Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes.
Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes.
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DOI：
10.3390/cancers12102731
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发表时间：
2020-09-23
期刊：
影响因子：
5.2
通讯作者：
Seki N
中科院分区：
文献类型：
--
作者：
Tanaka T;Okada R;Hozaka Y;Wada M;Moriya S;Satake S;Idichi T;Kurahara H;Ohtsuka T;Seki N
在胰腺导管腺癌（PDAC）中，共有10个基因（YWHAZ、F3、TMOD 3、NFE 2L 3、ENDOD 1、ITGA 3、RRAS、PRSS 2 - 3、TOP 2A和LRRIP 1）被确定为肿瘤抑制性miR-30 c-5 p和miR-30 c-2- 3 p靶点，这些基因的表达是患者生存的独立预后因素。此外，TOP 2A及其转录激活因子（SP1和HMGB 2）的异常表达增强了PDAC细胞的恶性转化。胰腺导管腺癌（PDAC）是最具侵袭性的癌症类型之一，其预后极差;只有25%的患者存活一年，5%存活五年。PDAC的microRNA（miRNA）特征分析显示，前miR-30 c的两条链（miR-30 c-5 p，引导链; miR-30 c-2- 3 p，过客链）均显著下调，表明它们在PDAC细胞中起肿瘤抑制因子的作用。异位表达测定表明，这些miRNA减弱了PDAC细胞的侵袭性，例如，细胞增殖、迁移和侵袭。通过计算机模拟分析和基因表达数据的组合，我们确定了216个基因作为PDAC细胞中miR-30 c-5 p和miR-30 c-2- 3 p调控的假定致癌靶基因。其中18个基因的表达与PDAC患者的5年生存率有显著相关性（p < 0.01）。重要的是，发现10个基因（YWHAZ、F3、TMOD 3、NFE 2L 3、ENDOD 1、ITGA 3、RRAS、PRSS 23、TOP 2A和LRRIP 1）的表达水平是患者生存的独立预后因素（p < 0.01）。我们专注于TOP 2A（DNA拓扑异构酶II α），并研究其作为PDAC治疗靶点的潜力。TOP 2A及其转录激活因子（SP1和HMGB 2）在PDAC临床标本中的过表达。此外，TOP 2A的敲除增强了PDAC细胞对抗癌药物的敏感性。我们对PDAC miRNA特征和肿瘤抑制性miRNA的分析为PDAC的分子发病机制提供了重要的见解。
A total of 10 genes (YWHAZ, F3, TMOD3, NFE2L3, ENDOD1, ITGA3, RRAS, PRSS23, TOP2A, and LRRFIP1) were identified as tumor suppressive miR-30c-5p and miR-30c-2-3p targets in pancreatic ductal adenocarcinoma (PDAC), and expression of these genes were independent prognostic factors for patient survival. Furthermore, aberrant expression of TOP2A and its transcriptional activators (SP1 and HMGB2) enhanced malignant transformation of PDAC cells. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer, and its prognosis is abysmal; only 25% of patients survive one year, and 5% live for five years. MicroRNA (miRNA) signature analysis of PDAC revealed that both strands of pre-miR-30c (miR-30c-5p, guide strand; miR-30c-2-3p, passenger strand) were significantly downregulated, suggesting they function as tumor-suppressors in PDAC cells. Ectopic expression assays demonstrated that these miRNAs attenuated the aggressiveness of PDAC cells, e.g., cell proliferation, migration, and invasiveness. Through a combination of in silico analyses and gene expression data, we identified 216 genes as putative oncogenic targets of miR-30c-5p and miR-30c-2-3p regulation in PDAC cells. Among these, the expression of 18 genes significantly predicted the 5-year survival rates of PDAC patients (p < 0.01). Importantly, the expression levels of 10 genes (YWHAZ, F3, TMOD3, NFE2L3, ENDOD1, ITGA3, RRAS, PRSS23, TOP2A, and LRRFIP1) were found to be independent prognostic factors for patient survival (p < 0.01). We focused on TOP2A (DNA Topoisomerase II Alpha) and investigated its potential as a therapeutic target for PDAC. The overexpression of TOP2A and its transcriptional activators (SP1 and HMGB2) was detected in PDAC clinical specimens. Moreover, the knockdown of TOP2A enhanced the sensitivity of PDAC cells to anticancer drugs. Our analyses of the PDAC miRNA signature and tumor-suppressive miRNAs provide important insights into the molecular pathogenesis of PDAC.
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影响因子：
4.6
作者：
Kim, Im-Kyung;Lee, Yun Sun;Yoon, Dong Sup
通讯作者：
Yoon, Dong Sup
DOI：
10.1016/j.ejca.2017.06.019
发表时间：
2017-09
期刊：
European journal of cancer (Oxford, England : 1990)
影响因子：
--
作者：
Heestand GM;Schwaederle M;Gatalica Z;Arguello D;Kurzrock R
通讯作者：
Kurzrock R
影响因子：
5.7
作者：
Idichi T;Seki N;Kurahara H;Fukuhisa H;Toda H;Shimonosono M;Okato A;Arai T;Kita Y;Mataki Y;Kijima Y;Maemura K;Natsugoe S
通讯作者：
Natsugoe S
影响因子：
3.8
作者：
Daoud, Afra Z.;Mulholland, Eoghan J.;McCarthy, Helen O.
通讯作者：
McCarthy, Helen O.
影响因子：
7.5
作者：
Cao, Jing-mei;Li, Gao-zhong;Huang, Kun-ming
通讯作者：
Huang, Kun-ming