scholarly journals Loss of microRNA-135b Enhances Bone Metastasis in Prostate Cancer and Predicts Aggressiveness in Human Prostate Samples

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6202
Author(s):  
Mireia Olivan ◽  
Marta Garcia ◽  
Leticia Suárez ◽  
Marc Guiu ◽  
Laura Gros ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Bone Growth ◽  
Target Genes ◽  
Molecular Heterogeneity ◽  
High Throughput Analysis ◽  
Percutaneous Injection ◽  
Migratory Capacity ◽  
Pc3 Cells

About 70% of advanced-stage prostate cancer (PCa) patients will experience bone metastasis, which severely affects patients’ quality of life and progresses to lethal PCa in most cases. Hence, understanding the molecular heterogeneity of PCa cell populations and the signaling pathways associated with bone tropism is crucial. For this purpose, we generated an animal model with high penetrance to metastasize to bone using an intracardiac percutaneous injection of PC3 cells to identify PCa metastasis-promoting factors. Using genomic high-throughput analysis we identified a miRNA signature involved in bone metastasis that also presents potential as a biomarker of PCa progression in human samples. In particular, the downregulation of miR-135b favored the incidence of bone metastases by significantly increasing PCa cells’ migratory capacity. Moreover, the PLAG1, JAKMIP2, PDGFA, and VTI1b target genes were identified as potential mediators of miR-135b’s role in the dissemination to bone. In this study, we provide a genomic signature involved in PCa bone growth, contributing to a better understanding of the mechanisms responsible for this process. In the future, our results could ultimately translate into promising new therapeutic targets for the treatment of lethal PCa.

Anticancer Activity of Sweroside Nanoparticles in Prostate Cancer Bone Metastasis in PC-3 Cells Involved in Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 17 (10) ◽  
pp. 1960-1971
Author(s):  
Sheng Huang ◽  
Changye Zou ◽  
Shangyan Xie ◽  
Bin Wang ◽  
Xitao LingHu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cell ◽  
Bone Metastasis ◽  
Cyclin D1 ◽  
Signaling Pathway ◽  
Colony Formation ◽  
Target Genes ◽  
Downstream Target ◽  
Sphere Formation ◽  
In Cells

Bone metastasis is a significant cause of morbidity and mortality in patients with prostate cancer (PCa). This study is aimed at illustrating the mechanism of sweroside-mediated regulation in bone metastasis in PCa cells. Owing to the limitations of antitumor drugs in terms of their physical and chemical properties, making them into nanomaterials can effectively improve drug stability and bioavailability. Apoptosis was assessed with flow cytometry using the annexin V/propidium iodide binding assay; proteins, including p53, P21, Bcl-2, and Bax; and induction of intracellular reactive oxygen species (ROS). Using colony formation assay, sphere formation assay, and the expression changes in CD133 and CD44, stem cell characteristics were assessed. Epithelial–mesenchymal transition (EMT) activity was accessed by levels of the expression changes of EMT-related markers, vimentin and E-cadherin. Wnt/β-catenin signaling pathway was examined to detect the levels of the expression changes of snail and β-catenin. PC-3 cells were treated with lithium chloride (LiCl), which is an agonist of Wnt/β-catenin signaling, and the levels of CD133, CD44, vimentin, E-cadherin, snail, and β-catenin were detected. T-cell factor/lymphocyte enhancer factor (TCF/LEF) activity in cells overexpressing β-catenin was used to detect the effects on β-catenin transcription, and the expression of c-myc, Cyclin D1, Survivin, and MMP-7 were used to detect Wnt downstream target genes. Our results suggest that sweroside induces apoptosis and intracellular ROS; upregulates apoptotic proteins; and suppresses proliferation, invasion, and migration, preventing stem cell characteristics, including sphere formation, colony formation, and CD133 and CD44 expressions. Furthermore, sweroside nanoparticles exerts inhibitory effects on β-catenin transcription by suppressing TTCF/LEF activity in cells overexpressing β-catenin and downregulation of the expression of Wnt downstream target genes, including c-myc, Cyclin D1, Survivin, and MMP-7. The potential therapeutic effect of sweroside nanoparticles on bone metastatis of PCa was suggested, by these findings.

scholarly journals Downregulation of miRNA-205 Expression and Biological Mechanism in Prostate Cancer Tumorigenesis and Bone Metastasis

