Alternative polyadenylation is associated with lower expression of PABPN1 and poor prognosis in non‐small cell lung cancer

Cancer Science

Junji Ichinose¹  Kousuke Watanabe⁴  Atsushi Sano¹  Takahide Nagase⁴  Jun Nakajima¹  Masashi Fukayama²  Yutaka Yatomi³  Nobuya Ohishi⁴ 

[1] Department of Thoracic Surgery, University of Tokyo Hospital, Tokyo, Japan;Department of Pathology, University of Tokyo Hospital, Tokyo, Japan;Department of Clinical Laboratory, University of Tokyo Hospital, Tokyo, Japan;Department of Respiratory Medicine, University of Tokyo Hospital, Tokyo, Japan

关键词: Alternative polyadenylation;    lung cancer;    PABPN1;    prognosis;    rmodel;   

DOI  :  10.1111/cas.12472

来源: Wiley

【 摘 要 】

Abstract

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.

【 授权许可】

CC BY-NC-ND   
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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