scholarly journals RIPK2 Stabilizes c-Myc and is an Actionable Target for Inhibiting Prostate Cancer Metastasis

2020 ◽  
Author(s):  
Yiwu Yan ◽  
Bo Zhou ◽  
Chen Qian ◽  
Alex Vasquez ◽  
Avradip Chatterjee ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Drug Targets ◽  
Cancer Metastasis ◽  
Therapeutic Interventions ◽  
Interacting Protein ◽  
Prostate Cancer Metastasis ◽  
Prostate Cancers

AbstractDespite advances in diagnosis and treatment, metastatic prostate cancer remains incurable and is associated with high mortality rates. Thus, novel actionable drug targets are urgently needed for therapeutic interventions in advanced prostate cancer. Here we report receptor-interacting protein kinase 2 (RIPK2) as an actionable drug target for suppressing prostate cancer metastasis. RIPK2 is frequently amplified in lethal prostate cancers and its overexpression is associated with disease progression and aggressiveness. Genetic and pharmacological inhibition of RIPK2 significantly suppressed prostate cancer progression in vitro and metastasis in vivo. Multi-level proteomic analysis revealed that RIPK2 strongly regulates c-Myc protein stability and activity, largely by activating the MKK7/JNK/c-Myc phosphorylation pathway—a novel, non-canonical RIPK2 signaling pathway. Targeting RIPK2 inhibits this phosphorylation pathway, and thus promotes the degradation of c-Myc—a potent oncoprotein for which no drugs have been approved for clinical use yet. These results support targeting RIPK2 for personalized therapy in prostate cancer patients towards improving survival.

scholarly journals Hsa_circ_0003258 promotes prostate cancer metastasis by complexing with IGF2BP3 and sponging miR-653-5p

2022 ◽  
Vol 21 (1) ◽  
Author(s):  
Yu-Zhong Yu ◽  
Dao-Jun Lv ◽  
Chong Wang ◽  
Xian-Lu Song ◽  
Tao Xie ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Metastasis ◽  
Rho Gtpase ◽  
Underlying Mechanism ◽  
Circular Rnas ◽  
Rna Immunoprecipitation ◽  
Prostate Cancer Metastasis ◽  
Mesenchymal Transformation

Abstract Background More and more studies have shown that circular RNAs (circRNAs) play a critical regulatory role in many cancers. However, the potential molecular mechanism of circRNAs in prostate cancer (PCa) remains largely unknown. Methods Differentially expressed circRNAs were identified by RNA sequencing. The expression of hsa_circ_0003258 was evaluated using quantitative real-time PCR and RNA in situ hybridization. The impacts of hsa_circ_0003258 on the metastasis of PCa cells were investigated by a series of in vitro and in vivo assays. Lastly, the underlying mechanism of hsa_circ_0003258 was revealed by Western blot, biotin-labeled RNA pulldown, RNA immunoprecipitation, luciferase assays and rescue experiments. Results Increased expression of hsa_circ_0003258 was found in PCa tissues and was associated with advanced TNM stage and ISUP grade. Overexpression of hsa_circ_0003258 promoted PCa cell migration by inducing epithelial mesenchymal transformation (EMT) in vitro as well as tumor metastasis in vivo, while knockdown of hsa_circ_0003258 exerts the opposite effect. Mechanistically, hsa_circ_0003258 could elevate the expression of Rho GTPase activating protein 5 (ARHGAP5) via sponging miR-653-5p. In addition, hsa_circ_0003258 physically binds to insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) in the cytoplasm and enhanced HDAC4 mRNA stability, in which it activates ERK signalling pathway, then triggers EMT programming and finally accelerates the metastasis of PCa. Conclusions Upregulation of hsa_circ_0003258 drives tumor progression through both hsa_circ_0003258/miR-653-5p/ARHGAP5 axis and hsa_circ_0003258/IGF2BP3 /HDAC4 axis. Hsa_circ_0003258 may act as a promising biomarker for metastasis of PCa and an attractive target for PCa intervention.

scholarly journals Ephrin-A2 promotes prostate cancer metastasis by enhancing angiogenesis and promoting EMT

2020 ◽  
Author(s):  
Yao Zhao ◽  
Chenchen Cai ◽  
Lubing Shi ◽  
Jiwei Wang ◽  
Miaomiao Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
Prostate Cancer Cells ◽  
Eph Receptor ◽  
Prostate Cancer Metastasis

