Oncogene In Prostate Cancer Research Articles

Targeting the MALAT1 gene with the CRISPR/Cas9 technique in prostate cancer.

BackgroundThe MALAT1 lncRNA acts as an oncogene in Prostate cancer (PC); thus, it can be severe as a cancer biomarker.MethodsUsing bioinformatics datasets including (HTSeq-Counts, GDC, and TCGA) 5501 gene expression profiling specimens were gathered. Then, expression profiles and sample survival of lncRNA were investigated using COX regression analyses, ROC curve analysis. The Database for Annotation, Visualization, and Integrated Discovery was used to conduct GO and KEGG studies on the lncRNA-related PCGs. After MALAT1 Knockout via CRISPR/Cas9 technique, the MALAT1 expression was assessed in DU-145 cells. The deletion of the target fragment was examined by polymerase chain reaction (PCR). Also, the expression of apoptosis genes was investigated by qRT-PCR. The viability and cell proliferation were measured using the MTT assay. Cell migration capability was determined using the cell scratch assay. The results of qRT-PCR were assessed by the ΔΔCt method, and finally, statistical analysis was performed in SPSS software.ResultsA maximum of 451 lncRNAs were discovered to reflect different expressions between PC and non-carcinoma tissue samples, with 307 being upregulated and 144 being down-regulated. Thirty-six lncRNAs related to OS were carefully selected, which were then subjected to stepwise multivariate Cox regression analysis, with 2 lncRNAs (MALAT1, HOXB-AS3). MALAT1 is highly expressed in PC cells. MALAT1 Knockout in DU-145 cells increases apoptosis and prevents proliferation and migration, and DU-145 transfected cells were unable to migrate based on the scratch recovery test. Overall, data suggest that MALAT1 overexpression in PC helps metastasis and tumorigenesis. Also, MALAT1 knockout can be considered a therapeutic and diagnostic target in PC.ConclusionTargeting MALAT1 by CRISPR/Cas9 technique inhibit the cell proliferation and migration, and in addition induce apoptosis. Thus, MALAT1 can act as a tumor biomarker and therapeutic target.Supplementary InformationThe online version contains supplementary material available at 10.1186/s41021-022-00252-3.

FOXA1 regulates alternative splicing in prostate cancer.

SummaryDysregulation of alternative splicing in prostate cancer is linked to transcriptional programs activated by AR, ERG, FOXA1, and MYC. Here, we show that FOXA1 functions as the primary orchestrator of alternative splicing dysregulation across 500 primary and metastatic prostate cancer transcriptomes. We demonstrate that FOXA1 binds to the regulatory regions of splicing-related genes, including HNRNPK and SRSF1. By controlling trans-acting factor expression, FOXA1 exploits an “exon definition” mechanism calibrating alternative splicing toward dominant isoform production. This regulation especially impacts splicing factors themselves and leads to a reduction of nonsense-mediated decay (NMD)-targeted isoforms. Inclusion of the NMD-determinant FLNA exon 30 by FOXA1-controlled oncogene SRSF1 promotes cell growth in vitro and predicts disease recurrence. Overall, we report a role for FOXA1 in rewiring the alternative splicing landscape in prostate cancer through a cascade of events from chromatin access, to splicing factor regulation, and, finally, to alternative splicing of exons influencing patient survival.

Positive epigenetic regulation loop between AR and NSUN2 promotes prostate cancer progression.

