Prostate Cancer Migration Research Articles

MicroRNA‑195‑5p is associated with cell proliferation, migration and invasion in prostate cancer and targets MIB1.

Mind bomb 1 (MIB1) is a well-known E3 ubiquitin ligase. MicroRNAs (miRNAs/miRs) have been found to serve important functions in cancer cell physiology. However, the clinical significance and biological function of MIB1 and miRNAs in prostate cancer (PCa) are yet to be fully elucidated. The current study predicted the interaction between MIB1 and miR-195-5p using TargetScan, and the results were confirmed by performing a dual-luciferase reporter assay. The mRNA expression level of MIB1 and miR-195-5p in PCa and adjacent normal tissues, and PCa cell lines was detected using reverse transcription-quantitative PCR. Cell Counting Kit-8 and Transwell assays were used to measure the proliferation, and migration and invasion of VCaP and DU145 PCa cell lines, respectively, while western blot analysis was used to detect the protein expression level of MIB1. The results revealed that the mRNA expression level of MIB1 was increased, while the mRNA expression level of miR-195-5p was decreased in PCa tissues (P<0.001 and P<0.01, respectively) and in various cell lines, including PC-3 (P<0.001 and P<0.05, respectively), VCaP (P<0.001 and P<0.01, respectively), 22Rv1 (P<0.001 and P<0.05, respectively), DU145 (P<0.001 and P<0.01, respectively) and LNCaP (P<0.001 and P<0.05, respectively). miR-195-5p mimics rescued the inhibitory effects caused by knockdown of MIB1 on cell proliferation, migration and invasion in the VCaP and DU145 cell lines. In addition, MIB1 overexpression restored the miR-195-5p overexpression-induced repression of cell proliferation and invasion. The current study revealed that the MIB1 gene was an effector of cell proliferation, migration and invasion in PCa cell lines. Furthermore, miR-195-5p may regulate PCa cell proliferation and invasion by regulating MIB1, indicating its potential therapeutic application for PCa in the future.

ZBTB38 suppresses prostate cancer cell proliferation and migration via directly promoting DKK1 expression

Prostate cancer is still one of the most common malignancies in men all around the world. The mechanism of how prostate cancer initiates and develops is still not clear. Here in this study, we show that tumor suppressor ZBTB38 could suppress the migration and proliferation of prostate cancer cells. We find lower ZBTB38 expression in prostate cancer tissues, which also strongly predicts a poorer prognosis of prostate cancer. ZBTB38 binds DKK1 (Dickkopf WNT signaling pathway inhibitor 1) locus and promotes DKK1 expression in prostate cancer cell lines. Consistently, reduction of DKK1 expression significantly restores ZBTB38-mediated suppression of migration and proliferation of prostate cancer cell lines. Mechanistically, we find that ZBTB38 primarily binds the promoters of target genes, and differentially regulates the expression of 1818 genes. We also identify PRKDC (protein kinase, DNA-activated, catalytic subunit) as a ZBTB38-interacting protein that could repress the function of ZBTB38 in suppressing migration and proliferation of prostate cancer cells. Taken together, our results indicate that ZBTB38 could repress cell migration and proliferation in prostate cancer via promoting DKK1 expression, and also provide evidence supporting ZBTB38 as a potential prognosis marker for prostate cancer.

Enzalutamide-Resistant Progression of Castration-Resistant Prostate Cancer Is Driven via the JAK2/STAT1-Dependent Pathway.