Abstract Background Ephrin-A2, a member of the Eph receptor subgroup, is used in diagnosing and determining the prognosis of prostate cancer. However, the role of ephrin-A2 in prostate cancer is still unclear. Methods We established stable clones overexpressing or silencing ephrin-A2 from prostate cancer cells. Then, CCK-8 was used in analyzing the proliferation ability of cells. CD31 staining was used in evaluating angiogenesis. Migration and invasion assay were conducted in vivo and in vitro. The expression of EMT-related markers was evaluated in prostate cancer cells through Western blotting. Results We revealed that the ectopic expression of ephrin-A2 in prostate cancer cells facilitated cell migration and invasion in vitro and promoted tumor metastasis and angiogenesis in vivo and that the silencing of ephrin-A2 completely reversed this effect. Although ephrin-A2 did not affect tumor cell proliferation in vitro, ephrin-A2 significantly promoted primary tumor growth in vivo. Furthermore, to determine the biological function of ephrin-A2, we assayed the expression of EMT-related markers in stable established cell lines. Results showed that the overexpression of ephrin-A2 in prostate cancer cells down-regulated the expression of epithelial markers (ZO-1, E-cadherin, and claudin-1) and up-regulated the expression of mesenchymal markers (N-cadherin, β-catenin, vimentin, Slug, and Snail), but the knocking out of ephrin-A2 opposed the effects on the expression of EMT markers. Conclusions These findings indicate that ephrin-A2 promotes prostate cancer metastasis by enhancing angiogenesis and promoting EMT and may be a potentially therapeutic target in metastatic prostate cancer.

scholarly journals In Vitro and In Vivo Prostate Cancer Metastasis and Chemoresistance Can Be Modulated by Expression of either CD44 or CD147

PLoS ONE ◽  
2012 ◽  
Vol 7 (8) ◽  
pp. e40716 ◽  
Author(s):  
Jingli Hao ◽  
Michele C. Madigan ◽  
Aparajita Khatri ◽  
Carl A. Power ◽  
Tzong-Tyng Hung ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Metastasis ◽  
Prostate Cancer Metastasis

scholarly journals m6A Methylation Regulators Are Predictive Biomarkers for Tumour Metastasis in Prostate Cancer

2020 ◽  
Author(s):  
Xiaobo Wu ◽  
Qianwen Ge ◽  
Chen Yang ◽  
Yishuo Wu ◽  
Mengbo Hu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Consensus Clustering ◽  
Prostate Cancer Progression ◽  
Prostate Cancer Metastasis ◽  
Prostate Cancers

Abstract BackgroundProstate cancer is one of the most common cancers in men. Usually, most prostate cancers are localized in initial diagnoses and grow slowly. Patients with localized prostate cancers have a nearly 100% 5-year survival rate; however, the 5-year survival rate of metastatic or progressive prostate cancer is still dismal. N6-methyladenosine (m6A) is the most common post-transcriptional mRNA modification and is dynamically regulated by m6A regulators. A few studies have shown that the abnormal expression of m6A regulators is significantly associated with cancer progression and immune cell infiltration, but the roles of these regulators in prostate cancer remain unclear. MethodsHere, we comprehensively examined the patterns of 21 m6A regulators across 494 prostate cancers and systematically correlated m6A regulators with prostate cancer progression and immune cell infiltration. Consensus clustering was utilized for the subtype identification of m6A regulators for prostate cancers. Each subtype signature genes were obtained by the pairwise differentially expressed genes. Featured pathways of m6A subtypes were predicted consequently. The m6A score was constructed to predict the m6A activation. The association of m6A score with patients’ survival, metastasis and immune cell infiltration were also investigated. ResultsWe identified three distinct clusters in prostate cancer based on the expression profiles of 21 m6A regulators by consensus clustering. The differential expression and pathway analyses on the three clusters uncovered the m6A regulators involved in metabolic processes and immune responses in prostate cancer. Moreover, we established an m6A score to perceive the m6A regulator activation for prostate cancer. The m6A score is significantly associated with Gleason scores and metastasis in prostate cancer. The predictive capacity of m6A score on prostate cancer metastasis was also validated in another independent cohort. ConclusionOur study revealed the critical role of m6A regulators in prostate cancer progression and m6A score is promising predictive biomarker for prostate cancer metastasis.

scholarly journals TFEB Promotes Prostate Cancer Progression via Regulating ABCA2-Dependent Lysosomal Biogenesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Xuejin Zhu ◽  
Yangjia Zhuo ◽  
Shulin Wu ◽  
Yanfei Chen ◽  
Jianheng Ye ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Macrophage Polarization ◽  
Clinical Value ◽  
Tissue Samples ◽  
Invasion And Migration

Transcription factor EB (TFEB), a member of the MiT family, is dysregulated in different cancers and exerts specific biological functions within the tumor microenvironment. Downregulation of TFEB induces macrophage polarization in the TME and promotes tumor progression. However, the biological role and clinical significance of TFEB in prostate cancer (PCa) remain unknown. This study aimed to identify the role of TFEB in PCa and its potential clinical value. We explored TFEB expression in PCa using public databases and verified its prognostic value using immunohistochemistry in PCa tissue samples. The results revealed that TFEB expression was up-regulated in PCa tissues and was associated with cancer metastasis. Next, overexpression of TFEB promoted PCa cell malignant behavior in in vivo and in vitro experiments. RNA-sequencing and bioinformatics analysis showed high expression of TFEB promoted lysosomal biogenesis and knockdown of TFEB expression decreased the number of lysosomes. Furthermore, the ATP-binding cassette transporter A2 (ABCA2) was identified as a target gene of TFEB, which was verified using the cleavage under targets and release using nuclease (CUT&RUN) assay and qRT-PCR. Silencing of ABCA2 reduced lysosomal biogenesis and decreased matrix metalloproteinases expression, which reduced PCa cell invasion and migration in the tumor microenvironment. Our study suggests that TFEB promotes PCa progression by regulating ABCA2 through lysosomal biogenesis and may serve as a prognostic factor or as a potential therapeutic target of PCa.