BackgroundProstate cancer (PCa) is a major type of cancer in man worldwide. Androgen deprivation therapy (ADT) and the next‐generation androgen receptor (AR) pathway inhibitors have acquired great success in treating PCa. However, patients treated with ADT or AR targeted therapy are inevitably developing into castration‐resistant prostate cancer (CRPC) or becoming drug resistance. The role of mRNA 5‐methylcytosine (m5C) modification in cancers is largely unknown. This study aimed to explore the role of the m5C methyltransferase NSUN2 in Prostate cancer (PCa).MethodsThe expression of NSUN2 and its clinicopathological impact were evaluated in PCa cohorts. The effect of NSUN2 on the biological characteristics of PCa cells was investigated on the basis of gain‐offunction and loss‐of‐function analyses. Subcutaneous models further uncovered the role of NSUN2 in tumor growth. Epi‐transcriptome assays with RNA bisulfite sequencing (RNA‐BisSeq) analysis and in vitro enzyme reaction assays were performed to validate the targeted effect of NSUN2 on AR. AR‐binding sites in the NSUN2 promoter were investigated by ChIP and luciferase assays to uncover the interplay between NSUN2 and AR signaling. RIP‐qPCR and EMSA methods were performed to confirm that YBX1 binds to AR m5C sites.ResultsNSUN2 is highly expressed in PCa and predicts poor outcome. NSUN2 plays roles as a PCa oncogene both in vitro and in vivo. Depletion of NSUN2 results in decreased expression and activities of AR, including AR‐V7. Mechanistically, NSUN2 posttranscriptionally stabilized AR by cluster m5C modification in a m5CYBX1‐dependent manner. Strikingly, treatment with enzalutamide, an effective AR inhibitor, reduces NSUN2 expression and decreases the m5C modification level in prostate cancer cells. Finally, we found that AR transcriptionally regulates NSUN2.ConclusionNSUN2 stabilizes AR mRNA through cluster 5‐methylcytosine modification and activates a positive feedback loop to promote prostate cancer.

Verification of cell cycle-associated cyclin-dependent kinases facilitated prostate cancer progression by integrated bioinformatic analysis and experimental validation

IntroductionCell cycle-associated cyclin-dependent kinases (ccCDKs) are essential regulators known to control cell division and facilitate tumorigenesis and progression. However, there is currently no comprehensive study of distinct ccCDKs in prostate cancer (PCa). The purpose of this study was to determine the value of ccCDK expression in predicting the prognosis of patients with PCa and to identify the gene functions of ccCDK in PCa. MethodsThe UALCAN databases were analyzed to examine the expression of CDKs in prostate cancer. The Human Protein Atlas was used to verify the expression of CDKs online. Then, we assessed the prognostic values of CDKs using GEPIA. GeneMANIA and Metascape analyses were used to predict biological functions. We analyzed the mutation of CDKs by cBioPortal. The TIMER database was used to evaluate the correlation of CDKs and immune infiltration. The expression of CDKs in tissue was examined through quantitative real-time polymerase chain reaction. After that, we focused on CDK3 and identified the expression of CDK3 by immunohistochemistry and western blot. The functions of CDK3 in C4-2 cell proliferation were determined by CCK-8 assays. C4-2 cells were tested for their ability to invade and migrate through transwell and wound healing assays. ResultsThe results showed that CDK1/3/4/5/6/16 was expressed at relatively higher levels in PCa tissues than in normal tissues. Patients with low expression of CDK1/3/5/16 exhibited significantly better disease-free survival than those with high expression. ccCDKs were enriched in the IL-18 signaling pathway and correlated with the infiltration of immune cells in PCa. Moreover, our cohort study data verified that there were significantly higher expression of CDK1/3/5/16 in PCa tissues compared to benign prostate hyperplasia tissues, and CDK3 was remarkably associated with a shorter progression-free survival for biochemical recurrence in PCa patients. CDK3 was positively expressed in PCa cells and tissues, and functional experiments demonstrated that silencing CDK3 inhibited PCa cell proliferation, migration, and invasion. ConclusionsOur study provides new evidence of ccCDKS in promoting PCa progression and implies that CDK3 may serve as an oncogene in PCa and may be valuable in the prognosis of biochemical recurrence in PCa patients.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

