Long Noncoding RNA PVT1 Promotes Prostate Cancer Metastasis by Increasing NOP2 Expression via Targeting Tumor Suppressor MicroRNAs
Received 15 December 2019
Accepted for publication 17 June 2020
Published 10 July 2020 Volume 2020:13 Pages 6755—6765
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr William Cho
Feng Sun, Ke Wu, Zhixian Yao, Xingyu Mu, Zhong Zheng, Menghao Sun, Yong Wang, Zhihong Liu, Yiyong Zhu
Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, People’s Republic of China
Correspondence: Yiyong Zhu; Ke Wu
Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, People’s Republic of China
Tel +86 15902190823
; +86 15800567782
Email [email protected]; [email protected]
Background: Metastatic disease caused by prostate cancer (PCa) is the principal cause of PCa-related mortality. Long non-protein-coding RNAs may possess significant cellular functions. Plasmacytoma variant translocation 1 (PVT1), a long non-coding RNA encoded by the human PVT1 gene, is an oncogene, which can regulate several tumor-related genes. In PCa, the function and mechanism of PVT1 are unclear. NOP2 is being pursued as a prognostic marker for cancer aggressiveness, which promotes mouse fibroblast growth and tumor formation. Essentially, nothing is known about the specific interactions between the PVT1 and NOP2.
Methods: 190 pairs of PCa tissues and adjacent normal tissues were collected and RNA sequencing was used to identify the differential lncRNAs. Real-time quantitative real-time PCR (RT-qPCR) confirmed these results and gene regulatory relationship. Lentiviral vectors were used to alter PVT1 and genes to analyze their effects on PCa progression. Transwell migration and invasion assays were performed to test the metastasis ability. Biofunction of PVT1 and NOP2 were confirmed in vitro and in vivo.
Results: In this study, we reported that the long noncoding RNA-PVT1 was upregulated in PCa metastasis tissues and promoted migration of PCa cells in vitro and their metastasis in vivo. High levels of PVT1 significantly downregulated tumor suppressor microRNAs (miRNAs), such as miR-15b-5p, miR-27a-3p, miR-143-3p, and miR-627-5p, whose levels in metastasis tissues were low compared to those in non-metastasis tissues. In vitro and in vivo, PVT1 promotes PCa metastasis via targeting miRNAs. Furthermore, the expression level of PVT1 was positively associated with the expression of NOP2, a cancer metastasis-related protein. We demonstrated that NOP2 promoted invasion and migration of PCa. For specific mechanism, correlation analysis showed that PVT1 promoted metastasis by up-regulating NOP2.
Conclusion: Taken together, our results show that PVT1 acts as an inducer of PCa metastasis via targeting miRNAs, thereby promoting NOP2. This axis may have diagnostic and therapeutic potential for advanced PCa.
Keywords: lncRNA PVT1, miRNAs, NOP2, metastasis, prostate cancer
Prostate cancer (PCa) is the most frequently diagnosed cancer and the most common cause of death due to malignancy among men.1 Bone metastasis, the most common distant metastatic event of PCa, is the leading cause of mortality in PCa patients. However, the specific mechanisms of PCa metastasis are still not very clear.2 Therefore, identifying the causes and molecular mechanisms of PCa metastasis is important to establish early diagnosis and treatment system.
