Ribosomal L22-like1 (RPL22L1) Promotes Ovarian Cancer Metastasis by Inducing Epithelial-to-Mesenchymal Transition

Nan Wu,Jingshu Geng,Yan Jin,Ying Qin,Jia Wei,Ki-Young Lee,Bo Pang,Wenjing Sun,Yuhui Wang,Chunyu Zhang,Songbin Fu,Xiangning Meng,Feng Chen,Haiming Sun,Donglin Sun,Yang Yu,Dandan Tong,Jinyan Yan,Jing Bai

doi:10.1371/journal.pone.0143659

Abstract

Double minute chromosomes (DMs) have important implications for cancer progression because oncogenes frequently amplified on them. We previously detected a functionally undefined gene amplified on DMs, Ribosomal L22-like1 (RPL22L1). The relationship between RPL22L1 and cancer progression is unknown. Here, RPL22L1 was characterized for its role in ovarian cancer (OC) metastasis and its underlying mechanism was examined. DNA copy number and mRNA expression of RPL22L1 in OC cells was analyzed using data obtained from The Cancer Genome Atlas and the Gene Expression Omnibus database. An immunohistochemical analysis of clinical OC specimens was performed and the relationships between expression level and clinicopathological factors were evaluated. Additionally, in vivo and in vitro assays were performed to understand the role of RPL22L1 in OC. RPL22L1 expression was higher in OC specimens than in normal tissues, and its expression level was highly positively correlated with invasion and lymph node metastasis (P < 0.05). RPL22L1 over-expression significantly enhanced intraperitoneal xenograft tumor development in nude mice and promoted invasion and migration in vitro. Additionally, RPL22L1 knockdown remarkably inhibited UACC-1598 cells invasion and migration. Further, RPL22L1 over-expression up-regulated the mesenchymal markers vimentin, fibronectin, and α-SMA, reduced expression of the epithelial markers E-cadherin, α-catenin, and β-catenin. RPL22L1 inhibition reduced expression of vimentin and N-cadherin. These results suggest that RPL22L1 induces epithelial-to-mesenchymal transition (EMT). Our data showed that the DMs amplified gene RPL22L1 is critical in maintaining the aggressive phenotype of OC and in triggering cell metastasis by inducing EMT. It could be employed as a novel prognostic marker and/or effective therapeutic target for OC.

Highlights

Ovarian cancer (OC) is the second most common gynecological malignancy and the first cause of death [1]
Using a fluorescence in situ hybridization (FISH) analysis, we detected amplified regions of RPL22L1 that co-localized with MYCN on Double minute chromosomes (DMs) (Fig 1B)
Many oncogenes are amplified via DMs in malignant tumor cells [34.38.39], such as EIF5A2 and MYCN, both of which are located at the same locus as RPL22L1 on DMs

Summary

Introduction

Ovarian cancer (OC) is the second most common gynecological malignancy and the first cause of death [1]. Rather than primary tumors, are responsible for most cancer deaths [2]. Double minute chromosomes (DMs) are cytogenetic hallmarks of gene amplification [4]. As extra-chromosomal elements carrying amplifications of genomic DNA sequences, DMs contribute to cancer formation and progression, oncogenes are frequently present in the amplified sequences and the proteins they encode are often over-expressed [6]. Examples of genes amplified on DMs include MYC in colon cancer [7], MYCN in neuroblastoma [8], EGFR in gliomas [9], and EIF5A2 [10, 11] in ovarian cancer [12]. As DMs are vehicles of amplified genes including many oncogenes, functional studies of genes that are amplified on DMs is a good way to explore candidate oncogenes

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Results

Conclusion