PD07-09 MEIS PROTEINS INHIBIT HOXB13-DEPENDENT PROSTATE CANCER METASTASIS AND ANDROGEN RECEPTOR SIGNALING

You have accessJournal of UrologyCME1 May 2022PD07-09 MEIS PROTEINS INHIBIT HOXB13-DEPENDENT PROSTATE CANCER METASTASIS AND ANDROGEN RECEPTOR SIGNALING Srikanth Perike, Calvin VanOpstall, Mathias Morales, Sophia Lamperis, Steve Kregel, Ryan Brown, and Donald J. Vander Griend Srikanth PerikeSrikanth Perike More articles by this author , Calvin VanOpstallCalvin VanOpstall More articles by this author , Mathias MoralesMathias Morales More articles by this author , Sophia LamperisSophia Lamperis More articles by this author , Steve KregelSteve Kregel More articles by this author , Ryan BrownRyan Brown More articles by this author , and Donald J. Vander GriendDonald J. Vander Griend More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002526.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) is one of the most frequently diagnosed malignancies in men, and its incidence and mortality continue to be a significant clinical problem. Recent evidence from our lab identified MEIS1, an important HOX protein cofactor, as a potential tumor suppressor. Patients bearing MEIS1-positive prostate tumors were significantly less likely to have biochemical recurrence and metastasis compared to men bearing MEIS-negative tumors. Androgen receptor (AR), the major oncogene in PCa, has been shown to interact with HOXB13 to promote prostate cancer progression, but the function of MEIS proteins to antagonize AR/HOXB13 interactions are unknown. We hypothesize that MEIS1 proteins interact with HOXB13 to suppress cancer initiation and progression, and loss of MEIS1 expression in a portion of prostate tumors enables oncogenic AR/HOXB13 interactions. METHODS: We determined the impact of MEIS1 expression and dependency of HOXB13 on AR signaling using cell lines ectopically expressing MEIS1 and/or CRISPR-mediated HOXB13 deletion in both androgen-sensitive LAPC4 and castration-resistant CWR22Rv1 cells. Western blots, qPCR, Proximity Ligation Assay and co-IPs were performed to evaluate the relationship between expression of MEIS1, HOXB13 and AR. Hormonally-intact and castrated male nude mice were used to test the in vivo capability of MEIS1-mediated tumor xenograft formation and rate of tumor growth in the presence and absence of AR ligand. RNA sequencing and informatics analyses was performed on tumor xenografts to determine the global impact of MEIS expression on AR gene targeting in PCa. RESULTS: We found that AR expression was significantly increased when MEIS1 was ectopically expressed compared to controls and HOXB13 knock-out lines. Re-expression of MEIS1 enhanced the binding between HOXB13-MEIS and AR-MEIS, and reduced AR-HOXB13 interaction. In castrated mice, re-expression of MEIS1 significantly decreased the tumor formation and tumor growth rate compared to hormonally intact nude mice. Conversely, xenografts of HOXB13-knockout tumors showed an increased rate of tumor growth and tumor formation compared to MEIS1-expressing cells and controls in both hormonally intact and castrated nude mice. Our preliminary RNA-Seq analysis demonstrate that when MEIS is present, AR pathway activation in response to androgen was associated with increased differentiation and growth suppression. CONCLUSIONS: Our collective data supports our hypothesis that increased MEIS1 expression reduces the AR/HOXB13 interaction and increases the in vivo sensitivity to host castration; this suggests that MEIS-positive cells have decreased oncogenic AR signaling. Future RNA-Seq studies combined with AR ChIP-Seq data will enable us to identify the MEIS-AR targeted genes that are involved in AR pathway modulation that inhibit prostate cancer cell proliferation and suppress tumor progression. These data provide us a strong rationale to support the potential utility of MEIS proteins as predictive clinical biomarkers of metastatic progression. Source of Funding: Funding: This work was supported by the Urology Care Foundation Research Scholar Award sponsored by Chesapeake Urology Associates, DOD grant PC130587, and DOD grant PC180414 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e102 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Srikanth Perike More articles by this author Calvin VanOpstall More articles by this author Mathias Morales More articles by this author Sophia Lamperis More articles by this author Steve Kregel More articles by this author Ryan Brown More articles by this author Donald J. Vander Griend More articles by this author Expand All Advertisement PDF DownloadLoading ...

Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation.

Prostate cancer remains the second leading cause of cancer death among American men. Radiotherapy is a potentially curative treatment for localized prostate cancer, and failure to control localized disease contributes to the majority of prostate cancer deaths. Neuroendocrine differentiation (NED) in prostate cancer, a process by which prostate adenocarcinoma cells transdifferentiate into neuroendocrine-like (NE-like) cells, is an emerging mechanism of resistance to cancer therapies and contributes to disease progression. NED also occurs in response to treatment to promote the development of treatment-induced neuroendocrine prostate cancer (NEPC), a highly aggressive and terminal stage disease. We previously demonstrated that by mimicking clinical radiotherapy protocol, fractionated ionizing radiation (FIR) induces prostate cancer cells to undergo NED in vitro and in vivo. Here, we performed transcriptomic analysis and confirmed that FIR-induced NE-like cells share some features of clinical NEPC, suggesting that FIR-induced NED represents a clinically relevant model. Furthermore, we demonstrated that protein arginine methyltransferase 5 (PRMT5), a master epigenetic regulator of the DNA damage response and a putative oncogene in prostate cancer, along with its cofactors pICln and MEP50, mediate FIR-induced NED. Knockdown of PRMT5, pICln, or MEP50 during FIR-induced NED and sensitized prostate cancer cells to radiation. Significantly, PRMT5 knockdown in prostate cancer xenograft tumors in mice during FIR prevented NED, enhanced tumor killing, significantly reduced and delayed tumor recurrence, and prolonged overall survival. Collectively, our results demonstrate that PRMT5 promotes FIR-induced NED and suggests that targeting PRMT5 may be a novel and effective radiosensitization approach for prostate cancer radiotherapy.

