These authors contributed equally to this work.
Alternative polyadenylation is associated with lower expression of PABPN1 and poor prognosis in non-small cell lung cancer
Article first published online: 3 SEP 2014
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Volume 105, Issue 9, pages 1135–1141, September 2014
How to Cite
Cancer Sci 105 (2014) 1135–1141
This work was supported by grants from the Takeda Science Foundation, and JSPS KAKENHI (23390147). (24659267). (25830098). (24791455). (23249045). (22249017 ). (24390326).
- Issue published online: 23 SEP 2014
- Article first published online: 3 SEP 2014
- Accepted manuscript online: 28 JUN 2014 04:27AM EST
- Manuscript Accepted: 24 JUN 2014
- Manuscript Revised: 16 JUN 2014
- Manuscript Received: 14 MAY 2014
- Takeda Science Foundation
- JSPS KAKENHI. Grant Numbers: 23390147, 24659267, 25830098, 24791455, 23249045, 22249017 , 24390326
- Alternative polyadenylation;
- lung cancer;
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.