Abstract
The nucleus accumbens-associated protein 1 (NACC1) is a transcription factor constitutively expressed in the urothelium, where it regulates cell growth, senescence, autophagy, and epithelial-mesenchymal transition. microRNA (miRNA) constitutes a class of small non-coding RNAs which are involved in cell proliferation, differentiation, and progression of tumors. miRNAs and their target molecules are utilized for molecular diagnosis of urothelial carcinoma. NACC1 is one of several putative target molecules of miR-331-3p, and is associated with cell proliferation in cancers such as prostate and cervical cancer. Functional experiments involving miR-331-3p and its target molecule NACC1 were conducted using the urothelial carcinoma (UC) cell lines, T24, UMUC6, and KU7. Furthermore, quantitative reverse transcription polymerase chain reaction and immunostaining were performed to evaluate the expression of NACC1 in UC derived from transurethral resection of bladder tumor (TUR-Bt) specimens. The methane thiosulfonate (MTS) assay revealed that cell proliferation was significantly reduced after transient transfection of miR-331-3p precursor and/or NACC1 siRNA in UC cells. Cell senescence via cell cycle arrest at the G1 phase was induced by NACC1 inhibition. On the other hand, suppression of NACC1 induced cell migration and invasion abilities. Immunohistochemical analysis of TUR-Bt specimens revealed that over 70% of UC cells presented strongly positive results for NACC1. In contrast, normal urothelial cells were weakly positive for NACC1. It was also found that NACC1 expression was lower in invasive UC cells than in non-invasive UC cells. Loss of NACC1 induced vessel invasion in invasive UC tissues. The present results indicate that NACC1 regulated by miR-331-3p contributes to cell proliferation, and is involved in cell migration and invasion. This suggests that NACC1 can serve as a potential target molecule for the prediction and prognosis of UC, and can contribute to effective treatment strategies.
Highlights
Urothelial carcinoma (UC) typically occurs in the urinary system and is the most common type of bladder cancer
We evaluated the expression of nucleus accumbens-associated protein 1 (NACC1) in urothelial carcinoma (UC) tissues of the urinary bladder
NACC1 was found to be localized in the nucleus of UC cells, and its expression was significantly higher in UC than in the normal or hyperplastic urothelium
Summary
Urothelial carcinoma (UC) typically occurs in the urinary system and is the most common type of bladder cancer. Despite advances in pathological diagnosis and clinical treatment, including transurethral resection of bladder tumors (TUR-Bt) or intravesical instillation of bacillus calmette-guérin (BCG), UC remains a major cause of cancer-related morbidity and mortality. UC constitutes approximately 90% of urinary bladder cancer and is classified into two types, high-grade invasive and low-grade non-invasive carcinomas. 70% of patients diagnosed with UC present non-invasive UC [2]. Many clinicians are confronted with early recurrence post initial treatment and a lack of clinically proven second-line therapies. To address this problem, numerous studies have been conducted; little experimental or clinical data exist to validate biomarkers associated with tumor occurrence/recurrence, progression, and metastasis. It is of great importance to characterize the molecular mechanism of UC tumorigenesis for the development of new therapeutic strategies
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