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Yu Sun ◽  
Sheng-Hua Li ◽  
Ji-Wen Cheng ◽  
Gang Chen ◽  
Zhi-Guang Huang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Protein Level ◽  
Target Genes ◽  
Mrna Level ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Forest Plot ◽  
Biological Mechanism

Background. The expression and mechanism of microRNA-205 (miRNA-205) in prostate cancer (PCa) and its bone metastasis remain controversial. Materials and Methods. The expression and discriminating capability of miRNA-205 were assessed by drawing a forest plot and a summarized receiver operating characteristic (SROC) curve, using data available from 27 miRNA-array and miRNA-sequencing datasets. The miRNA-205 target genes were acquired from online prediction tools, differentially upregulated genes in PCa, and differentially expressed genes (DEGs) after miRNA-205 transfection into PCa cell lines. Functional enrichment analysis was conducted to explore the biological mechanism of miRNA-205 targets. Immunohistochemistry (IHC) was applied to verify the protein level of the hub gene. Results. The expression of miRNA-205 in the PCa group (1,461 samples) was significantly lower than that in the noncancer group (510 samples), and the downregulation of miRNA-205 showed excellent sensitivity and specificity in differentiating between the two groups. In bone metastatic PCa, the miRNA-205 level was further reduced than in nonbone metastatic PCa, and it showed a good capability in distinguishing between the two groups. In total, 153 miRNA-205 targets were screened through the three aforementioned methods. Based on the results of functional enrichment analysis, the targets of miRNA-205 were mainly enriched during chromosome segregation and phospholipid-translocating ATPase activity and in the spindle microtubule and the p53 signaling pathway. CDK1 had the highest connectivity in the PPI network analysis and was screened as one of the hub genes. A statistically significant negative correlation between miRNA-205 and CDK1 was observed. The expression of CDK1 in PCa samples was pronouncedly upregulated in terms of both the mRNA level and the protein level when compared with noncancer samples. Conclusion. miRNA-205 may play a vital role in PCa tumorigenesis and bone metastasis by targeting CDK1.

scholarly journals Estrogen Receptors β1 and β2 Have Opposing Roles in Regulating Proliferation and Bone Metastasis Genes in the Prostate Cancer Cell Line PC3

2012 ◽  
Vol 26 (12) ◽  
pp. 1991-2003 ◽  
Author(s):  
Prasenjit Dey ◽  
Philip Jonsson ◽  
Johan Hartman ◽  
Cecilia Williams ◽  
Anders Ström ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Prostate Cancer Cell ◽  
Mrna Level ◽  
Gleason Grade ◽  
Mrna Levels ◽  
Proliferation Markers ◽  
Pc3 Cells

Abstract The estrogen receptor (ER)β1 is successively lost during cancer progression, whereas its splice variant, ERβ2, is expressed in advanced prostate cancer. The latter form of cancer often metastasizes to bone, and we wanted to investigate whether the loss of ERβ1 and/or the expression of ERβ2 affect such signaling pathways in prostate cancer. Using PC3 and 22Rv1 prostate cancer cell lines that stably express ERβ1 or ERβ2, we found that the ERβ variants differentially regulate genes known to affect tumor behavior. We found that ERβ1 repressed the expression of the bone metastasis regulator Runx2 in PC3 cells. By contrast, RUNX2 expression was up-regulated at the mRNA level by ERβ2 in PC3 cells, whereas Slug was up-regulated by ERβ2 in both PC3 and 22Rv1 cells. In addition, the expression of Twist1, a factor whose expression strongly correlates with high Gleason grade prostate carcinoma, was increased by ERβ2. In agreement with the increased Twist1 expression, we found increased expression of Dickkopf homolog 1; Dickkopf homolog 1 is a factor that has been shown to increase the RANK ligand/osteoprotegerin ratio and enhance osteoclastogenesis, indicating that the expression of ERβ2 can cause osteolytic cancer. Furthermore, we found that only ERβ1 inhibited proliferation, whereas ERβ2 increased proliferation. The expression of the proliferation markers Cyclin E, c-Myc, and p45Skp2 was differentially affected by ERβ1 and ERβ2 expression. In addition, nuclear β-catenin protein and its mRNA levels were reduced by ERβ1 expression. In conclusion, we found that ERβ1 inhibited proliferation and factors known to be involved in bone metastasis, whereas ERβ2 increased proliferation and up-regulated factors involved in bone metastasis. Thus, in prostate cancer cells, ERβ2 has oncogenic abilities that are in strong contrast to the tumor-suppressing effects of ERβ1.

