MicroRNA-329-mediated PTTG1 downregulation inactivates the MAPK signaling pathway to suppress cell proliferation and tumor growth in cholangiocarcinoma
MicroRNA-329-mediated PTTG1 downregulation inactivates the MAPK signaling pathway to suppress cell proliferation and tumor growth in cholangiocarcinoma
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MicroRNA-329介导的PTTG1下调使MAPK信号通路失活，从而抑制胆管癌中的细胞增殖和肿瘤生长
DOI：
10.1002/jcb.28279
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发表时间：
2019-06-01
影响因子：
4
通讯作者：
He, Song-Qing
中科院分区：
文献类型：
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作者：
Hu, Zhi-Gao;Zheng, Chao-Wen;He, Song-Qing
胆管细胞癌(CCA)是一种严重的恶性肿瘤，预后差，死亡率高。MicroRNAs(MiRNAs)已被报道与CCA相关；然而，miR-329在CCA疾病中所起的作用仍不清楚。因此，本研究旨在探讨miR-329影响CCA进展的潜在机制。本工作研究了从基因表达总览数据库中获得的CCA表达芯片的差异分析。接下来，为了确定垂体肿瘤转化基因-1(Pttg1)在CCA中的表达和作用，我们预测了调节Pttg1的miRNAs。在miR-329上调或抑制并同时沉默Pttg1的CCA细胞中，检测miR-329、Pttg1、p-p38/p38、p-ERK5/ERK5、增殖细胞核抗原(PCNA)、Cyclin D1、Bcl2相关X蛋白(Bax)、B细胞CLL/淋巴瘤2(Bcl2)和caspase 3的表达。同时检测miR-329和Pttg1对细胞增殖、细胞周期分布和细胞凋亡的影响。MiR-329可能通过调节Pttg1介导的丝裂原活化蛋白激酶(MAPK)信号通路影响CCA的发育。MiR-329靶向Pttg1，导致MAPK信号通路失活。MiR-329的上调和Pttg1的沉默抑制了CCA细胞的增殖，诱导了细胞周期停滞，随后促进了细胞的凋亡，Bax、裂解caspase-3和总caspase-3的表达升高，而增殖细胞核抗原、细胞周期蛋白D1和Bcl-2的表达下降。此外，miR-329还通过下调Pttg1的表达来抑制肿瘤的生长。综上所述，miR-329通过抑制Pttg1的表达，使MAPK信号通路失活，从而抑制CCA的进展，从而为CCA的治疗提供了基础。
Cholangiocarcinoma (CCA) is a severe malignancy usually producing a poor prognosis and high mortality rate. MicroRNAs (miRNAs) have been reported in association with CCA; however, the role miR-329 plays in the CCA condition still remains unclear. Therefore, this study was conducted to explore the underlying mechanism of which miR-329 is influencing the progression of CCA. This work studied the differential analysis of the expression chips of CCA obtained from the Gene Expression Omnibus database. Next, to determine both the expression and role of pituitary tumor transforming gene-1 (PTTG1) in CCA, the miRNAs regulating PTTG1 were predicted. In the CCA cells that had been intervened with miR-329 upregulation or inhibition, along with PTTG1 silencing, expression of miR-329, PTTG1, p-p38/p38, p-ERK5/ERK5, proliferating cell nuclear antigen (PCNA), Cyclin D1, Bcl-2-associated X protein (Bax), B-cell CLL/lymphoma 2 (Bcl-2), and caspase-3 were determined. The effects of both miR-329 and PTTG1 on cell proliferation, cell-cycle distribution, and apoptosis were also assayed. The miR-329 was likely to affect the CCA development through regulation of the PTTG1-mediated mitogen-activated protein kinase (MAPK) signaling pathway. The miR-329 targeted PTTG1, leading to inactivation of the MAPK signaling pathway. Upregulation of miR-329 and silencing of PTTG1 inhibited the CCA cell proliferation, induced cell-cycle arrest, and subsequently promoted apoptosis with elevations in Bax, cleaved caspase-3, and total caspase-3, but showed declines in PCNA, Cyclin D1, and Bcl-2. Moreover, miR-329 was also found to suppress the tumor growth by downregulation of PTTG1. To summarize, miR-329 inhibited the expression of PTTG1 to inactivate the MAPK signaling pathway, thus suppressing the CCA progression, thereby providing a therapeutic basis for the CCA treatment.