PCa metastasis is closely related to non-coding RNAs.3 It has been observed that non-protein-coding RNAs may possess significant cellular functions.4 High-resolution sequencing technologies allowed the detection of novel transcripts, such as long noncoding RNAs (lncRNAs), which participate in a broad spectrum of biological pathways, from gene transcription to protein translation.5 Recent research has showed that several lncRNAs play pivotal roles in cell chemo-resistance, proliferation, and cancer metastasis in various malignancies.6 Further, lncRNAs can also function as competing endogenous RNAs (ceRNAs) by competitively integrating with miRNAs and then modulating the targets of miRNAs, resulting in abnormal expression of downstream genes.7 Aberrant expression of lncRNAs has been observed in cancer and may serve as predicting tools for patient outcomes.8 Plasmacytoma variant translocation 1 (PVT1), a long non-coding RNA encoded by the human PVT1 gene, is located in the well-known cancer-related region, 8q24. Non-coding RNAs (ncRNAs) are RNA transcripts from genes not encoding for a protein.9
Murine NOP2 is homologous to yeast protein NOP2p and human NOP2 (also named NSUN1 or P120).10 NOP2 belongs to the NOP2/SUN (NSUN) RNA-methyltransferase family, which includes six other members: NSUN2 through NSUN7.11 NOP2 promotes mouse fibroblast growth and tumor formation and is highly expressed in diverse tumor types but not in normal cells.12 Therefore, NOP2 is being pursued as a prognostic marker for cancer aggressiveness. Limited studies in mammals have demonstrated expression of Nop2 in brain tissue and fetal liver, but the expression pattern and function of Nop2 during preimplantation development have not yet been investigated.10
In our study, we found that PVT1 was highly upregulated in metastatic PCa tissues and associated with worse outcomes. Loss- and gain-of-function assays demonstrated that PVT1 increases by up-regulating NOP2 mRNA via targeting miRNAs. In summary, our results show that PVT1-NOP2 is an oncogenic axis and a driving force for PCa progression and may be a promising candidate for future targeted treatment.
Materials and Methods
All animal studies were approved by the institutional Animal Care and Use Committee of Shanghai Jiao Tong University. All mice were maintained in pathogen-free conditions and cared for in compliance with the ethical regulations at Shanghai General Hospital. Transgenic adenocarcinomas of mouse prostate (TRAMP) and ProbCre/Ptenfl/fl mice were provided by the Shanghai Model Organisms Center (Shanghai, China) sacriﬁced 12 weeks post-castration unless indicated otherwise. Prostates, TdLNs, livers, lungs, and bones were collected for hematoxylin and eosin (H&E) and immunohistochemistry staining. The diagnosis of tumor metastasis was made independently by two pathologists. The genetic background of all mice used in this study was C57BL/6.
Two human prostate cancer cell lines (DU 145, and PC-3) and a normal prostate cell line (RWPE-1) were purchased from the Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences (China). DU 145 and PC-3 cells were cultured in Ham’s F12 medium and RWPE-1 cells were cultured in K-SFM medium supplemented with 10% fetal bovine serum (FBS), 100 mg/mL streptomycin (Invitrogen), and 100 U/mL penicillin in humidiﬁed air at 37°C with 5% CO2. All cell lines were authenticated by short tandem repeat DNA proﬁling.
RNA Extraction and Quantitative RT-qPCR Assays
Total RNA was extracted from tissues or cultured cells using TRIzol reagent (Invitrogen) according to the manufacturer’s instructions. RNA (1 mg) was reverse transcribed in a ﬁnal volume of 20 mL using random primers under standard conditions using the PrimeScript RT Reagent Kit (TaKaRa). Real-time PCR analyses were performed with SYBR Premix Ex Taq (TaKaRa). Levels of PVT1 (primer: forward 5ʹ-CCTGTGACCTGTGGAGACAC-3ʹ, reverse: 5ʹ-GTCCGTCCAGAGTGCTGAAA-3ʹ) and NOP2 (primer: forward 5ʹ-AAATGGGAGAAGGTGGCGTC-3ʹ, reverse: 5ʹ-CTCTCGGACATTAACCCGCA-3ʹ) were normalized to the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Primers for miR-15b-5p (primer: forward 5ʹ-ACTGTAGCAGCACATCATGG-3ʹ, reverse: 5ʹ-TTTCCTTAAATTTCTAGAGCAGCAA-3ʹ), miR-27a-3p (primer: forward 5ʹ-GCGGAACTTAGCCACTGTGA-3ʹ, reverse: 5ʹ-TTTCCTTAAATTTCTAGAGCAGCAA-3ʹ), miR-143-3p (primer: forward 5ʹ-CAGTGCTGCATCTCTGGTCA-3ʹ, reverse: 5ʹ-TGCAGAACAACTTCTCTCTTCCT-3ʹ), miR-143-3p (primer: forward 5ʹ-CAGTGCTGCATCTCTGGTCA-3ʹ, reverse: 5ʹ-TGCAGAACAACTTCTCTCTTCCT-3ʹ), miR-143-3p (primer: forward 5ʹ-CCCTACCCCAGTAATCCCCA-3ʹ, reverse: 5ʹ-AGACTGCCTTTGGGTTGAGG-3ʹ) and U6 (miRNA0002-1-200) were purchased from RiboBio. RT-qPCR and data collection were conducted on an ABI 7500 real-time PCR system (Applied Biosystems). RT-qPCR results were analyzed and expressed relative to threshold cycle (Ct) values, and then converted to fold changes.
