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

Pangestu,Norma Sainstika; Chueakwon,Piyasiri; Talabnin,Krajang; Khiaowichit,Juthamas; Talabnin,Chutima

doi:10.3892/ol.2021.13107

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

Authors:
- Norma Sainstika Pangestu
- Piyasiri Chueakwon
- Krajang Talabnin
- Juthamas Khiaowichit
- Chutima Talabnin
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Affiliations: School of Chemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand, School of Pathology, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand, School of Translational Medicine, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand
Published online on: October 21, 2021 https://doi.org/10.3892/ol.2021.13107
Article Number: 846
Copyright: © Pangestu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

RING finger protein 43 (RNF43) 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 RNF43 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, RNF43 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 [AXIN2, survivin (BIRC5), CCND1, MMP‑7, c‑MYC and ABCB1 (MDR1)]; ii) a reduction of cell proliferation; iii) a significant decrease in KKU‑213B cell migration with RNF43 overexpression via upregulation of E‑cadherin (CDH1); and iv) a reduction in N‑cadherin (CDH2), MMP‑2, MMP‑7 and MMP‑9. In addition, overexpression of RNF43 increased 5‑fluorouracil sensitivity and downregulation of ABC transporter genes [including ABCB1 and ABCC1 (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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