Increased expression of TRIP13 drives the tumorigenesis of bladder cancer in association with the EGFR signaling pathway

Thyroid hormone receptor interactor 13 (TRIP13) is a crucial regulator of the spindle apparatus checkpoint and double-stranded break repair. The abnormal expression of TRIP13 was recently found in several human cancers, whereas the role of TRIP13 in the development of bladder cancer (BCa) has not been fully elucidated. Here, we reported that TRIP13 expression was elevated in BCa tissues compared with normal bladder tissues. Notably, the increased expression of TRIP13 was correlated with advanced tumor stage, lymph node metastasis, distant metastasis and reduced survival in BCa patients. Knockdown of TRIP13 in bladder cancer cells suppressed proliferation, induced cell cycle arrest, promoted apoptosis, and impaired cell motility, ultimately inhibiting tumor xenograft growth. Mechanistic investigations revealed that TRIP13 directly bound to epidermal growth factor receptor (EGFR), modulating the EGFR signaling pathway. Furthermore, TRIP13 expression was positively correlated with EGFR expression in BCa specimens, and the high expression of both TRIP13 and EGFR predicted poor survival. Overall, our results underscore the crucial role of TRIP13 in the tumorigenesis of BCa and provide a novel biomarker and therapeutic target for BCa treatment.

[1]  Xavier Paoletti,et al.  EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype , 2014, Science Translational Medicine.

[2]  G. Vader.  Pch2TRIP13: controlling cell division through regulation of HORMA domains , 2015, Chromosoma.

[3]  R. Poon,et al.  TRIP13 Functions in the Establishment of the Spindle Assembly Checkpoint by Replenishing O-MAD2. , 2018, Cell reports.

[4]  Eun-Jung Kim,et al.  Predictive value of progression-related gene classifier in primary non-muscle invasive bladder cancer , 2010, Molecular Cancer.

[5]  K. Baggerly,et al.  Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. , 2014, Cancer cell.

[6]  V. Jin,et al.  Interferon-Stimulated Genes Are Transcriptionally Repressed by PR in Breast Cancer , 2017, Molecular Cancer Research.

[7]  R. Benezra,et al.  Mad2 Overexpression Uncovers a Critical Role for TRIP13 in Mitotic Exit. , 2017, Cell reports.

[8]  R. Poon,et al.  TRIP13 Regulates Both the Activation and Inactivation of the Spindle-Assembly Checkpoint. , 2016, Cell reports.

[9]  E. Zwarthoff,et al.  Targeted therapies in bladder cancer: an overview of in vivo research , 2015, Nature Reviews Urology.

[10]  A. Moeller,et al.  TRIP13 is a protein-remodeling AAA+ ATPase that catalyzes MAD2 conformation switching , 2015, eLife.

[11]  F. Hamdy,et al.  Neural network analysis of clinicopathological and molecular markers in bladder cancer. , 2000, The Journal of urology.

[12]  S. Groshen,et al.  Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  K. Grigor,et al.  HER2/neu gene amplification and protein overexpression in G3 pT2 transitional cell carcinoma of the bladder: a role for anti-HER2 therapy? , 2004, European journal of cancer.

[14]  Yong Duan,et al.  Integrated Analysis of Genome-Wide Copy Number Alterations and Gene Expression Profiling of Lung Cancer in Xuanwei, China , 2017, PloS one.

[15]  T. H. van der Kwast,et al.  Molecular grading of urothelial cell carcinoma with fibroblast growth factor receptor 3 and MIB-1 is superior to pathologic grade for the prediction of clinical outcome. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  Wang Dazhi,et al.  Elevated expression of thyroid hormone receptor-interacting protein 13 drives tumorigenesis and affects clinical outcome. , 2017, Biomarkers in medicine.

[17]  S. Noguchi,et al.  C-ERBB-2 gene amplification as a prognostic marker in human bladder cancer. , 2000, Urology.

[18]  J. Wiśniewski,et al.  Translating Proteomic Into Functional Data: An High Mobility Group A1 (HMGA1) Proteomic Signature Has Prognostic Value in Breast Cancer* , 2015, Molecular & Cellular Proteomics.

[19]  H. Ji,et al.  EGFR Targeted Therapy: View from Biological Standpoint , 2006, Cell cycle.

[20]  S. Seal,et al.  Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation , 2017, Nature Genetics.

[21]  K. Hoadley,et al.  Bladder Cancer Molecular Taxonomy: Summary from a Consensus Meeting , 2016, Bladder cancer.

[22]  Carlos Cordon-Cardo,et al.  Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  J. Schimenti,et al.  Mouse Pachytene Checkpoint 2 (Trip13) Is Required for Completing Meiotic Recombination but Not Synapsis , 2007, PLoS genetics.

[24]  H. Ozen.  Bladder cancer. , 1998, Current opinion in oncology.

[25]  Ju-Han Lee,et al.  High expression of spindle assembly checkpoint proteins CDC20 and MAD2 is associated with poor prognosis in urothelial bladder cancer , 2013, Virchows Archiv.

[26]  G. Netto.  Molecular biomarkers in urothelial carcinoma of the bladder: are we there yet? , 2012, Nature Reviews Urology.

[27]  M. Zeegers,et al.  Protein shedding in urothelial bladder cancer: prognostic implications of soluble urinary EGFR and EpCAM , 2015, British Journal of Cancer.

[28]  Y. Lotan,et al.  The economics of bladder cancer: costs and considerations of caring for this disease. , 2014, European urology.

[29]  S. Varambally,et al.  TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer , 2014, Nature Communications.

[30]  Christopher U. Jones,et al.  Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. , 2006, The New England journal of medicine.

[31]  M. Litwin,et al.  The future of bladder cancer care in the USA , 2014, Nature Reviews Urology.

[32]  Jens-Peter Volkmer,et al.  Three differentiation states risk-stratify bladder cancer into distinct subtypes , 2012, Proceedings of the National Academy of Sciences.

[33]  C. Cordon-Cardo,et al.  Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression. , 1993, Journal of the National Cancer Institute.

[34]  Yair Lotan,et al.  Nomograms including nuclear matrix protein 22 for prediction of disease recurrence and progression in patients with Ta, T1 or CIS transitional cell carcinoma of the bladder. , 2005, The Journal of urology.