Transduction of BC Cell Lines and RNA Extraction
The short hairpin RNA (shRNA) and green fluorescent protein (GFP)-labeled lentivirus vectors containing the PVT1 overexpression lentivirus (OE-PVT1), NOP2 overexpression lentivirus (OE-NOP2), NOP2 silencing lentivirus (SH-NOP2) and the corresponding control lentivirus (NC) were obtained from GeneChem (Shanghai, China). Cells were seeded in 6-well plates (5 × 105 cells/well) before transduction. The shRNA transduction was conducted using the HiPerFect Transfection Reagent according to the manufacturer’s instructions (Qiagen). Transduction with the lentiviral vectors was conducted using transduction reagents and 8 mg/mL polybrene (GeneChem) for 12 h. For viral transduction, cells were transduced with a multiplicity of infection (MOI) of 10, 100 or 1000. Overexpression, silencing, and the corresponding control stable cell lines were then established, and the efficiency of transduction was confirmed by RT-qPCR.
Cell Migration and Cell Invasion Assays
Transwell migration and invasion assays were performed as previously described. DU 145 was seeded in the upper chambers, and conditioned medium was placed in the lower chambers. Cells were stained with crystal violet and observed under an optical microscope. All experiments were performed in triplicate.
The RNA quality and integrity were analyzed by Qubit 2.0 (Life Technologies) and Bioanalyzer 2100 (Agilent). For library preparation, 3 μg total RNA was captured by NEBNext Oligo d (T) 25 beads (NEB), sheared to yield fragments of approximately 250 bp, and reverse transcribed using NEBNext RNA ﬁrst and second Strand Synthesis Module (NEB, USA). The products were end-repaired, A-tailed, ligated to Illumina sequencing adapters, and ampliﬁed by PCR. The quality of the sequencing library was assayed by using the Qubit 2.0 fluorometer (Life technologies, USA) and the Bioanalyzer 2100 (Agilent) and then sequenced using an Illumina Hiseq X Ten with 2 × 150 bp paired-end sequencing, controlled by HiSeq Control Software (HCS). Raw sequence reads were initially examined using FastQC for quality control. Raw reads were processed to trim low-quality sequences and adapters using Trimmomatic. Clean reads were then mapped to hg19 for human samples and mm9 for mouse samples using STAR, and only uniquely mapped reads were kept. Read counts were calculated by htseq-count. Differential expression analysis was performed using DESeq2.
The signiﬁcance of differences between groups was assessed by a paired, two-tailed Student’s t-test. The univariate and multivariate Cox proportional hazards model was used to determine the effects of variables on survival. The Kaplan–Meier method test was utilized for survival analysis. Spearman correlation analysis was used to calculate the correlation between PVT1, miR-542-3p, and NOP2. All statistical analyses were performed using SPSS 17.0 software. A P value of <0.05 determined statistical signiﬁcance.