Long Non-coding RNA AFAP1-AS1 Facilitates Prostate Cancer Progression by Regulating miR-15b/IGF1R Axis.

Prostate cancer (PCa) is a commonly diagnosed malignant cancer and is the second- highest cause of cancer death in men worldwide. Enzalutamide is the second-generation inhibitor of androgen receptor signaling and is the fundamental drug for the treatment of advanced PCa. However, the disease will eventually progress to metastatic castration-resistant prostate cancer (CRPC) and aggressive neuroendocrine prostate cancer (NEPC) because of androgen-deprivation therapy (ADT) resistance. The aim of the study was to investigate the role of long non-coding RNA (lncRNA) AFAP1-AS1 in ADT resistance. Quantitative real-time PCR analysis (qPCR) was used to assess the expression of AFAP1-AS1 in PCa cell lines and tissues. Cell proliferation and invasion were assessed after AFAP1-AS1 knockdown using Cell Counting Kit (CCK)-8 and Transwell assay, respectively. A dual-luciferase reporter gene assay was carried out to validate the regulatory relationship among AFAP1-AS1, microRNA (miR)-15b, and insulin-like growth factor1 receptor (IGF1R). AFAP1-AS1 level was markedly increased in castration-resistant C4-2 cells and NE-like cells (PC3, DU145, and NCI-H660), compared with androgen-sensitive LNCaP cells. Enzalutamide treatment increased the expression of AFAP1-AS1 in vitro and in vivo. Functionally, AFAP1-AS1 knockdown repressed tumor cell proliferation and invasion. Mechanistically, AFAP1-AS1 functioned as an oncogene in PCa through binding to miR-15b and destroying its tumor suppressor function. Finally, we identified that AFAP1-AS1 up-regulated IGF1R expression by competitively binding to miR-15b to de-repress IGF1R. AFAP1-AS1 facilitates PCa progression by regulating miR-15b/IGF1R axis, indicating that AFAP1-AS1 may serve as a diagnostic biomarker and therapeutic target for PCa.

