Open Access

ARTICLE

RNF43 is a novel tumor-suppressor and prognostic indicator in clear cell renal cell carcinoma

by DAWEI ZHU^1,#, LEI ZHANG^1,#, XIAOKAI SHI¹, SHENGLIN GAO¹, CHUANG YUE¹, LIFENG ZHANG¹, YU BAI¹, QIFENG WANG², ATSUSHI OKADA³, TAKAHIRO YASUI³, CHAO WANG^1,4, XINGANG CUI^4,5,*, LI ZUO^1,*

1 Department of Urology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, China
2 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
3 Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan
4 Department of Urinary Surgery, Gongli Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
5 Department of Urinary Surgery, The Third Affiliated Hospital of Naval Medical University (Eastern Hepatobiliary Surgery Hospital), Shanghai, China

* Corresponding Authors: Li Zuo, ; Xingang Cui,
# These authors contributed equally to the study

Oncology Research 2021, 29(3), 159-174. https://doi.org/10.32604/or.2022.03458

Received 20 February 2022; Accepted 24 June 2022; Issue published 01 August 2022

Abstract

Identifying prognostic indicators of clear cell renal cell carcinoma (ccRCC) and elucidating the mechanisms underlying ccRCC progression are crucial for improving ccRCC patient prognosis. This study investigated the clinical significance and biological role of Ring finger protein 43 (RNF43) in ccRCC. Two independent cohorts of patients with ccRCC were employed to determine the prognostic significance of RNF43 by immunohistochemistry and statistical analyses. In vitro and in vivo experiments, RNA-seq, and other techniques were used to determine the biological role of RNF43 in ccRCC and related molecular mechanisms. RNF43 expression was commonly decreased in ccRCC specimens, and low expression of RNF43 indicated a higher TNM stage, SSIGN score, and WHO/ISUP grade and short survival in patients with ccRCC. Additionally, RNF43 overexpression suppressed the proliferation, migration, and targeted drug resistance of ccRCC cells, while the knockdown of RNF43 enhanced these characteristics of ccRCC. RNF43 knockdown activated YAP signaling by decreasing YAP phosphorylation by p-LATS1/2 and increasing the transcription and nuclear distribution of YAP. By contrast, RNF43 overexpression showed the opposite effects. Decreasing YAP abolished the effect of RNF43 knockdown in promoting the malignant features of ccRCC. Additionally, restoring RNF43 expression suppressed the resistance of the targeted drug pazopanib in in vivo orthotopic ccRCC. Furthermore, combining the expression of RNF43 and YAP with TNM stage or the SSIGN score exhibited greater accuracy than any of these indicators alone in assessing the postoperative prognosis of ccRCC patients. In summary, our study identified a novel tumor suppressor, RNF43, which is also a prognostic indicator and potential target for ccRCC.

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