scholarly journals miR-145-5p Mimic Inhibits Bone Metastasis of Prostate Cancer Via the Regulation of Epithelial Mesenchymal Transition

2021 ◽  
Author(s):  
Bingfeng Luo ◽  
Yuan Yuan ◽  
Jian Hou ◽  
Guanming Kuang ◽  
Ping Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Wound Healing ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Western Blotting ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Western Blotting Analysis

Abstract Background: The bone is the most common site of distant metastasis in prostate cancer. However, treatments for the bone metastasis of prostate cancer remain unsatisfactory. MicroRNAs (miRNAs) are small noncoding RNAs that play a variety of critical roles in tumor development and progression. Studies have confirmed that miRNA mimics could regulate the response to therapy in many cancers. Methods: In this study, a set of forty-four miRNAs were reduced in prostate cancer patients with bone metastases by high-throughput sequencing analysis. Wound healing, transwell assays and western blotting analysis were used to explore the role of miRNA mimic in prostate cancer bone metastasis. Results: Further gene ontology and pathway analysis showed that these miRNAs target genes are mainly involved in cellular metabolic process, intracellular membrane-bounded organelle, as well as proteoglycans in cancer and focal adhesion. Therefore, these down-regulated miRNAs may play a key role for prostate cancer bone metastasis treatment, including hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-133a-3p, hsa-miR-222-5p, hsa-miR-204-3p, hsa-miR-145-5p, hsa-miR-3681-5p, hsa-miR-184, hsa-miR-144-3p, hsa-miR-204-5p, and hsa-miR-221-5p. To further investigate the role of these miRNA mimics on prostate cancer bone metastasis, miR-145-5p was randomly selected for validation. Bioinformatics analysis showed that miR-145-5p target genes significantly affected TGF-beta and adherens junction signaling pathway. Wound healing and transwell assays and western blotting analysis revealed that miR-145-5p mimic inhibited proliferation, migration and invasion. Importantly, miR-145-5p mimic increased the expression of E-cadherin and reduced the expression of matrix metalloproteinase 2 and 9. These results revealed that miR-145-5p mimic mediated epithelial mesenchymal transition. Meanwhile, miR-145-5p mimic enhanced the level of caspase 9, which is an important promoter of apoptosis. Conclusions: These results indicate that miR-145-5p mimic could inhibit the progress of prostate cancer bone metastasis via regulation of epithelial mesenchymal transition. In addition, miR-145-5p mimic could induce the apoptosis of prostate cancer cells with bone metastases. In summary, the miR-145-5p mimic is expected to become a novel strategy for the treatment of tumor metastasis.

scholarly journals The Role of S100A4 for Bone Metastasis in Prostate Cancer Cells

2020 ◽  
Author(s):  
Bongjun Kim ◽  
Haemin Kim ◽  
Suhan Jung ◽  
Jun-Oh Kwon ◽  
Min-Kyong Song ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Cell Surface Receptor ◽  
Prostate Cancer Cells ◽  
S100a4 Protein ◽  
Knock Down ◽  
Pc3 Cells

Abstract Background: Prostate cancers frequently metastasize to bone, where the best microenvironment for distant colonization is provided. Since osteotropic metastasis of prostate cancer is a critical determinant of patients’ survival, searches for preventive measures are ongoing in the field. Therefore, it is important to dissect the mechanisms of each step of bone metastasis, including the epithelial-mesenchymal transition (EMT) and cross-talk between metastatic niches and cancer cells.Methods: In this study, we established a highly bone-metastatic subline of human prostate cancer cells by selecting bone-homing population of PC3 cells after cardiac injection of eight-week-old male BALB/c-nude mice. Then we assessed the proliferation, EMT, and migration properties of the subline (mtPC3) cells in comparison with the parental PC3 cells. To investigate the role of S100A4, we performed gene knock-down by lentiviral transduction, or treated cells with recombinant S100A4 protein or a S100A4-neutralizing antibody. The effect of cancer cells on osteoclastogenesis was evaluated after treatment of pre-osteoclasts with conditioned medium (CM) from cancer cells.Results: The mtPC3 cells secreted a markedly high level of S100A4 protein and showed elevated cell proliferation and mesenchymal properties. The increased proliferation and EMT of mtPC3 cells was inhibited by S100A4 knock-down, but was not affected by exogenous S100A4. Furthermore, S100A4 released from mtPC3 cells stimulated osteoclast development via the cell surface receptor RAGE. Down-regulation or neutralization of S100A4 in the CM of mtPC3 cells attenuated cancer-induced osteoclastogenesis. Conclusion: Altogether, our results suggest that intracellular S100A4 promotes cell proliferation and EMT in tumor cells, and that secreted S100A4 activates osteoclastogenesis, contributing to osteolytic bone metastasis. Thus, S100A4 upregulation in cancer cells highly metastatic to bone might be a key element in regulating bone metastasis.

