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

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.

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

10.1101/2020.05.14.096867 ◽

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.

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

10.21203/rs.3.rs-78710/v1 ◽

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.

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

PLoS ONE ◽

10.1371/journal.pone.0040716 ◽

2012 ◽

Vol 7 (8) ◽

pp. e40716 ◽

Cited By ~ 48

Author(s):

Jingli Hao ◽

Michele C. Madigan ◽

Aparajita Khatri ◽

Carl A. Power ◽

Tzong-Tyng Hung ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Metastasis ◽

Prostate Cancer Metastasis

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A Small Molecule Agonist of EphA2 Receptor Tyrosine Kinase Inhibits Tumor Cell Migration In Vitro and Prostate Cancer Metastasis In Vivo

PLoS ONE ◽

10.1371/journal.pone.0042120 ◽

2012 ◽

Vol 7 (8) ◽

pp. e42120 ◽

Cited By ~ 77

Author(s):

Aaron Petty ◽

Eugene Myshkin ◽

Haina Qin ◽

Hong Guo ◽

Hui Miao ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Migration ◽

Tumor Cell ◽

Small Molecule ◽

Receptor Tyrosine Kinase ◽

Cancer Metastasis ◽

Tumor Cell Migration ◽

Prostate Cancer Metastasis

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Mechanobiological evaluation of prostate cancer metastasis to bone using an in vitro prostate cancer testbed

Journal of Biomechanics ◽

10.1016/j.jbiomech.2020.110142 ◽

2021 ◽

Vol 114 ◽

pp. 110142

Author(s):

MD Shahjahan Molla ◽

Dinesh R. Katti ◽

Kalpana S. Katti

Keyword(s):

Prostate Cancer ◽

Cancer Metastasis ◽

Prostate Cancer Metastasis

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

JBMR Plus ◽

10.1002/jbm4.10256 ◽

2019 ◽

Vol 4 (2) ◽

Cited By ~ 3

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

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CircDOCK1 promotes the tumorigenesis and cisplatin resistance of osteogenic sarcoma via the miR-339-3p/IGF1R axis

Molecular Cancer ◽

10.1186/s12943-021-01453-0 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Shenglong Li ◽

Fei Liu ◽

Ke Zheng ◽

Wei Wang ◽

Enduo Qiu ◽

...

Keyword(s):

Cell Lines ◽

Cisplatin Resistance ◽

Osteogenic Sarcoma ◽

Mg63 Cell ◽

Circular Rnas ◽

Rna Immunoprecipitation ◽

Cisplatin Sensitivity ◽

Regulatory Effects

Abstract Background Circular RNAs (circRNAs), a class of noncoding RNAs (ncRNAs), may modulate gene expression by binding to miRNAs. Additionally, recent studies show that circRNAs participate in some pathological processes. However, there is a large gap in the knowledge about circDOCK1 expression and its biological functions in osteogenic sarcoma (OS). Methods Differentially expressed circRNAs in OS cell lines and tissues were identified by circRNA microarray analysis and quantitative real-time PCR (qRT–PCR). To explore the actions of circDOCK1 in vivo and in vitro, circDOCK1 was knocked down or overexpressed. To assess the binding and regulatory associations among miR-339-3p, circDOCK1 and IGF1R, we performed rescue experiments, RNA immunoprecipitation (RIP), RNA pulldown assays and dual-luciferase assays. Moreover, we performed apoptosis assays to reveal the regulatory effects of the circDOCK1/miR-339-3p/IGF1R axis on cisplatin sensitivity. Results CircDOCK1 expression remained stable in the cytoplasm and was higher in OS tissues and cells than in the corresponding controls. Overexpression of circDOCK1 increased oncogenicity in vivo and malignant transformation in vitro. In the U2OS and MG63 cell lines, circDOCK1 modulated tumor progression by regulating IGF1R through sponging of miR-339-3p. Additionally, in the U2OS/DDP and MG63/DDP cell lines, cisplatin sensitivity was regulated by circDOCK1 via the miR-339-3p/IGF1R axis. Conclusions CircDOCK1 can promote progression and regulate cisplatin sensitivity in OS via the miR-339-3p/IGF1R axis. Thus, the circDOCK1/miR-339-3p/IGF1R axis may be a key mechanism and therapeutic target in OS.

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Prostate tumor-induced stromal reprogramming generates Tenascin C that promotes prostate cancer metastasis through YAP/TAZ inhibition

10.1101/2021.11.08.467778 ◽

2021 ◽

Author(s):

Sue-Hwa Lin ◽

Yu-Chen Lee ◽

Song-Chang Lin ◽

Guoyu Yu ◽

Ming Zhu ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Migration ◽

Cancer Metastasis ◽

Neutralizing Antibody ◽

Metastatic Potential ◽

In Vivo Studies ◽

Hybrid Cells ◽

Tenascin C

Metastatic prostate cancer (PCa) in bone induces bone-forming lesions that enhance PCa progression. How tumor-induced bone formation enhances PCa progression is not known. We have previously shown that PCa-induced bone originates from endothelial cells (EC) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition by tumor-secreted BMP4. Here, we show that EC-to-OSB transition leads to changes in the tumor microenvironment that increases the metastatic potential of PCa cells. We found that conditioned medium (CM) from EC-OSB hybrid cells increases the migration, invasion and survival of PC3-mm2 and C4-2B4 PCa cells. Quantitative mass spectrometry (iTRAQ) identified Tenascin C (TNC) as one of the major proteins secreted from EC-OSB hybrid cells. TNC expression in tumor-induced osteoblasts was confirmed by immunohistochemistry of MDA-PCa118b xenograft and human bone metastasis specimens. Mechanistically, BMP4 increases TNC expression in EC-OSB cells through the Smad1-Notch/Hey1 pathway. How TNC promotes PCa metastasis was next interrogated by in vitro and in vivo studies. In vitro studies showed that a TNC neutralizing antibody inhibits EC-OSB-CM-mediated PCa cell migration and survival. TNC knockdown decreased, while addition of recombinant TNC or TNC overexpression increased migration and anchorage-independent growth of PC3 or C4-2b cells. When injected orthotopically, PC3-mm2-shTNC clones decreased metastasis to bone, while C4-2b-TNC overexpressing cells increased metastasis to lymph nodes. TNC enhances PCa cell migration through α5β1 integrin-mediated YAP/TAZ inhibition. These studies elucidate that tumor-induced stromal reprogramming generates TNC that enhances PCa metastasis and suggest that TNC may be a target for PCa therapy.

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