Previous studies showed that CXCR7 expression was upregulated after enzalutamide (ENZ) treatment, and an increased level of CXCR7 could increase the invasion, migration, and angiogenesis of castration-resistant prostate cancer (CRPC) cells. This study demonstrated that the levels of p-JAK2, p-STAT1, C-Myc, and VEGFR2 were significantly reduced after CCX771, a specific CXCR7 inhibitor, treatment. This effect further increased after the combination treatment of ENZ and CCX771. Then, we verified that targeting the inhibition of JAK2 or STAT1 could remarkably increase apoptosis and DNA damage and decrease the migration of CRPC cells. More importantly, the combination treatment of ENZ + JAK2/STAT1 led to much greater suppression than the single-agent treatment of JAK2 or STAT1. Subcutaneous CRPC xenograft tumor growth was also reduced by single-agent ENZ treatment and single-agent FLUD, a specific STAT1 antagonist, treatment; but much superior effect was elicited by the combination treatment of ENZ + FLUD. The proliferative indices significantly decreased following combination treatment in tumor tissues compared with control-treatment tissues and single-agent-treatment tissues. Our results demonstrated that CXCR7, which signifies an androgen receptor (AR)-independent signaling pathway, caused CRPC progression via the downstream JAK2/STAT1 signal transduction cascade. Combined inhibition targeting both the AR and JAK2/STAT1 resulted in substantial tumor suppression due to the reduction in DNA damage repair ability and increment in apoptosis.

SNHG10 Is a Prognostic Biomarker Correlated With Immune Infiltrates in Prostate Cancer.

SNHG10 is a long non-coding RNA (lncRNA) found to be overexpressed in multiple human cancers including prostate cancer (PC). However, the underlying mechanisms of SNHG10 driving the progression of PC remains unclear. In this study, we investigated the role of SNHG10 in PC and found that SNHG10 expression was significantly increased in datasets extracted from The Cancer Genome Atlas. Increased expression of SNHG10 was related to advanced clinical parameters. Receiver operating curve analysis revealed the significant diagnostic ability of SNHG10 (AUC = 0.805). In addition, immune infiltration analysis, and GSEA showed that SNHG10 expression was correlated with oxidative phosphorylation and immune infiltrated cells. Finally, we determined that SNHG10 regulated cell proliferation, migration, and invasion of PC in vitro. In conclusion, our data demonstrated that SNHG10 was correlated with progression and immune infiltration, and could serve as a prognostic biomarker for PC.

P4HA2-induced prolyl hydroxylation suppresses YAP1-mediated prostate cancer cell migration, invasion, and metastasis.

Yes-associated protein 1 (YAP1), a key player in the Hippo pathway, has been shown to play a critical role in tumor progression. However, the role of YAP1 in prostate cancer cell invasion, migration, and metastasis is not well defined. Through functional, transcriptomic, epigenomic, and proteomic analyses, we showed that prolyl hydroxylation of YAP1 plays a critical role in the suppression of cell migration, invasion, and metastasis in prostate cancer. Knockdown (KD) or knockout (KO) of YAP1 led to an increase in cell migration, invasion, and metastasis in prostate cancer cells. Microarray analysis showed that the EMT pathway was activated in Yap1-KD cells. ChIP-seq analysis showed that YAP1 target genes are enriched in pathways regulating cell migration. Mass spectrometry analysis identified P4H prolyl hydroxylase in the YAP1 complex and YAP1 was hydroxylated at multiple proline residues. Proline-to-alanine mutations of YAP1 isoform 3 identified proline 174 as a critical residue, and its hydroxylation suppressed cell migration, invasion, and metastasis. KO of P4ha2 led to an increase in cell migration and invasion, which was reversed upon Yap1 KD. Our study identified a novel regulatory mechanism of YAP1 by which P4HA2-dependent prolyl hydroxylation of YAP1 determines its transcriptional activities and its function in prostate cancer metastasis.

PLK1 downregulation by RO3280 prevents cell proliferation, migration, and invasion via the Wnt/β-catenin pathway in prostate cancer

