Research Paper Volume 13, Issue 10 pp 14015—14038
NUPR1 is a novel potential biomarker and confers resistance to sorafenib in clear cell renal cell carcinoma by increasing stemness and targeting the PTEN/AKT/mTOR pathway
- 1 Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- 2 Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- 3 Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
- 4 Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- 5 Department of Urology, Shandong Provincial ENT Hospital Affiliated to Shandong University, Jinan, Shandong, China
Received: December 17, 2020 Accepted: March 31, 2021 Published: May 24, 2021
https://doi.org/10.18632/aging.203012How to Cite
Copyright: © 2021 He et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Sorafenib can improve the survival of metastatic clear cell renal cell carcinoma (ccRCC) patients. However, its benefits are modest, as patients eventually become resistant, and the mechanisms remain elusive. NUPR1, a stress-induced protein, has been reported in malignancies and functions as an oncogene by modulating the stress response, facilitating survival in harsh environments and conferring drug resistance. However, its role in ccRCC has not been explored.
Methods: The expression and clinical significance of NUPR1 were analyzed in ccRCC patients in in-house patients and The Cancer Genome Atlas (TCGA) cohorts. The biological functions of NUPR1 were investigated. Xenografts were performed to confirm the effects of NUPR1 on tumorigenesis. The molecular mechanism of NUPR1 was investigated in vitro and in vivo.
Results: NUPR1 expression was upregulated in tumor tissue. Further analysis showed that NUPR1 overexpression was associated with an aggressive phenotype and predicted a poor prognosis. Depletion of NUPR1 suppressed tumorigenesis and sensitized cells to sorafenib treatment. Finally, mechanistic investigations indicated that NUPR1 promoted tumorigenesis in ccRCC by increasing stemness and activating the PTEN/AKT/mTOR signaling pathway.
Conclusions: Collectively, our results suggest that NUPR1 may serve as a predictor of ccRCC. Notably, NUPR1 silencing reversed sorafenib resistance in ccRCC. These findings provide a novel potential therapeutic target in the clinical management of ccRCC.
Abbreviations
CCK-8: cell counting kit-8; ccRCC: clear cell renal cell carcinoma; chRCC: chromophobe renal cell carcinoma; DFS: disease-free survival; GBM: glioblastoma multiforme; GSEA: gene set enrichment analysis; HIF: hypoxia inducible factor; IC50: 50%inhibiting concentration; IHC: Immunohistochemistry; KICH: Kidney chromophobe cell carcinoma; KIRC: Kidney renal clear cell carcinoma; KIRP: Kidney renal papillary cell carcinoma; mTOR: mammalian target of rapamycin; NUPR1: nuclear protein 1; OS: overall survival; PCR: Polymerase Chain Reaction; pRCC: papillary renal cell carcinoma; RCC: renal cell carcinoma; qRT-PCR: quantitative real-time reverse transcription PCR; TCGA: The Cancer Genome Atlas database; TKI: tyrosine kinase inhibitor; VEGF: vascular endothelial growth factor; VHL: von Hippel-Lindau.