Correction: Humanized bone facilitates prostate cancer metastasis and recapitulates therapeutic effects of Zoledronic acid in vivo

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

Molecular Cancer ◽

10.1186/s12943-021-01480-x ◽

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.

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IN VIVO MODELS OF PROSTATE CANCER METASTASIS TO BONE

The Journal of Urology ◽

10.1097/01.ju.0000169133.82167.aa ◽

2005 ◽

Vol 174 (3) ◽

pp. 820-826 ◽

Cited By ~ 46

Author(s):

ARUN S. SINGH ◽

WILLIAM D. FIGG

Keyword(s):

Prostate Cancer ◽

Cancer Metastasis ◽

In Vivo Models ◽

Prostate Cancer Metastasis

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Humanized bone facilitates prostate cancer metastasis and recapitulates therapeutic effects of zoledronic acid in vivo

Bone Research ◽

10.1038/s41413-019-0072-9 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 7

Author(s):

Marietta Landgraf ◽

Christoph A. Lahr ◽

Alvaro Sanchez-Herrero ◽

Christoph Meinert ◽

Ali Shokoohmand ◽

...

Keyword(s):

Prostate Cancer ◽

Zoledronic Acid ◽

Bone Metastasis ◽

Mouse Model ◽

Cancer Metastasis ◽

New Drugs ◽

Therapeutic Effects ◽

Humanized Mouse ◽

Preclinical Research ◽

Humanized Mouse Model

Abstract Advanced prostate cancer (PCa) is known for its high prevalence to metastasize to bone, at which point it is considered incurable. Despite significant effort, there is no animal model capable of recapitulating the complexity of PCa bone metastasis. The humanized mouse model for PCa bone metastasis used in this study aims to provide a platform for the assessment of new drugs by recapitulating the human–human cell interactions relevant for disease development and progression. The humanized tissue-engineered bone construct (hTEBC) was created within NOD-scid IL2rgnull (NSG) mice and was used for the study of experimental PC3-Luc bone metastases. It was confirmed that PC3-Luc cells preferentially grew in the hTEBC compared with murine bone. The translational potential of the humanized mouse model for PCa bone metastasis was evaluated with two clinically approved osteoprotective therapies, the non-species-specific bisphosphonate zoledronic acid (ZA) or the human-specific antibody Denosumab, both targeting Receptor Activator of Nuclear Factor Kappa-Β Ligand. ZA, but not Denosumab, significantly decreased metastases in hTEBCs, but not murine femora. These results highlight the importance of humanized models for the preclinical research on PCa bone metastasis and indicate the potential of the bioengineered mouse model to closely mimic the metastatic cascade of PCa cells to human bone. Eventually, it will enable the development of new effective antimetastatic treatments.

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