IntroductionHigher expression levels of serine/threonine-protein kinase 1 (PLK1) are significantly associated with tumorigenesis and poor clinical prognoses. Consequently, PLK1 is considered a latent target in cancer treatment. We aimed to determine the cytotoxic effects of RO3280 on prostate cancer cells.Material and methodsPLK1 expression was investigated using real-time PCR and western blotting in prostate cancer tissues and paired normal tissues. Real-time cell analysis, cell counting kit-8 assays, and 5-ethynyl-2¢-deoxyuridine cell proliferation assays were applied for the examination of cell proliferation ability. Wound healing assays and transwell assays were used to assess the migratory and invasive abilities of the prostate cancer cell lines with or without RO3280 treatment. Moreover, the target genes and pathways were detected by transcriptomics RNA sequencing in the cells cultured in RO3280 and through a series of bioinformatics analyses. Finally, the Wnt/β-catenin pathway was screened out and verified by western blotting.ResultsWe observed the mRNA and protein overexpression of PLK1 in the prostate cancer cells and tissues. The inhibition of PLK1 by RO3280 significantly reduced the migratory, invasive, and proliferative properties of the RO3280-treated cancer cell lines compared with their controls. RO3280 mediated the inactivation of the Wnt/β-catenin pathway, and reduced the rates of cell proliferation, migration, and invasion in prostate cancer cells.ConclusionsThis study’s findings are significant owing to the identification of the specific anticancer mechanism of RO3280, which may have therapeutic effects. This trial provides clarity on the feasibility of the use of RO3280 as a cancer therapeutic agent for prostate cancer.

MiR‑184 delays cell proliferation, migration and invasion in prostate cancer by directly suppressing DLX1

A number of previous studies have reported that dysregulated miR-184 expression is associated with the development of cancer. The aim of the present study was to investigate the role of miR-184 in prostate cancer (PC) and the mechanism underlying its effects. Data from human tumor tissue samples were collected from The CEancer Genome Atlas to determine the expression levels of miR-184 and DLX1. The miR-184 mimic and pcDNA3.1-DLX1 plasmid were utilized to induce overexpression of miR-184 and DLX1 in Du145 cells, respectively. Cell Counting Kit-8, wound healing and Transwell assays were performed to examine the effects of miR-184 on the aggressiveness of PC cells. Dual-luciferase reporter gene assay was used to investigate the association between miR-184 and DLX1, and reverse transcription-quantitative PCR and western blot analyses were utilized to determine the mRNA and protein levels. miR-184 expression was found to be downregulated whereas DLX1 was upregulated in PC tissues compared with normal prostate tissues. Cell propagation, migration and invasion were all inhibited by miR-184 upregulation in Du145 cells. Dual luciferase reporter assay confirmed the association between miR-184 and DLX1. The inhibitory effect of miR-184 mimic on cell behaviors was reversed by upregulation of DLX1. These findings suggest that miR-184 plays a beneficial role in suppressing the tumorigenesis of PC by directly targeting DLX1, and it may represent a potential therapeutic strategy for PC.

Abstract 2293: Role of phosphatidylinositol 4-kinase IIIα in chemokine signaling

Abstract The CXCR4-CXCL12 chemokine signaling axis plays a key role in migration and bone metastasis in prostate cancer (PC). Androgens regulate CXCR4 expression and its receptor activation in lipid-raft micro domains of PC cells, resulting in higher protease expression and invasion. In order to identify some novel CXCR4 co-regulators associated within the lipid-raft, a SILAC (Stable isotope labeling using amino acid in cell culture)-based proteomic analysis was performed with PC3 stable cell-lines over-expressing or knocking-down CXCR4. Phosphatidylinositol 4-kinase III alpha (PI4KIIIα or PI4KA) and SAC1 lipid phosphatase were identified as candidate proteins enriched in CXCR4 expressing cells. PI4KA is an evolutionarily conserved mammalian kinase that converts PI to PI4P; and SAC1 dephosphorylates PI4P to PI. PI4K is required for the maintenance and functioning of the plasma-membrane and vesicular trafficking in the Golgi apparatus. PI4KA is also needed to maintain a steady pool of PI(4,5)P2 in the plasma-membrane, to be utilized in various signaling pathways. We show that CXCR4 interacts with PI4KA through its adaptor proteins EFR3B and TTC7B, recruiting it to the plasma-membrane for PI4P generation. Similarly PI4KA was closely linked to CXCR4 induced PC cell invasion, and knockdown of PI4KA in CXCR4 over-expressing PC3 cell lines reduced cell invasion. Also localized productions of PI4P was evident in invasive projections of CXCR4 over-expressing cell lines through immunofluorescence microscopy. PC tumor microarray data show increased PI4K expression in metastatic PC tissue vs localized or normal adjacent tissue. These data suggest a novel interaction between PI4KA and CXCR4, promoting tumor cell invasion and metastasis. Pharmacological targeting of PI4KA, its adaptor proteins or its signaling-related proteins might prove therapeutically beneficial and enhance survival in PC patients. Citation Format: Barani Govindarajan, Sreenivasa Chinni, Diego Sbrissa. Role of phosphatidylinositol 4-kinase IIIα in chemokine signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2293.