PD44-06 MEIS PROTEINS INHIBIT HOXB13-DEPENDENT PROSTATE CANCER METASTASIS AND ANDROGEN RECEPTOR SIGNALING

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II (PD44)1 Sep 2021PD44-06 MEIS PROTEINS INHIBIT HOXB13-DEPENDENT PROSTATE CANCER METASTASIS AND ANDROGEN RECEPTOR SIGNALING Srikanth Perike, Calvin VanOpstall, Ryan Brown, Sophia Lamperis, and Donald J. Vander Griend Srikanth PerikeSrikanth Perike More articles by this author , Calvin VanOpstallCalvin VanOpstall More articles by this author , Ryan BrownRyan Brown More articles by this author , Sophia LamperisSophia Lamperis More articles by this author , and Donald J. Vander GriendDonald J. Vander Griend More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002058.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) is one of the most frequently diagnosed malignancies in men, and its incidence and mortality continue to be a significant clinical problem. Recent evidence from our lab identified MEIS1, an important HOX protein cofactor, as a potential tumor suppressor. Patients bearing MEIS1-positive prostate tumors were less likely to have biochemical recurrence and metastasis compared to men bearing MEIS-negative tumors. Androgen receptor (AR), the major oncogene in PCa, has been shown to interact with HOXB13 to promote prostate cancer progression, but the function of MEIS proteins to antagonize AR/HOXB13 interactions are unknown. We hypothesize that MEIS1 proteins interact with HOXB13 to suppress cancer initiation and progression, and loss of MEIS1 expression in a portion of prostate tumors enables oncogenic AR/HOXB13 interactions. METHODS: We determined the impact of MEIS1 expression and dependency of HOXB13 on AR signaling using cell lines ectopically expressing MEIS1 and/or CRISPR-mediated HOXB13 deletion in both androgen-sensitive LAPC4 and castration-resistant CWR22Rv1 cells. Western blots, qPCR, Proximity Ligation Assay and co-IPs were performed to evaluate the relationship among MEIS1, HOXB13 and AR. Hormonally-intact and castrated male nude mice were used to test the in vivo capability of MEIS1-mediated tumor formation and rate of tumor growth in the presence and absence of AR ligand. RESULTS: We found that AR expression was significantly increased when MEIS1 was ectopically expressed compared to controls and HOXB13 knock-out lines. Re-expression of MEIS1 enhanced the binding between HOXB13-MEIS and AR-MEIS, and reduced the AR-HOXB13 interaction. In castrated mice, re-expression of MEIS1 significantly decreased the tumor formation and tumor growth rate compared to hormonally intact nude mice. Conversely, xenografts of HOXB13-knockout tumors showed an increased rate of tumor growth and tumor formation compared to MEIS1-expressing cells and controls in both hormonally intact and castrated nude mice. CONCLUSIONS: Our collective data supports our hypothesis that increased MEIS1 expression reduces the AR/HOXB13 interaction and increases the in vivo sensitivity to host castration; this suggests that MEIS-positive cells have decreased oncogenic AR signaling. Future RNAseq studies will determine the global impact of MEIS expression on AR gene targeting in PCa and provide us a strong rationale to support the potential utility of MEIS proteins as predictive clinical biomarkers of metastatic progression. Source of Funding: This work was supported by the Urology Care Foundation Research Scholar Award sponsored by Chesapeake Urology Associates Sanford J. Siegel, MD Prostate Cancer Research Award, DOD grant PC130587, and DOD grant PC180414 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e739-e739 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Srikanth Perike More articles by this author Calvin VanOpstall More articles by this author Ryan Brown More articles by this author Sophia Lamperis More articles by this author Donald J. Vander Griend More articles by this author Expand All Advertisement Loading ...

Identification of ARHGEF38, NETO2, GOLM1, and SAPCD2 Associated With Prostate Cancer Progression by Bioinformatic Analysis and Experimental Validation.

Prostate cancer (PCa) represents one of the most prevalent types of cancers and is a large health burden for men. The pathogenic mechanisms of PCa still need further investigation. The aim of this study was to construct an effective signature to predict the prognosis of PCa patients and identify the biofunctions of signature-related genes. First, we screened differentially expressed genes (DEGs) between PCa and normal control tissues in The Cancer Genome Atlas (TCGA) and GSE46602 datasets, and we performed weighted gene co-expression network analysis (WGCNA) to determine gene modules correlated with tumors. In total, 124 differentially co-expressed genes were retained. Additionally, five genes (ARHGEF38, NETO2, PRSS21, GOLM1, and SAPCD2) were identified to develop the prognostic signature based on TCGA dataset. The five-gene risk score was verified as an independent prognostic indicator through multivariate Cox regression analyses. The expression of the five genes involved in the signature was detected in the Gene Expression Omnibus (GEO), Gene Expression Profiling Interactive Analysis (GEPIA), and Oncomine databases. In addition, we utilized DiseaseMeth 2.0 and MEXPRESS for further analysis and found that abnormal methylation patterns may be a potential mechanism for these five DEGs in PCa. Finally, we observed that these genes, except PRSS21, were highly expressed in tumor samples and PCa cells. Functional experiments revealed that silencing ARHGEF38, NETO2, GOLM1, and SAPCD2 suppressed the proliferation, migration, and invasiveness of PCa cells. In summary, this prognostic signature had significant clinical significance for treatment planning and prognostic evaluation of patients with PCa. Thus, ARHGEF38, NETO2, GOLM1, and SAPCD2 may serve as oncogenes in PCa.

