The lncRNA PVT1 Contributes to the Cervical Cancer Phenotype and Associates with Poor Patient Prognosis.

Marissa Iden,Keguo Li,Janet S Rader,Ramani Ramchandran,Tamjid Chowdhury,Samantha Fye,Bibekanand Mallick

doi:10.1371/journal.pone.0156274

Abstract

The plasmacytoma variant translocation 1 gene (PVT1) is an lncRNA that has been designated as an oncogene due to its contribution to the phenotype of multiple cancers. Although the mechanism by which PVT1 influences disease processes has been studied in multiple cancer types, its role in cervical tumorigenesis remains unknown. Thus, the present study was designed to investigate the role of PVT1 in cervical cancer in vitro and in vivo. PVT1 expression was measured by quantitative PCR (qPCR) in 121 invasive cervical carcinoma (ICC) samples, 30 normal cervix samples, and cervical cell lines. Functional assays were carried out using both siRNA and LNA-mediated knockdown to examine PVT1’s effects on cervical cancer cell proliferation, migration and invasion, apoptosis, and cisplatin resistance. Our results demonstrate that PVT1 expression is significantly increased in ICC tissue versus normal cervix and that higher expression of PVT1 correlates with poorer overall survival. In cervical cancer cell lines, PVT1 knockdown resulted in significantly decreased cell proliferation, migration and invasion, while apoptosis and cisplatin cytotoxicity were significantly increased in these cells. Finally, we show that PVT1 expression is augmented in response to hypoxia and immune response stimulation and that this lncRNA associates with the multifunctional and stress-responsive protein, Nucleolin. Collectively, our results provide strong evidence for an oncogenic role of PVT1 in cervical cancer and lend insight into potential mechanisms by which PVT1 overexpression helps drive cervical carcinogenesis.

Highlights

Long noncoding RNAs provide important targets for cancer diagnostics and therapeutics due to their critical role in numerous cellular processes such as epigenetic changes, gene enhancer and tumor suppressor activity, and miRNA sequestering
Plasmacytoma variant translocation 1 (PVT1) expression was examined in vitro, with the SiHa cervical cancer cell line expressing the highest levels of the Long noncoding RNAs (lncRNAs) compared to others
PVT1 knockdown in cervical cancer cells was associated with decreased proliferation, migration and invasion and increased apoptosis and cisplatin sensitivity, suggesting that this lncRNA likely plays a pivotal and multifaceted role in cervical carcinogenesis

Summary

Introduction

Long noncoding RNAs (lncRNAs) provide important targets for cancer diagnostics and therapeutics due to their critical role in numerous cellular processes such as epigenetic changes, gene enhancer and tumor suppressor activity, and miRNA sequestering. PVT1 in Cervical Cancer expression, and can influence many cellular processes via multiple disparate mechanisms [1]. Plasmacytoma variant translocation 1 (PVT1) is a highly conserved lncRNA ~50kb downstream of MYC that has attracted significant attention from the cancer field due to its frequent co-amplification with MYC in several solid tumors [2]. The first studies providing evidence that PVT1 may contribute to carcinogenesis demonstrated frequent translocations in mouse plasmacytomas [3,4] and human Burkitt’s lymphomas [5,6,7]. The oncogenic effects of PVT1 have been further highlighted by more recent studies demonstrating its overexpression and amplification in multiple cancer types [8,9,10,11,12,13,14,15,16,17]. PVT1 expression has been significantly correlated with clinical features such as risk, recurrence, and survival in various cancers [8,11,12,13,18]

Methods

Results

Conclusion