Abstract 2393: The systematic evaluation of the oncogenic lncRNA LINC00963 using a CRISPRScan technique

Abstract Long non-coding RNAs (LncRNAs) have been found to play important roles in maintaining and promoting cellular proliferation in cancerous cells. One such lncRNA, LINC00963 has been found to promote cellular proliferation, migration and tumorigenesis in prostate, ovarian, breast and non-small cell lung (NSCLC) cancer. In this study, we aim to identify important functional regions of this lncRNA with a view to identify unique regions for targeted drug therapy. In order to achieve this, we sought to investigate this lncRNA in the A549 NSCLC cell line. We found that LINC00963 was highly expressed and when targeted with either siRNAs or antisense oligonucleotides, cells rapidly undergo apoptosis. Using cell death as a proxy for loss-of-function, we characterized LINC00963 at the genomic level using a CRIPSRScan approach. CRISPRScan is a novel way of determining lncRNA functional domains through the introduction of local mutations. These mutations could potentially disrupt lncRNA function, which for LINC00963 would lead to apoptosis of the cell. We created a unique lentivirus library comprised of 1784 single guide RNAs spanning the length of LINC00963 in order to precisely identify regions of functional importance. Upon transduction in a stably expressing Cas9-A549 cell line, we collected cellular fractions over time, and using high-throughput sequencing (NextSeq, Illumina), evaluated the depletion of these sgRNAs as a proxy for their importance in LINC00963 function. The identification of these key genomic regions that may render LINC00963 non-functional may offer new lncRNA target sites for anti-cancer therapies in the future. Additionally, the utilization of an in-depth CRISPR-Cas9 approach to determine important lncRNA domains provides a novel and precise way in which to evaluate lncRNA function. Citation Format: Roslyn M. Ray, Lu Lang, Sheela P. Pokharel, Denis O'Meally, Tristan A. Scott, Chun-Wei Chen, Kevin V. Morris. The systematic evaluation of the oncogenic lncRNA LINC00963 using a CRISPRScan technique [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2393.

Twenty-year trends in prostate cancer stage and grade migration in a large contemporary german radical prostatectomy cohort.

A trend towards inverse stage migration in prostate cancer (PCa) was reported. However, previous analyses did not take into account potential differences in sampling strategies (number of biopsy cores), which might have confounded these reports. Within our single-institutional database we identified PCa patients treated with radical prostatectomy (RP) between 2000 and 2020 (n = 21,646). We calculated the estimated annual percentage change (EAPC) for D'Amico risk groups, biopsy Gleason Grade Group (GGG), PSA and cT stage as well as postoperative RP GGG and pT stage relying on log linear regression methodology. Subsequently, we repeated the analyses after adjustment for number of cores obtained at biopsy. Absolute rates of D'Amico low risk decreased (-30.1%), while intermediate and high risk increased (+21.2% and +9.0%, respectively). Rates of GGG I decreased (-50.0%), while GGG II-V increased, with the largest increase in GGG II (+22.5%). This trend, albeit less pronounced, was also recorded after adjusted EAPC analyses (p < .05). Specifically, EAPC values for D'Amico low vs intermediate vs high risk were -1.07%, +0.37%, +0.45%, respectively, and EAPC values for GGG ranged between -0.71% (GGG I) and +0.80% (GGG IV). Finally, an increase in ≥cT2 (EAPC: +3.16%) was displayed (all p < .001). These trends were confirmed in EAPC calculations in RP GGG and pT stages (p < .001). Our findings confirm the trend towards less frequent treatment of low risk PCa and more frequent treatment of high risk PCa, also after adjustment for number of biopsy cores.