Long non-coding RNA LINC01116 acts as an oncogene in prostate cancer cells through regulation of miR-744-5p/UBE2L3 axis

BackgroundLong non-coding RNA (lncRNA) has been confirmed to exert a critical effect on the progression of tumors, including prostate cancer. Previous literature has demonstrated LINC01116 involves in activities of multiple cancers. However, the underlying role of LINC01116 in prostate cancer remains unclear.MethodsqRT-PCR measured the expression of LINC01116 in prostate cancer cells. EdU experiment was used to detect cell proliferation. Transwell assays detected cell migration and invasion. Immunofluorescence staining and western blot assays were utilized to measure EMT progress. The binding relationship between RNAs was confirmed by a series of mechanism assays. In addition, rescue experiments were conducted to verify the relationship among RNAs.ResultsLINC01116 was found to be highly expressed in prostate cancer cells. Functional assays indicated that inhibition of LINC01116 could suppress cell proliferation, migration, invasion and EMT progress. Also, miR-744-5p was proven to bind with LINC01116. Moreover, UBE2L3 was verified as the target gene of miR-744-5p. In rescue assays, we discovered that inhibited miR-744-5p or overexpressed UBE2L3 could offset the suppressive influence of silencing LINC01116 on prostate cancer cells.ConclusionOur study suggested that lncRNA LINC01116 acted as an oncogene in prostate cancer and accelerated prostate cancer cell growth through regulating miR-744-5p/UBE2L3 axis.

Calcium-binding and coiled-coil domain 2 promotes the proliferation and suppresses apoptosis of prostate cancer cells.

Prostate cancer (PCa) is considered to be one of the most common tumors in men. Calcium-binding and coiled-coil domain 2 (CALCOCO2) is a known important xenophagy receptor, which mediates intracellular bacterial degradation. To the best of the authors' knowledge, the present study is the first to demonstrate that CALCOCO2 functions as an oncogene in PCa. The results of the current study indicated that CALCOCO2 knockdown suppressed cell proliferation and colony formation, whereas it promoted apoptosis of PCa cells. In addition, knockdown of CALCOCO2 in PCa cells reduced cyclin-E1 and increased p53 protein expression. Bioinformatics analysis revealed that CALCOCO2 was associated with 'autophagosome assembly', 'nucleophagy' and 'nucleic acid metabolic process' biological processes and interacted with sequestosome-1, microtubule-associated proteins 1A/1B light chain 3 (MAP1LC3)B, γ-aminobutyric acid receptor-associated protein, IκB kinase subunit γ and MAP1LC3C. Moreover, CALCOCO2 protein levels were indicated to be significantly increased in PCa samples compared with normal prostate tissues. These results suggested that CALCOCO2 may be of value as a diagnostic and therapeutic target in PCa.

A Novel Androgen-Induced lncRNA FAM83H-AS1 Promotes Prostate Cancer Progression via the miR-15a/CCNE2 Axis.

Prostate cancer (PCa) is one of the most common types of tumors among males worldwide. However, the roles of long noncoding RNAs (lncRNAs) in PCa remain unclear. This study shows that lncRNA FAM83H-AS1 is upregulated in prostate adenocarcinoma, bladder urothelial carcinoma, and kidney renal papillary cell carcinoma samples. Androgen receptor (AR) signaling plays the most important role in PCa tumorigenesis and development. In this study, the results validate that AR signaling is involved in upregulating FAM83H-AS1 expression in PCa cells. Loss-of-function assays demonstrate that FAM83H-AS1 acts as an oncogene in PCa by modulating cell proliferation, cell cycle, and migration. Bioinformatics analysis demonstrates that FAM83H-AS1 is remarkably related to the regulation of the cell cycle and DNA replication through affecting multiple regulators related to these pathways, such as CCNE2. Mechanically, we found that FAM83H-AS1 plays its roles through sponging miR-15a to promote CCNE2 expression. These findings indicate that FAM83H-AS1 is a novel diagnostic and therapeutic marker for PCa.

Long noncoding RNA SNHG14 acts as an oncogene in prostate cancer via targeting miR-613.

Since this article has been suspected of research misconduct and the corresponding authors did not respond to our request to prove originality of data and figures, "Long noncoding RNA SNHG14 acts as an oncogene in prostate cancer via targeting miR-613, by B. Sun, K.-B. Ke, D.-F. Liu, Q. Wang, Y.-N. Li, J.-H. Chen, J.-H. Zhang, published in Eur Rev Med Pharmacol Sci 2020; 24 (2): 633-638-DOI: 10.26355/eurrev_202001_20039-PMID: 32016964" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/20039.