PVT1 is Aberrantly Upregulated in Metastatic Tissues
PCa is prone to distant metastases.13 We explored the changes of lncRNAs between PCa metastatic tissues and primary PCa tissues. We used the TRAMP mouse model and ProbCre/Ptenfl/fl mouse to establish PCa model (Figure 1A). To identify lncRNAs that may be involved in the emergence of metastasis, we ﬁrst analyzed RNA sequencing (RNA-seq) data of 3 metastatic tissues and 3 primary PCa tissues from the TRAMP and ProbCre/Ptenfl/fl mouse models. We found that the expression levels of 142 and 149 lncRNAs in metastatic tissues from the TRAMP mouse (Figure 1B) and the ProbCre/Ptenfl/fl mouse (Figure 1C) were signiﬁcantly changed (Fold change > 2, P < 0.05) compared to those of primary PCa tissues. The expression levels of the top 10 upregulated lncRNAs were examined by RT-qPCR. The trends in the expression of lncRNAs in metastatic tissues from TRAMP mice (Figure 1D) and ProbCre/Ptenfl/fl mice (Figure 1E) were in line with the RNA-seq data. To explore the crucial lncRNA, we took the two sets of differentially expressed lncRNAs together. The results showed that there are 36 repeated lncRNAs in RNA-seq data (Figure 1G) and singular repeated lncRNA in RT-qPCR assays (Figure 1H).
PVT1 Silencing Inhibits PCa Metastasis
To investigate the functions of PVT1 in PCa cell metastasis, we examined PVT1 expression levels in the PCa cell lines, VCaP, PC-3, DU 145, and 22RV1, and compared them to those in the normal prostate cell line, RWPE-1. RT-qPCR analysis showed that the levels of PVT1 in PCa cells were significantly higher than those in RWPE-1 cells (Figure 2A). To confirm these results, we collected primary PCa tissues and PCa metastatic tissues from TRAMP mouse and ProbCre/Ptenfl/fl mouse. RT-qPCR analysis showed that the levels of PVT1 in PCa metastatic tissues were higher than primary PCa tissues (Figure 2B and C). Then, we knocked down PVT1 in DU 145 cells by transfection with the SH-PVT1 lentivirus. The expression of PVT1 was effectively downregulated in cells transfected with the SH-PVT1 lentivirus compared with that in cells transfected with the empty lentivirus vector (Figure 2D). To investigate the role of PVT1 in PCa metastasis, we used SH-PVT1 lentivirus to knockdown PVT1 during carcinogenesis of TRAMP mice and ProbCre/Ptenfl/fl mice (Figure 2E). We injected SH-PVT1 lentivirus every 3 days for a total of 4 times. Histopathological analysis revealed that, compared to that of the isotype vector controls, downregulation of PVT1 resulted in signiﬁcantly reduced incidence of tumor metastases (Figure 2F). Low levels of PVT1 also resulted in significantly prolonged survival time (Figure 2G). Taken together, these results showed that silencing PVT1 could effectively inhibit the progression of PCa metastasis.