Long ncRNA MALAT1 promotes cell proliferation, migration, and invasion in prostate cancer via sponging miR-145.

BackgroundThe long non-coding (lncRNA) RNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) is known to promote tumorigenesis, whereas microRNA-145 (miR-145) plays an antitumor role in several cancers. In this study, we aimed to elucidate the role of MALAT1 and miR-145 in prostate cancer cells and investigate the effect of MALAT1 downregulation on prostate cancer (PCa) cells in vitro in vivo.MethodsThe Cancer Genome Atlas (TCGA) datasets were used to carry out the initial bioinformatics analysis; the findings were then tested in LNCaP and CWR22Rv1 cell lines. Western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to evaluate the levels of MALAT1 and miR-145 along with related biomarkers. Furthermore, wound-healing and Transwell assays were performed to test the migratory and invasive abilities of PCa cells. Luciferase reporter assays were used to validate the relationship between MALAT1 and miR-145; their down-stream target genes were also studied. To further substantiate these findings in an animal model, tumor studies including immunofluorescence staining of tissues were carried in nude mice.ResultsThe expression of MALAT1 was upregulated in both LNCaP cell lines and CWR22Rv1 cell lines (F=2.882, t=13.370, P<0.001; F=2.268, t=15.859, P<0.001). Knockdown of MALAT1 reduced the migratory and invasive capabilities of PCa cells (F=0.017, t=12.212, P<0.001; F=10.723, t=6.016, P=0.002). Using direct binding, MALAT1 suppressed the antitumor function of miR-145, which in turn upregulated transforming growth factor-β1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) via SMAD3 and TGFBR2 (F=2.097, t=5.389, P=0.006; F=1.306, t=4.155, P=0.014).ConclusionsWe confirmed that MALAT1 acts as a competing endogenous RNA (ceRNA) of miR-145. The MALAT1 based regulation of MiR-145-5p-SMAD3/TGFBR2 interactions could be an intriguing molecular pathway for the progression of PCa.

MiR-217-5p Inhibits Invasion and Metastasis of Prostate Cancer by Targeting Clusterin.

Prostate cancer is not easy to metastasize because it is difficult to diagnose at an early stage, and there is no effective treatment currently. miRNA-217-5p has been reported to be a regulator in the process of prostate cancer. This study aimed to investigate how miRNA-217-5p affects the invasion and migration of prostate cancer. Luciferase assay was used to clarify whether the target gene Clusterin (CLU) was interacted directly with miR-217-5p. miR-217-5p and CLU were knocked down by transfecting respective siRNA into DU145 cells. The expression level of epithelial-mesenchymal transition (EMT)-related proteins was detected by Western blotting. Invasion and migration of DU145 cell were examined by wound healing assay. The results showed that miR-217-5p directly interacted with its target gene CLU, and the transfection of si-CLU and si-miR-217-5p had similar ability to regulate the expression level of EMT-related proteins, which in turn affected the migration and invasion of prostate cancer cell line DU145. In addition, miR-217-5p inhibited the expression of EMT-related proteins by regulating the expression of the target gene CLU, and further inhibited the invasion and migration of prostate cancer cells. Our findings provide a theoretical target basis for the treatment of prostate cancer.

Receptor Tyrosine Kinase‐like Orphan Receptor 1 (ROR1) as a Selective Molecular Target in Androgen‐Dependent and Androgen‐Independent Prostate Cancer

