DNA Hypomethylation Is Associated with the Overexpression of INHBA in Upper Tract Urothelial Carcinoma.

Chien-Chang Kao,Hao-Lun Luo,Hui-Ying Liu,Sheng-Tang Wu,En Meng,Yin-Lun Chang,Dah-Shyong Yu,Tai-Lung Cha,Guang-Huan Sun

doi:10.3390/ijms23042072

Abstract

Urothelial carcinoma includes upper urinary tract cancer (UTUC) and bladder cancer. Although nephroureterectomy is the standard treatment for UTUC, the recurrence rate is approximately half and the tumor is associated with poor prognoses. Metastases are the most devastating and lethal clinical situation in urothelial carcinoma. Despite its clinical importance, few potential diagnostic biomarkers are suitable for early UC detection. We compared high-stage/high-grade urothelial carcinoma tissues to adjacent normal urothelial tissues using methyl-CpG binding domain protein capture for genome-wide DNA methylation analysis. Based on our findings, inhibin βA (INHBA) might be associated with carcinogenesis and metastasis. Further, clinical UC specimens had significant INHBA hypomethylation based on pyrosequencing. INHBA was detected by real-time PCR and immunohistochemistry staining, and was found to be highly expressed in clinical tissues and cell lines of urothelial carcinoma. Further, INHBA depletion was found to significantly reduce BFTC-909 cell growth and migration by INHBA-specific small interfering RNA. Interestingly, a positive correlation was found between SMAD binding and extracellular structure organization with INHBA using gene set enrichment analysis and gene ontology analysis. Together, these results are the first evidence of INHBA promoter hypomethylation and INHBA overexpression in UTUC. INHBA may affect urothelial carcinoma migration by reorganizing the extracellular matrix through the SMAD pathway.

Highlights

Urothelial cancer is the fourth most common cancer in the world and is located in the lower or upper urinary tract
We reported that SPARCL1 is a hypermethylated gene and a tumor suppressor-like gene in the National Health Research Institute (NHRI) bioinformatics database for urinary tract urothelial carcinoma (UTUC) [19]
inhibin βA (INHBA) overexpression may be affected by promoter methylation in lung adenocarcinoma and esophageal adenocarcinoma [23,24]

Summary

Introduction

Urothelial cancer is the fourth most common cancer in the world and is located in the lower (bladder and urethra) or upper (pyelocaliceal cavities and ureter) urinary tract. Bladder cancer is the most common urothelial cancer, while upper urinary tract urothelial carcinoma (UTUC), which is more malignant, accounts for 5% to 10% of cases [1–3]. Radical nephroureterectomy (RNU) with bladder cuff excision is the gold standard surgical treatment for patients with UTUC [5,6]. Several possible predictive factors for poor prognosis have been reported, including gender [9], stage [10], grade [11], lymphovascular invasion [12,13], and tumor architecture [8,14]. As there are few diagnostic biomarkers for UTUC, the investigation of potential prognostic factors for evaluating prognosis could help predict this high incidence of disease recurrence and promote effective treatment

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Methods

Results