PVT1 Down-Regulated Several miRNAs
Recent studies have shown that lncRNAs can regulate target gene expression by interacting with RNA-binding proteins, such as polycomb repressive complex 2 (PRC2), or by acting as ceRNAs for miRNAs.14 To investigate the molecular mechanism by which PVT1 promotes PC cells metastasis, we ﬁrst analyzed its subcellular localization. The levels of PVT1 in nuclear and cytoplasmic fractions were assayed by RT-qPCR. The isolated nuclear fraction displayed high levels of nuclear markers (U6 snRNA) but low levels of cytoplasmic markers (GAPDH). Furthermore, PVT1 was found to be more abundant in the cytoplasm than in the nucleus (Figure 3A), suggesting that PVT1 may regulate target gene expression at the posttranscriptional level. Indeed, RNA-binding protein immunoprecipitation assays using PCa cell extracts revealed that PVT1 binds directly to Ago2, a component of the RNA-induced silencing complex involved in miRNA-mediated repression of mRNAs (Figure 3B). This ﬁnding suggested that PVT1 may function as a ceRNA of miRNAs. Sequencing results showed that there were 12 miRNAs down-regulated in metastatic tissues of both TRAMP mice and ProbCre/Ptenfl/fl mice (Figure 3B). To confirm these results, RT-qPCR analysis was used to test these miRNAs in metastatic tissues compared to primary PCa tissues. The results showed that 12 miRNAs down-regulated in metastatic tissues (Figure 3D). Hence, we chose miR-15b-5p, miR-27a-3p, miR-143-3p, and miR-627-5p for further investigation and confirmed their correlation with PVT1. As expected, all of these miRNAs were negatively correlated with PVT1 (Figure 3E–H). Taken together, these results showed that PVT1 played as a sponge to decreased many miRNAs.
NOP2 Is a PVT1 Target Gene
To determine the target gene of miRNAs in PCa, we analyzed the potential mRNAs of miR-15b-5p, miR-27a-3p, miR-143-3p, and miR-627-5p. As shown, there are 14 potential target mRNAs in the interaction (Figure 4A). To confirm these results, the levels of potential target genes were assayed by RT-qPCR. The result showed that these mRNAs were increased in metastatic tissues compared to primary PCa tissues (Figure 4B). We used miRmap (http://mirmap.ezlab.org/), microT (http://www.microrna.gr/microT), miRanda (http://www.microrna.org/microrna/home.do), and PITA (http://genie.weizmann.ac.il/pubs/mir07/mir07_data.html) to predict potential target miRNAs of NOP2. The results showed that 6 miRNAs, included miR-15b-5p, miR-27a-3p, miR-143-3p, and miR-627-5p, were NOP2-related miRNAs (Figure 4C). Then, we analyzed PVT1 and NOP2 related miRNAs and found that there were 21 miRNAs in the interaction, which also included miR-15b-5p, miR-27a-3p, miR-143-3p, and miR-627-5p (Figure 4D). These results indicated that PVT1 up-regulated NOP2 by targeting several miRNAs.
NOP2 Promotes PCa Metastasis and Progression
To investigate the oncogenic role of NOP2 in PCa, it was overexpressed or down-regulated in DU 145 cells. RT-qPCR results showed that the levels of NOP2 were decreased by SH-NOP2 lentivirus transfection and increased by OE-NOP2 lentivirus transfection (Figure 5A). As for migration assays, scratch wound healing assay showed that SH-NOP2 lentivirus inhibited migration ability and OE-NOP2 lentivirus promoted migration ability of DU 145 cells (Figure 5B). Microscope observation showed that invasion ability of DU 145 cells was increased after treated with OE-NOP2 lentivirus and decreased after treated with SH-NOP2 lentivirus (Figure 5C). In vivo, low levels of NOP2 also resulted in significantly prolonged survival time and overexpressed NOP2 also resulted in poor prognosis (Figure 5D). These results showed that NOP2 promotes PCa metastasis and progression.
PVT1 Promoted PCa Metastasis by Up-Regulating NOP2
To investigate the specific mechanism of metastasis-promoting function of PVT1, we analyzed the correlation between PVT1 and NOP2. The results showed that PVT1 was positive correlated with NOP2 (Figure 6A). In vivo, over-expressed PVT1 induced poor prognosis and low levels of NOP2 resulted in significantly prolonged survival time. Knocking down NOP2 improved the bad results caused by PVT1 (Figure 6B). In vitro, OE-PVT1 lentivirus and/or SH-NOP2 lentivirus treated DU 145 cells. As for migration assays, scratch wound healing assay showed that OE-PVT1 lentivirus promoted migration ability and SH-NOP2 lentivirus blocked this phenomenon (Figure 6C). Microscope observation showed that invasion ability of DU 145 cells was increased after treated with OE-PVT1 lentivirus and SH-NOP2 lentivirus blocked this phenomenon (Figure 6D). Collectively, PVT1 promoted PCa metastasis by up-regulating NOP2.