Prostate cancer is a disease that has a high prevalence and mortality amongst men. The severity of the cancer is stratified by risk, which is based on the Gleason grade, prostate-specific antigen (PSA) level, and clinical staging. Unlike breast cancer which can be classified into subtypes based on molecular heterogeneity, prostate cancer has no such classification and is therefore treated with non-specific chemotherapy and radiation if local, and androgen deprivation therapy (ADT) if metastatic. It is of the utmost importance to investigate molecular targets that can specifically eradicate prostate cancer while retaining the functions of normal tissue. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a receptor that is highly expressed in embryogenesis and cancer, while being minimally expressed in normal tissue. In particular, prostate cancer exhibits moderate to high levels of ROR1 expression. The goal of this study is to elucidate the role of ROR1 in aggressive prostate cancer and selectively target it for treatment. Our laboratory had previously characterized Strictinin, a ROR1 inhibitor, as being selectively cytotoxic against TNBC via inhibition of the ROR1 receptor. We hypothesize that Strictinin can reduce the proliferation and invasion of prostate cancer and may potentially serve as a specific therapeutic agent. Preliminary results indicate that Strictinin is selectively lethal to androgen-dependent and androgen-independent prostate cancer cell lines. Strictinin treatment reduced expression of proteins downstream of ROR1 implicated in promoting migration, invasion, and anti-apoptosis. Furthermore, Strictinin treatment decreased migration and invasion while inducing apoptosis in PC3 and LnCAP cell lines, providing evidence that inhibition of the ROR1 molecular pathway is linked to reduction of cancerous phenotypes. These preliminary results indicate that ROR1 could be a novel molecular target that can be utilized for subtyping and treating prostate cancer. The data from this study will establish Strictinin as a potential therapeutic that targets ROR1 to reduce migration, invasion, and survival of prostate cancer.

Inhibition of cancer cell-derived exosomal microRNA-183 suppresses cell growth and metastasis in prostate cancer by upregulating TPM1

BackgroundEmerging evidence continues to highlight the significant role of microRNAs (miRNAs) in the regulation of cancer growth and metastasis. Herein, the current study aimed to elucidate the role of exosomal miR-183 in prostate cancer development.MethodsInitially, public microarray-based gene expression profiling of prostate cancer was employed to identify differentially expressed miRNAs. The putative target gene TPM1 of miR-183 was subsequently predicted, followed by the application of a luciferase reporter assay and examination of the expression patterns in prostate cancer patients and cell lines. The effects of miR-183 and TPM1 on processes such as cell proliferation, invasion and migration were evaluated using in vitro gain- and loss-of-function experiments. The effect of PC3 cells-derived exosomal miR-183 was validated in LNCaP cells. In vivo experiments were also performed to examine the effect of miR-183 on prostate tumor growth.ResultsHigh expression of miR-183 accompanied with low expression of TPM1 was detected in prostate cancer. Our data indicated that miR-183 could target and downregulate TPM1, with the overexpression of miR-183 and exosomal miR-183 found to promote cell proliferation, migration, and invasion in prostate cancer. Furthermore, the tumor-promoting effect of exosome-mediated delivery of miR-183 was subsequently confirmed in a tumor xenograft model.ConclusionsTaken together, the key findings of our study demonstrate that prostate cancer cell-derived exosomal miR-183 enhance prostate cancer cell proliferation, invasion and migration via the downregulation of TPM1, highlighting a promising therapeutic target against prostate cancer.

Novel circular RNA circSOBP governs amoeboid migration through the regulation of the miR-141-3p/MYPT1/p-MLC2 axis in prostate cancer.

