Whole-exome sequencing of muscle-invasive bladder cancer identifies recurrent copy number variation in IPO11 and prognostic significance of importin-11 overexpression on poor survival

Abstract

Non-muscle-invasive bladder cancer (NMIBC) often has a worse prognosis following its progression to muscle-invasive bladder cancer (MIBC), despite radical cystectomy with pelvic lymph node dissection combined with chemotherapy. Therefore, the discovery of novel biomarkers for predicting the progression of this disease and of therapeutic targets for preventing it is crucial. We performed whole-exome sequencing to analyze superficial tumor tissues (Tsup) and basal tumor tissues (Tbas) from 3 MIBC patients and identified previously unreported copy number variations in IPO11 that warrants further investigation as a molecular target. In addition, we identified a significant association between the absolute copy number and mRNA expression of IPO11 and found that high importin-11 expression was correlated with poor 3-year overall survival (OS), cancer-specific survival (CSS) and cancer-free survival (CFS) compared with low expression in the BCa patients. Importin-11 overexpression was also an independent risk factor for CSS and CFS in the BCa patients. Our study has revealed that IPO11 copy number amplification contributes to its overexpression and that these changes are unfavorable prognostic factors in NMIBC. Thus, IPO11 copy number amplification and importin-11 overexpression are promising biomarkers for predicting the progression and poor prognosis of patients with NMIBC.

IPO11 mediates βcatenin nuclear import in a subset of colorectal cancers

“…Interestingly, IPO11 was identified as a site of insertion for the mouse mammary tumor virus in mammary tumors ( Theodorou et al, 2007 ), the same context in which Wnt proteins were discovered ( Nusse et al, 1984 ). In bladder cancer, IPO11 overexpression promotes migration and correlates with poor survival ( Zhao et al, 2016 , 2018 ). IPO11 also regulates PTEN nuclear localization, where IPO11 KO leads to tumor progression in the prostate ( Chen et al, 2017 ).…”

Nuclear localization signal-tagged systems: relevant nuclear import principles in the context of current therapeutic design

“…Overexpression associated with poor prognosis. 93 Interestingly, there was an inverse relationship between NLStagging of S-NPs and nuclear localization efficiency. Taken together, the main outcome of this study was that tagging NPs at high NLS densities does not necessarily result in enhanced nuclear localization.…”

Emerging Biomarkers for Predicting Bladder Cancer Lymph Node Metastasis

“…In addition, Zhao et al. ( 76 ) identified a new oncogene candidate, IPO11, in BCa, which is located on chromosome 5q12. Importin-11, a 116 kD protein, is encoded by IPO11.…”