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

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.

MicroRNAs associated with lung squamous cell carcinoma: New prognostic biomarkers and therapeutic targets

“…Calcium is one of the key factors in stabilizing the cell cycle, and CALB1 can interfere with the resorption and homeostatic processes of calcium, ultimately regulating cell apoptosis . In addition, studies have shown that CALB1 can play a role in early tumor diagnosis and recurrence prediction . TOP2A, or topoisomerase IIa, has been shown to be involved in proliferation, apoptosis, and tumor resistance mechanisms in various studies .…”

Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions

“…In agreement with this hypothesis, known protein interaction sites, such as regions needed for interaction with SKIP (residues 2–145), stimulation of poly(A) polymerase alpha (PAPOLA, residues 119–147) and coiled-coil-based interaction (residues 115–151), are all located within the N-terminal IDPR. Being the only non-transcription factor with the pathogenic poly-Ala tract, PABP2/PABPN1 does not form an exception from the multipathogenicity rule, being associated with oculopharyngeal muscular dystrophy via the expansion mutations in its poly-Ala tract [ 269 ] and also being involved in metastatic duodenal cancer [ 270 ] and non-small cell lung cancer [ 271 ].…”

IKAROS: a multifunctional regulator of the polymerase II transcription cycle

“…The expression levels of the polyadenylation complex subunits can also be deregulated in solid cancer cells. For example, PABPN1 and CPSF4 are, respectively, downregulated [123] and upregulated [124] in lung tumors. devoted to the control of the different phases of the transcription cycle.…”