BackgroundMetastatic prostate cancer is a fatal disease despite multiple new approvals in recent years. Recent studies revealed that circular RNAs (circRNAs) can be involved in cancer metastasis. Defining the role of circRNAs in prostate cancer metastasis and discovering therapeutic targets that block cancer metastasis is of great significance for the treatment of prostate cancer.MethodsThe circSOBP levels in prostate cancer (PCa) were determined by qRT‐PCR. We evaluated the function of circSOBP using a transwell assay and nude mice lung metastasis models. Immunofluorescence assay and electron microscopic assay were applied to determine the phenotypes of prostate cancer cells’ migration. We used fluorescence in situ hybridization assay to determine the localization of RNAs. Dual luciferase and rescue assays were applied to verify the interactions between circSOBP, miR‐141‐3p, MYPT1, and phosphomyosin light chain (p‐MLC2).ResultsWe observed that circSOBP level was significantly lower in PCa specimens compared with adjacent noncancerous prostate specimens, and was correlated with the grade group of PCa. Overexpression of circSOBP suppressed PCa migration and invasion in vitro and metastasis in vivo. CircSOBP depletion increased migration and invasion and induced amoeboid migration of PCa cells. Mechanistically, circSOBP bound miR‐141‐3p and regulated the MYPT1/p‐MLC2 axis. Moreover, the depletion of MYPT1 reversed the inhibitory effect of circSOBP on the migration and invasion of PCa cells. Complementary intronic Alu elements induced but were not necessary for the formation of circSOBP. The nuclear export of circSOBP was mediated by URH49.ConclusionOur results suggest that circSOBP suppresses amoeboid migration of PCa cells and inhibits migration and invasion through sponging miR‐141‐3p and regulating the MYPT1/p‐MLC2 axis.

Loss of Speckle-Type POZ Protein Promotes Prostate Cancer Cell Migration and Invasion Through Upregulation of MCP-1.

BackgroundThe goal of this study is to verify that the loss of speckle-type POZ protein (SPOP) promotes the migration and invasion of prostate cancer cells, and that this process is brought about by an increase in MCP-1.Material/MethodsSPOP knockout C4-2 cells (C4-2 SPOP−/−) were verified by western blotting. Transwell and wound-healing assays were applied to verify different migration and invasion abilities between the C4-2 SPOP−/− and control cells. We used an antibody array to find different soluble chemokine factors in the C4-2 SPOP−/− cells. ELISA and qRT-PCR were applied for confirmation. To test MCP-1 function in conditioned medium, a transwell assay was applied with or without anti-MCP-1 antibody.ResultsThe western blot showed that SPOP was knocked out in sgSPOP-1 and sgSPOP-2 (different clones of C4-2 SPOP−/−). The transwell and wound-healing assays indicated that, compared with control cells, sgSPOP-1 and sgSPOP-2 had stronger migration and invasion abilities. The antibody array found that the expression of MCP-1 was upregulated in sgSPOP-1 and sgSPOP-2 conditioned medium. This result was verified by ELISA and qRT-PCR. In the prostate cancer cells, migration and invasion activity was greatly increased in C4-2 SPOP−/− conditioned medium, while this activity was decreased after anti-MCP-1 antibody neutralization.ConclusionsOur findings suggest that the loss of SPOP in C4-2 cells promotes increased cell migration and invasion abilities. This may be realized by upregulating the expression of MCP-1. The inhibition of MCP-1 expression may be an effective treatment for SPOP-mutant prostate cancer.

Long noncoding RNA TTN-AS1 promotes the proliferation and migration of prostate cancer by inhibiting miR-1271 level.

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 TTN-AS1 promotes the proliferation and migration of prostate cancer by inhibiting miR-1271 level, by Y. Zhu, Z. Yang, X.-H. Luo, P. Xu, published in Eur Rev Med Pharmacol Sci 2019; 23 (24): 10678-10684-DOI: 10.26355/eurrev_201912_19766-PMID: 31858535" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/19766.

Mechanism of WASP and WAVE family proteins in the progression of prostate cancer.

Prostate cancer (PCa) is the second most commonly diagnosed and third lethal cause of death from cancer in men worldwide. Despite the availability of vast treatment procedures, still the high occurrence of invasion and metastasis of PCa are reported in cancer patients. The WASP (Wiskott-Aldrich syndrome protein) and WAVE (WASP family verprolin homologous protein) family of proteins are actin cytoskeleton regulatory proteins, reported to enhance cancer cell invasion and migration in prostate cancer. Hence, this review sheds light on the studies that explored the potential role of WASP and WAVE family of proteins in invasion and metastasis of prostate cancer. The research articles explored for the completion of this review were mostly from PubMed and Google Scholar by using the appropriate keywords for indexing. The conserved function of WASP and WAVE protein family is to receive the upstream signals from the Rho GTPase family and transmit them to activate the Arp2/3 complex that leads to rapid actin polymerization at leading edge of cells, which is crucial for PCa metastasis. Therefore, targeting these proteins could reflect a very interesting therapeutic opportunity to combat prostate cancer.