scholarly journals The role of S100A4 for bone metastasis in prostate cancer cells

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Bongjun Kim ◽  
Suhan Jung ◽  
Haemin Kim ◽  
Jun-Oh Kwon ◽  
Min-Kyoung Song ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Cell Surface Receptor ◽  
Prostate Cancer Cells ◽  
S100a4 Protein ◽  
Knock Down ◽  
Pc3 Cells

Abstract Background Prostate cancers frequently metastasize to bone, where the best microenvironment for distant colonization is provided. Since osteotropic metastasis of prostate cancer is a critical determinant of patients’ survival, searches for preventive measures are ongoing in the field. Therefore, it is important to dissect the mechanisms of each step of bone metastasis, including the epithelial-mesenchymal transition (EMT) and cross-talk between metastatic niches and cancer cells. Methods In this study, we established a highly bone-metastatic subline of human prostate cancer cells by selecting bone-homing population of PC3 cells after cardiac injection of eight-week-old male BALB/c-nude mice. Then we assessed the proliferation, EMT characteristics, and migration properties of the subline (mtPC3) cells in comparison with the parental PC3 cells. To investigate the role of S100A4, we performed gene knock-down by lentiviral transduction, or treated cells with recombinant S100A4 protein or a S100A4-neutralizing antibody. The effect of cancer cells on osteoclastogenesis was evaluated after treatment of pre-osteoclasts with conditioned medium (CM) from cancer cells. Results The mtPC3 cells secreted a markedly high level of S100A4 protein and showed elevated cell proliferation and mesenchymal properties. The increased proliferation and EMT traits of mtPC3 cells was inhibited by S100A4 knock-down, but was not affected by exogenous S100A4. Furthermore, S100A4 released from mtPC3 cells stimulated osteoclast development via the cell surface receptor RAGE. Down-regulation or neutralization of S100A4 in the CM of mtPC3 cells attenuated cancer-induced osteoclastogenesis. Conclusion Altogether, our results suggest that intracellular S100A4 promotes cell proliferation and EMT characteristics in tumor cells, and that secreted S100A4 activates osteoclastogenesis, contributing to osteolytic bone metastasis. Thus, S100A4 upregulation in cancer cells highly metastatic to bone might be a key element in regulating bone metastasis.

scholarly journals Fli-1 Activation through Targeted Promoter Activity Regulation Using a Novel 3’, 5’-diprenylated Chalcone Inhibits Growth and Metastasis of Prostate Cancer Cells

2020 ◽  
Vol 21 (6) ◽  
pp. 2216
Author(s):  
Youfen Ma ◽  
Bixue Xu ◽  
Jia Yu ◽  
Lirong Huang ◽  
Xiaoping Zeng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
B Cell Lymphoma ◽  
Migration And Invasion ◽  
Matrix Metalloproteinase 1 ◽  
Pc3 Cells

