Abstract A27: Loss of PABPN1 and alternative polyadenylation yield poor prognosis in non-small cell lung cancer.

Abstract

Abstract Alternative polyadenylation (APA), which induces shortening of the 3'UTR, is emerging as an important layer in gene regulation. APA is involved in cell proliferation, development, and cancer. APA may lead to disruption of microRNA-mediated gene regulation 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 specifically 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 qRT-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 several proliferation markers (MKI67, TOP2A and MCM2). High APA scores were correlated with an advanced tumor stage and poor prognosis (P < 0.001). Multivariate analysis identified the APA score as an independent prognostic factor (hazard ratio, 3.0; P = 0.03). Both loss of PABPN1 and gain 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 recently identified suppressor of APA, promotes tumor aggressiveness by releasing the cancer cells from microRNA-mediated gene regulation. Citation Format: Junji Ichinose, Kousuke Watanabe, Atsushi Sano, Takahide Nagase, Jun Nakajima, Masashi Fukayama, Yutaka Yatomi, Nobuya Ohishi, Daiya Takai. Loss of PABPN1 and alternative polyadenylation yield poor prognosis in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A27.