Alternative polyadenylation is associated with lower expression of PABPN1 and poor prognosis in non-small cell lung cancer.
Alternative polyadenylation is associated with lower expression of PABPN1 and poor prognosis in non-small cell lung cancer.
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DOI：
10.1111/cas.12472
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发表时间：
2014-09
期刊：
影响因子：
5.7
通讯作者：
Takai D
中科院分区：
文献类型：
--
作者：
Ichinose J;Watanabe K;Sano A;Nagase T;Nakajima J;Fukayama M;Yatomi Y;Ohishi N;Takai D
选择性多聚腺苷酸化（阿帕）是基因调控中的一个重要现象，它导致3′UTR的缩短。阿帕参与发育、癌症和细胞增殖。阿帕可能通过分离microRNA结合位点导致癌细胞中microRNA介导的基因沉默的破坏。我们研究了肺癌病例中阿帕谱与肿瘤侵袭性之间的相关性。我们选择了前10个在肺癌中表现出显著3′UTR缩短的基因，使用Bioconductor软件包进行表达微阵列的探针水平分析。采用定量RT-PCR方法建立阿帕评分，并与临床预后及APA相关基因PABPN 1、CPEB 1、E2 F1和增殖标志物MKI 67、TOP 2A和MCM 2的表达水平进行比较。阿帕评分高与肿瘤分期晚、预后差相关（P < 0.001）。多变量分析确定阿帕评分为独立的预后因素（风险比，3.0; P = 0.03）。PABPN 1的低表达和增殖标记物的高表达均与阿帕评分高和预后差相关，抑制PABPN 1发挥其影响独立于增殖标记物的获得。阿帕评分与正电子发射断层扫描肿瘤最大标准摄取值相关（r = 0.53; P < 0.001）。我们的研究结果表明，PABPN 1，阿帕的抑制因子的损失，可能会通过释放癌细胞的microRNA介导的基因调控，促进肿瘤的侵袭性。
Alternative polyadenylation (APA), which induces shortening of the 3′UTR, is emerging as an important phenomenon in gene regulation. APA is involved in development, cancer and cell proliferation. APA may lead to disruption of microRNA-mediated gene silencing in cancer cells via detachment of microRNA binding sites. We studied the correlation between the APA profile and the tumor aggressiveness in cases of lung cancer. We selected the top 10 genes showing significant 3′UTR shortening in lung cancer, using the package of the Bioconductor for probe-level analyses of expression microarrays. We established and evaluated the APA score by quantitative RT-PCR in 147 clinical specimens of non-small cell lung cancer and compared the results with the clinical outcomes and expression levels of APA-related genes, including PABPN1, CPEB1, E2F1 and proliferation markers (MKI67, TOP2A and MCM2). High APA scores were correlated with an advanced tumor stage and a poor prognosis (P < 0.001). Multivariate analysis identified the APA score as an independent prognostic factor (hazard ratio, 3.0; P = 0.03). Both lower expression of PABPN1 and higher expression of the proliferation markers were correlated with high APA scores and a poor prognosis, with suppression of PABPN1 exerting its influence independent of gain of the proliferation markers. Moreover, the APA score was correlated with the maximum standardized uptake value of the tumors on positron emission tomography (r = 0.53; P < 0.001). Our results indicate that the loss of PABPN1, a suppressor of APA, might promote tumor aggressiveness by releasing the cancer cells from microRNA-mediated gene regulation.
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