Morita Kohei, Fujii Tomomi, Itami Hiroe, Uchiyama Tomoko, Nakai Tokiko, Hatakeyama Kinta, Sugimoto Aya, Miyake Makito, Nakai Yasushi, Tanaka Nobumichi, Shimada Keiji, Yamazaki Masaharu, Fujimoto Kiyohide, Ohbayashi Chiho
Department of Diagnostic Pathology, Nara Medical University School of Medicine, Nara 634-8521, Japan.
Department of Urology, Nara Medical University School of Medicine, Nara 634-8521, Japan.
Cancers (Basel). 2018 Sep 21;10(10):347. doi: 10.3390/cancers10100347.
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.
伏隔核相关蛋白1（NACC1）是一种在尿路上皮中组成性表达的转录因子，它在尿路上皮中调节细胞生长、衰老、自噬以及上皮-间质转化。微小RNA（miRNA）是一类参与细胞增殖、分化和肿瘤进展的小非编码RNA。miRNA及其靶分子被用于尿路上皮癌的分子诊断。NACC1是miR-331-3p的几个假定靶分子之一，并且与前列腺癌和宫颈癌等癌症中的细胞增殖有关。使用尿路上皮癌细胞系T24、UMUC6和KU7进行了涉及miR-331-3p及其靶分子NACC1的功能实验。此外，进行了定量逆转录聚合酶链反应和免疫染色以评估NACC1在经尿道膀胱肿瘤切除术（TUR-Bt）标本来源的尿路上皮癌中的表达。甲硫代磺酸酯（MTS）测定显示，在尿路上皮癌细胞中瞬时转染miR-331-3p前体和/或NACC1 siRNA后，细胞增殖显著降低。通过在G1期阻滞细胞周期诱导细胞衰老。另一方面，抑制NACC1可诱导细胞迁移和侵袭能力。TUR-Bt标本的免疫组织化学分析显示，超过70%的尿路上皮癌细胞NACC1呈强阳性结果。相比之下，正常尿路上皮细胞NACC1呈弱阳性。还发现侵袭性尿路上皮癌细胞中NACC1的表达低于非侵袭性尿路上皮癌细胞。NACC1的缺失诱导侵袭性尿路上皮癌组织中的血管侵袭。目前的结果表明，受miR-331-3p调控的NACC1促进细胞增殖，并参与细胞迁移和侵袭。这表明NACC1可作为尿路上皮癌预测和预后的潜在靶分子，并有助于制定有效的治疗策略。
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