Emerging data have shown that lncRNAs exert crucial influence in human ailment and cellular function. Dysregulation of lncRNAs may also lead to tumorigenesis and cancer drug resistance.15,16 We discovered that PVT1 is a novel PCa metastasis-related lncRNA, which is significantly upregulated in PCa tissues and cell lines. Higher expression of PVT1 was correlated with PCa distant metastasis. Moreover, elevated PVT1 expression was associated with shorter survival time. Experiments in vitro and in vivo indicated that the inhibition of PVT1 could restrain cell migration and cell invasion, whereas overexpression of PVT1 had the opposite effects. Collectively, these discoveries suggest the notion that PVT1 possesses a critical role in PCa oncogenesis and could be considered as a novel treatment target in PCa metastasis.
According to previous reports, there are novel and widespread interactive networks including ceRNAs, where lncRNAs could interact with protein-coding mRNAs in a miRNA-dependent manner.17 For instance, lncRNA HOTAIR functions as a promoter of PCa cell proliferation by acting as a ceRNA for miR-193a18. lncRNA CCAT1 promotes CRPC invasion and facilitates the expression of AR-regulated genes by acting as a ceRNA of miR-28-5p.19 In this study, we confirmed that PVT1 is localized in the cytoplasm and that it interacts with Ago2 in PCa cells, suggesting its potential role as an endogenous miRNA sponge. After searching various bioinformatical databases, we confirmed that miR-15b-5p, miR-27a-3p, miR-143-3p, and miR-627-5p are novel targets of PVT1.
Balu and colleagues have found that miR-15b-5p promotes breast cancer cell proliferation and metastasis by targeting HPSE2.20 In addition, upregulating the expression of miR-27a-3p indicates a poor prognosis in pancreatic carcinoma patients and promotes the angiogenesis and migration by epigenetic silencing of GATA6 and activating VEGFA/VEGFR2 signaling pathway.21 Furthermore, it has been shown that miR-143-3p targeting of ITGA6 suppresses tumor growth and angiogenesis by downregulating PLGF expression via the PI3K/AKT pathway in gallbladder carcinoma.22 In this study, we also found that miR-15b-5p, miR-27a-3p, miR-143-3p, and miR-627-5p were closely related with PVT1 and NOP2. It was indicated that miRNAs were important intermediate regulators in PVT1-NOP2 axis.
Generally, miRNA targets are an important part of ceRNA networks where lncRNAs can exert their biological function.23 Using reliable online predicting tools, we revealed that NOP2 is one of the potential targets of miR-15b-5p, miR-27a-3p, miR-143-3p, and miR-627-5p. RNA‐binding protein NOP2 can increase nucleolar activity and stimulate cell proliferation by influencing the cell cycle. In agreement with previous research reporting NOP2 in hepatocellular carcinoma,24 we found that NOP2 was highly expressed in CRPC tissues compared with the normal ones. PCa patients with higher levels of NOP2 demonstrate poorer OS. Furthermore, we showed that knockdown of NOP2 repressed PCa cell growth and induced cell death. Rescue experiments also confirmed that after knocking down NOP2, the inhibition effect induced by PVT1 overexpression was partially reversed.
In summary, lncRNA-PVT1 functions as a ceRNA that competitively binds to miR-15b-5p, miR-27a-3p, miR-143-3p and miR-627-5p, which then upregulates NOP2 and promotes PCa metastasis. The PVT1-NOP2 axis was shown to be involved in the development of PCa and targeting this pathway might have therapeutic potential for metastasis.
The authors declare that no conflicts of interest exist.
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