Long non-coding RNA LINC00173 serves as sponge for miR-338-3p to promote prostate cancer progression via regulating Rab25.

Long non-coding RNA LINC00173 (LINC00173) has been shown to facilitate the progression of a number of malignancies. In this study, we aimed to investigate the function of LINC00173 on prostate cancer (PCa) and discover the potential regulatory mechanism. RT-PCR was used to determine the levels of LINC00173, miR-338-3p and Rab25 in PCa patients and cell lines. The clinical significance of LINC00173 was statistically analyzed in 124 PCa patients. CCK-8, colony formation, transwell, scratch wound, Ethynyldeoxyuridine (EdU) assays and flow cytometry assays were used to detect the proliferation, apoptosis, invasion and migration of PCa cells. The mechanism of LINC00173 action was explored through bioinformatics, RNA pull-down assays and Luciferase reporter assays. We observed that the expression of LINC00173 and Rab25 was distinctly upregulated in both PCa specimens and cell lines, while miR-338-3p expression was significantly down-regulated. High LINC00173 expression was associated with Gleason score, preoperative PSA level and reduced patient survivals. Functional assays revealed that knockdown of LINC00173 suppressed the proliferation, migration and invasion of PCa cells, and promoted apoptosis. Mechanistically, LINC00173 acted as a competitive endogenous RNA in PCa and increased Rab25 expressions via sponging miR-338-3p. Moreover, LINC00173 promoted PCa progression by interacting with miR-338-3p and Rab25. Our findings, for the first time, identified a novel PCa-related lncRNA, LINC00173 which might serve as an oncogene in PCa. The discovery of the LINC00173/miR-338-3p/Rab25 pathways provided new thinking for the treatments of PCa.

MiR-137-3p Modulates the Progression of Prostate Cancer by Regulating the JNK3/EZH2 Axis.

BackgroundProstate cancer (PCa) is one of the most common cancers in men worldwide. Early detection of prostate cancer by prostate-specific antigen (PSA) screening still has limitations. The discovery of new candidates is urgent and can provide insights into the mechanism involved in prostate cancer tumorigenesis.MethodsWe conducted a cross-sectional study involving prostate cancer cell lines and clinical samples. qPCR and IHC were used to evaluate the expression of miR-137-3p/JNK3/EZH2. Furthermore, cell growth, migration, invasion, cell cycle and apoptosis were analyzed to describe the function of this axis. Moreover, xenograft models, pathology platforms and TCGA data were generated to confirm the role of the miR-137-3p/JNK3/EZH2 axis.ResultsIn this study, we determined that miR-137-3p was significantly reduced in prostate cancer, and low expression of miR-137-3p was correlated with tumor stage . The overexpression of miR-137-3p suppressed cell proliferation, migration and invasion in prostate cancer by enhancing cell apoptosis. We also validated JNK3 (MAPK10) as a direct target gene of miR-137-3p. Down-regulation of JNK3 in prostate cancer also inhibited cell proliferation and invasion and promoted apoptosis. Moreover, JNK3 expression was up-regulated and negatively correlated with miR-137-3p in prostate cancer tissues. Furthermore, JNK3 modulated EZH2 expression, which is a key oncogene in prostate cancer. Survival data indicated that patients with high levels of JNK3 and EZH2 had a worse prognosis.ConclusionCollectively, the identification of miR-137-3p and the JNK3/EZH2 pathway might facilitate the development of biomarkers and therapeutic targets for prostate cancer.

NOL6, a new founding oncogene in human prostate cancer and targeted by miR-590-3p.

We identified a new human prostate cancer oncogene, nucleolar protein 6 (NOL6), and screened for microRNAs that interfere with its expression in prostate cancer cells. A NOL6 shRNA plasmid was constructed and packaged into lentivirus to infect PC-3 cells. The ability of cell proliferation was evaluated by cell counting and colony formation. Cell cycle progression and apoptosis of PC-3 cells were detected by flow cytometry. A retrieval database was used to screen possible target microRNAs, and the effect of target miRNA overexpression on PC-3 cells was observed. The results showed that after NOL6 gene knockdown, PC-3 cell mitosis was blocked, proliferation was decreased, and the number of apoptotic cells were increased. The microRNA, hsa-miR-590-3p, that can regulate the NOL6 gene expression was identified. Overexpression of miR-590-3p in PC-3 cells by synthetic mimics resulted in abnormal mitosis, decreased cell proliferation, and an increase in apoptosis. In summary, we identified NOL6 as a novel oncogene in the human prostate cancer PC-3 cell line. The miRNA miR-590-3p interferes with NOL6 expression making it a potential treatment for prostate cancer.