scholarly journals lncRNA NORAD Contributes to Colorectal Cancer Progression by Inhibition of miR-202-5p

2018 ◽  
Vol 26 (9) ◽  
pp. 1411-1418 ◽  
Author(s):  
Jie Zhang ◽  
Xiao-Yan Li ◽  
Ping Hu ◽  
Yuan-Sheng Ding
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Cancer Metastasis ◽  
Cellular Proliferation ◽  
Inhibitory Effect ◽  
Migration And Invasion ◽  
Competing Endogenous Rna

Previous study indicates that long noncoding RNA NORAD could serve as a competing endogenous RNA to pancreatic cancer metastasis. However, its role in colorectal cancer (CRC) needs to be investigated. In the present study, we found that the expression of NORAD was significantly upregulated in CRC tissues. Furthermore, the expression of NORAD was positively related with CRC metastasis and patients’ poor prognosis. Knockdown of NORAD markedly inhibited CRC cell proliferation, migration, and invasion but induced cell apoptosis in vitro. In vivo experiments also indicated an inhibitory effect of NORAD on tumor growth. Mechanistically, we found that NORAD served as a competing endogenous RNA for miR-202-5p. We found that there was an inverse relationship between the expression of NORAD and miR-202-5p in CRC tissues. Moreover, overexpression of miR-202-5p in SW480 and HCT116 cells significantly inhibited cellular proliferation, migration, and invasion. Taken together, our study demonstrated that the NORAD/miR-202-5p axis plays a pivotal function on CRC progression.

scholarly journals Prostate Cancer Phenotype Influences Bone Mineralization at Metastasis: A Study Using an In Vitro Prostate Cancer Metastasis Testbed

JBMR Plus ◽  
2019 ◽  
Vol 4 (2) ◽  
Author(s):  
MD Shahjahan Molla ◽  
Dinesh R Katti ◽  
Jairam Iswara ◽  
Renugopalakrishnan Venkatesan ◽  
Ramasamy Paulmurugan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Metastasis ◽  
Bone Mineralization ◽  
Prostate Cancer Metastasis ◽  
Cancer Phenotype

Molecular characterization of neuroendocrine prostate cancer (NEPC) and identification of new drug targets.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 19-19 ◽  
Author(s):  
H. Beltran ◽  
D. Rickman ◽  
K. Park ◽  
A. Sboner ◽  
T. Macdonald ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Drug Targets ◽  
Kinase Activity ◽  
Aurora Kinase ◽  
Large Cohort ◽  
Small Subset ◽  
Aurora Kinases ◽  
New Drug

19 Background: NEPC is an aggressive variant of prostate cancer that can arise de novo or from existing prostate adenocarcinoma (PCA). We sought to better understand the molecular transformation of NEPC and identify new drug targets. Methods: We used Next Generation RNA sequencing and oligonucleotide arrays to profile 7 NEPC, 30 PCA, 5 benign prostate (BEN), and validated findings on tumors from a large cohort of patients (30 NEPC, 118 PCA, 30 BEN) using IHC and FISH. Functional studies were performed using NCI-H660 (NEPC), VCaP and LnCaP (PCA), RWPE (BEN). Results: ERG rearrangement was present in 47% of NEPC, but ERG protein expression was absent and corresponded directly with lack of AR expression. 936/25932 genes were differentially expressed in NEPC versus PCA (P<0.001). Aurora kinases (AURKA, AURKB) and N-myc (MYCN) were overexpressed in NEPC (P<0.001) and AURKA and MYCN amplified. Using IHC and FISH, we validated these findings on a large cohort and found majority (>80%) of NEPC showed Aurora overexpression, 35% had AURKA and MYCN amplification. A small subset of PCA (5%) and no BEN were positive. Transfection of MYCN induced AURKA expression and kinase activity in vitro, and MYCN or AURKA could induce expression of neuroendocrine (NE) markers (SYP, NSE). After validating NCI-H660 as model of NEPC, we observed dramatic and enhanced in vitro and in vivo sensitivity to the Aurora kinase inhibitor PHA-739358 in NCI-H660 compared to minimal to no effect in LnCaP and VCaP. Phospho-H3 expression, a downstream marker of Aurora kinase activity, was inhibited in the treated NCI-H660 and not in PCA. Notably, NE marker expression was also suppressed in the treated NCI-H660 xenografts, again supporting a role of Aurora kinase in modulating the NE phenotype. Conclusions: There is likely clonal origin of NEPC from PCA (with ERG fusion positivity seen in both), but ERG expression is limited to PCA and driven by AR signaling. We discovered significant overexpression and gene amplification of Aurora kinases and N-myc in NEPC and a small subset of PCA, and evidence that that they cooperate and induce a NE phenotype in prostate cells. In vitro and in vivo data confirms that these are novel drug targets for NEPC. No significant financial relationships to disclose.

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