catenin SLIT3 56 Slit guidance ligand 3 Suppresses GSK3β/β-catenin pathway Finally, our analysis identified four genes that have previously been associated with increased risk of developing Alzheimer's disease (AD), including MAPT, the key gene underlying tau pathology (Table 7). ).…”

Mechanism and Molecular Network of RBM8A-Mediated Regulation of Oxaliplatin Resistance in Hepatocellular Carcinoma

“…The ncRNAs miR-125 (35), miR-31 (37), H19 (38), and NR2F1 (39) have been linked to the development and progression of HCC and drug resistance. NF-kB, PI3K/Akt, GSK3b/b-catenin, and HIF-1a signaling pathways have also been implicated in HCC chemoresistance (40)(41)(42)(43).…”