Ubiquitin-specific protease 14 promotes prostate cancer progression through deubiquitinating the transcriptional factor ATF2

Activating Transcription Factor 2 (ATF2) is a member of the ATF/CREB bZIP family of transcription factors and an oncogene in prostate cancer. ATF2 has been reported to be a critical substrate of the CUL3-SPOP-RBX1 E3 ubiquitin ligase complex and the recurrent somatic mutation of SPOP has been believed to be a key feature of prostate cancer. However, the deubiquitinating enzyme required for ATF2 stabilization is still unknown. Here, we show that ATF2 is associated with ubiquitin-specific protease 14 (USP14), which increased the protein abundance and transcriptional activity of ATF2. Pharmacologic inhibition or siRNA-mediated depletion of USP14 resulted in the decline and inactivation of ATF2. USP14 deubiquitinates and activates ATF2, resulting in enhanced prostate cancer cells proliferation both in vitro and in vivo. Importantly, silencing of ATF2 largely attuned USP14-mediated prostate cancer cells proliferation. Thus, our data revealed a critical role of USP1-ATF2 axis in the progress of prostate cancer and the inhibition of USP14 might be a promising strategy against prostate cancer.

The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness

Neuroblastoma is an aggressive childhood cancer arising from sympatho-adrenergic neuronal progenitors. The low survival rates for high-risk disease point to an urgent need for novel targeted therapeutic approaches. Detailed molecular characterization of the neuroblastoma genomic landscape indicates that ALK-activating mutations are present in 10% of primary tumours. Together with other mutations causing RAS/MAPK pathway activation, ALK mutations are also enriched in relapsed cases and ALK activation was shown to accelerate MYCN-driven tumour formation through hitherto unknown ALK-driven target genes. To gain further insight into how ALK contributes to neuroblastoma aggressiveness, we searched for known oncogenes in our previously reported ALK-driven gene signature. We identified ETV5, a bona fide oncogene in prostate cancer, as robustly upregulated in neuroblastoma cells harbouring ALK mutations, and show high ETV5 levels downstream of the RAS/MAPK axis. Increased ETV5 expression significantly impacted migration, invasion and colony formation in vitro, and ETV5 knockdown reduced proliferation in a murine xenograft model. We also established a gene signature associated with ETV5 knockdown that correlates with poor patient survival. Taken together, our data highlight ETV5 as an intrinsic component of oncogenic ALK-driven signalling through the MAPK axis and propose that ETV5 upregulation in neuroblastoma may contribute to tumour aggressiveness.

High expression of citron kinase predicts poor prognosis of prostate cancer.

Citron kinase (CIT) is a Rho-effector protein kinase that is associated with several types of cancer. However, the role of CIT in prostate cancer (PCa) is unclear. The current study utilized microarray data obtained from The Cancer Genome Atlas, which was analyzed via Biometric Research Program array tools. Additionally, reverse transcription-quantitative (RT-q)PCR was performed to compare the mRNA expression of CIT in PCa tissue and in benign prostatic hyperplasia. The protein expression of CIT was detected in a consecutive cohort via immunochemistry and CIT was screened as a potential oncogene in PCa. The results of RT-qPCR demonstrated that the mRNA expression of CIT was increased in PCa tissues. Furthermore, immunochemistry revealed that CIT protein expression was positively associated with age at diagnosis, Gleason grade, serum PSA, clinical T stage, risk group, lymph node invasion and metastasis. When compared with the low expression group, patients with a high CIT expression exhibited shorter survival rates, cancer specific mortalities (CSM) and biochemical recurrence (BCR). In addition, multivariate analysis revealed that CIT was a potential predictor of CSM and BCR. The results revealed that CIT is overexpressed during the malignant progression of PCa and may be a predictor of a poor patient prognosis.