The friend leukemia integration 1 (Fli-1) gene is involved in the expression control of key genes in multiple pathogenic/physiological processes, including cell growth, differentiation, and apoptosis; this implies that Fli-1 is a strong candidate for drug development. In our previous study, a 3′,5′-diprenylated chalcone, (E)-1-(2-hydroxy-4-methoxy-3,5-diprenyl) phenyl-3-(3-pyridinyl)-propene-1-one (C10), was identified as a novel anti-prostate cancer (PCa) agent. Here, we investigated the molecular mechanisms underlying the anti-cancer effects of C10 on the growth, metastasis, and invasion of PC3 cells in vitro. Our results show that C10 exhibited a strong inhibitory effect on proliferation and metastasis of PC3 cells via several cellular and flow cytometric analyses. Further mechanism studies revealed that C10 likely serves as an Fli-1 agonist for regulating the expression of Fli-1 target genes including phosphatidylinositol 3-kinase (P110), murine double minute2 (MDM2), B-cell lymphoma-2 (Bcl-2), Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP-1), and globin transcription factor-1 (Gata-1) as well as the phosphorylation of extracellular-regulated protein kinases 1 (ERK1). Further, we confirmed that C10 can regulate the expressions of vascular endothelial growth factor 1 (VEGF-1), transforming growth factor-β2 (TGF-β2), intercellular cell adhesion molecule-1 (ICAM-1), p53, and matrix metalloproteinase 1 (MMP-1) genes associated with tumor apoptosis, migration, and invasion. Thus, C10 exhibits stronger anticancer activity with novel molecular targets and regulatory molecular mechanisms, indicating its great potency for development as a novel targeted anticancer drug.

scholarly journals Long Noncoding RNA HOXA11-AS and Transcription Factor HOXB13 Modulate the Expression of Bone Metastasis-Related Genes in Prostate Cancer

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 182
Author(s):  
Aya Misawa ◽  
Yukihiro Kondo ◽  
Hiroyuki Takei ◽  
Toshihiro Takizawa
Keyword(s):  
Prostate Cancer ◽  
Transcription Factor ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Noncoding Rna ◽  
Osteoblastic Cells ◽  
Prostate Cancer Cells ◽  
Upstream Regulator ◽  
Chemokine Ligand ◽  
Pc3 Cells

Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression, which play fundamental roles in cancer development. In this study, we found that homeobox A11 antisense RNA (HOXA11-AS), a highly expressed lncRNA in cell lines derived from prostate cancer bone metastases, promoted the cell invasion and proliferation of PC3 prostate cancer cells. Transcription factor homeobox B13 (HOXB13) was identified as an upstream regulator of HOXA11-AS.HOXA11-AS regulated bone metastasis-associated C-C motif chemokine ligand 2 (CCL2)/C-C chemokine receptor type 2 (CCR2) signaling in both PC3 prostate cancer cells and SaOS2 osteoblastic cells. The HOXB13/HOXA11-AS axis also regulated integrin subunits (ITGAV and ITGB1) specific to prostate cancer bone metastasis. HOXB13, in combination with HOXA11-AS, directly regulated the integrin-binding sialoprotein (IBSP) promoter. Furthermore, conditioned medium containing HOXA11-AS secreted from PC3 cells could induce the expression of CCL2 and IBSP in SaOS2 osteoblastic cells. These results suggest that prostate cancer HOXA11-AS and HOXB13 promote metastasis by regulation of CCL2/CCR2 cytokine and integrin signaling in autocrine and paracrine manners.

Distraction Osteogenesis in the Treatment of Craniofacial Anomalies: Applications and Outcomes

2020 ◽  
Vol 5 (6) ◽  
pp. 1469-1481 ◽  
Author(s):  
Joseph A. Napoli ◽  
Carrie E. Zimmerman ◽  
Linda D. Vallino
Keyword(s):  
Distraction Osteogenesis ◽  
Bone Growth ◽  
Upper Airway ◽  
Craniofacial Anomalies ◽  
Craniofacial Skeleton ◽  
Facial Skeleton ◽  
Psychosocial Impairment ◽  
And Function ◽  
Correct Structure

Purpose Craniofacial anomalies (CFA) often result in growth abnormalities of the facial skeleton adversely affecting function and appearance. The functional problems caused by the structural anomalies include upper airway obstruction, speech abnormalities, feeding difficulty, hearing deficits, dental/occlusal defects, and cognitive and psychosocial impairment. Managing disorders of the craniofacial skeleton has been improved by the technique known as distraction osteogenesis (DO). In DO, new bone growth is stimulated allowing bones to be lengthened without need for bone graft. The purpose of this clinical focus article is to describe the technique and clinical applications and outcomes of DO in CFA. Conclusion Distraction can be applied to various regions of the craniofacial skeleton to correct structure and function. The benefits of this procedure include improved airway, feeding, occlusion, speech, and appearance, resulting in a better quality of life for patients with CFA.

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