Stage and Grade Migration in Prostate Cancer Treated With Radical Prostatectomy in a Large German Multicenter Cohort.

Overdiagnosis and overtherapy in prostate cancer (PCa) treatment should be avoided, which has led to an awareness of the need to decrease treatment in cases of low-risk PCa with radical prostatectomy (RP). Simultaneously, prostate-specific antigen testing has become less popular in the last few years, which has resulted in higher cancer grade and stage at diagnosis. We evaluated stage and grade migration in the disease of patients treated with RP in a large German cohort. Overall, 4842 patients undergoing RP between 2000 and 2019 were included. Age, prostate-specific antigen level, biopsy, and pathologic Gleason score as well as clinical and pathologic stage were collected. D'Amico risk groups and Gleason score were evaluated over different time points. We detected a significant grade migration toward higher grade. The proportion of biopsy Gleason sum≤ 6 dropped from 45.8% to 20.6% between≤ 2010 and 2017-2019. Further, the proportion of patients with low D'Amico risk scores also decreased by almost 50% (20.8% vs 12.2%). Finally, the proportion of non-organ-confined PCa increased over time, and the proportion of postoperative Gleason sum≤ 6 decreased from 20% to 10% over time. Taken together, data indicate a significant preoperative grade and stage migration toward disease of higher grade in RP-treated PCa. Between the years 2000 and 2019, the proportion of biopsy Gleason sum≤ 6 and the proportions of D'Amico low risk disease decreased by approximately 50% (respectively, 45% to 20% and 20.8% to 12.2%). This might indicate better patient selection for RP, but might also be a telltale sign of the rising mortality and morbidity of PCa.

Muscleblind-like 1 antisense RNA 1 inhibits cell proliferation, invasion, and migration of prostate cancer by sponging miR-181a-5p and regulating PTEN/PI3K/AKT/mTOR signaling

ABSTRACT The present study aimed to investigate the role and underlying mechanisms of long non-coding RNA (lncRNA) muscleblind-like 1 antisense RNA 1 (MBNL1-AS1) in the progression of Prostate cancer (PCa). MBNL1-AS1 and microRNA (miR)-181a-5p expression in PCa tissues and several human PCa cell lines were analyzed, respectively, using StarBasev3.0 project and RT-qPCR assay. After MBNL1-AS1 overexpression, cell proliferation, invasion and migration were, respectively, evaluated using CCK-8, colony formation, transwell and wound healing assays. Dual luciferase assay were used for analysis of the interactions among MBNL1-AS1, miR-181a-5p, and phosphatase and tensin homolog (PTEN). Subsequently, the expression of PTEN and proteins in PI3K/AKT/mTOR signaling was examined using western blot analysis after transfection with miR-181a-5p mimic. The rescue assays were performed to investigate the effects of MBNL1-AS1 and miR-181a-5p on the functions of PCa cells and the expression of PTEN/PI3K/AKT/mTOR signaling by co-transfection with MBNL1-AS1 plasmid and miR-181a-5p mimic. Results indicated that MBNL1-AS1 was conspicuously downregulated while miR-181a-5p upregulating in PCa tissues and cell lines. MBNL1-AS1 overexpression decreased the abilities of cell proliferation, invasion, and migration. Further study revealed that MBNL1-AS1 acted as a sponge for miR-181a-5p and positively regulated PTEN by a sponge effect. Additionally, rescue assays proved that the effect of MBNL1-AS1-upregulation on the proliferation, invasion, and migration of PCa cells was dependent on miR-181a-5p. Furthermore, miR-181a-5p overexpression counteracted the expression of PTEN and proteins in PI3K/AKT/mTOR signaling exerted by MBNL1-AS1-upregulation in PCa cells. This study suggests that MBNL1-AS1 inhibits the progression of PCa via sponging miR-181a-5p and regulating PTEN/PI3K/AKT/mTOR pathway.