RNF43 overexpression attenuates the Wnt/β‑catenin signalling pathway to suppress tumour progression in cholangiocarcinoma

Abstract

RING finger protein 43 (<em>RNF43</em>) is a ubiquitin E3 ligase that negatively regulates Wnt/β‑catenin signalling. Mutation, inactivation and downregulation of RNF43 in cholangiocarcinoma (CCA) are associated with a less favourable prognosis. Since the functional role of <em>RNF43</em> in CCA has not yet been demonstrated, the present study aimed to assess the effect of its overexpression in mediating CCA suppression via Wnt/β‑catenin signalling pathway inhibition. Accordingly, <em>RNF43</em> was overexpressed, and various malignant phenotypic changes studied, including cell proliferation, cell migration, chemotherapeutic sensitivity and the expression of several Wnt/β‑catenin target genes. Overexpression of RNF43 in the CCA cell‑line KKU‑213B hindered activation of Wnt/β‑catenin signalling, evidenced by: i) Accumulation of β‑catenin in the cytoplasmic fraction and downregulation of several known Wnt target genes at the mRNA level [<em>AXIN2</em>, survivin (<em>BIRC5</em>), <em>CCND1, MMP‑7, c‑MYC</em> and <em>ABCB1 (MDR1)</em>]; ii) a reduction of cell proliferation; iii) a significant decrease in KKU‑213B cell migration with RNF43 overexpression via upregulation of E‑cadherin (<em>CDH1</em>); and iv) a reduction in N‑cadherin (<em>CDH2</em>), <em>MMP‑2, MMP‑7</em> and <em>MMP‑9</em>. In addition, overexpression of RNF43 increased 5‑fluorouracil sensitivity and downregulation of ABC transporter genes [including <em>ABCB1</em> and <em>ABCC1</em> (MRP1)]. The current results demonstrate a functional role for RNF43 in CCA by: i) Blocking β‑catenin nuclear translocation; and ii) the subsequent downregulation of Wnt/β‑catenin target genes (the latter being involved in the progression of CCA and chemotherapeutic drug susceptibility). Therefore, the present findings suggest that RNF43 could serve a tumour suppressive role in CCA.

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