1.Non-coding RNAs in castration-resistant prostate cancer.
National Journal of Andrology 2015;21(11):1014-1019
Non-coding RNAs (ncRNAs) are a large class of RNA molecules that do not encode proteins, regulate gene expressions multifacetedly, and influence the metabolism, proliferation, differentiation and apoptosis of cells as well as the occurrence and progression of tumors. Some of the ncRNAs act as cancer genes, such as miR-19a, miR-125b, miR-616, miR-7, miR-221, MALAT-1, and PRNCR1, which are upregulated in castration-resistant prostate cancer (CRPC) tissues or cell lines, and promote the development and progression of CRPC, some act as tumor suppressor genes, including miR-185, miR-342, miR-15, miR-16, and miR-146, which are downregulated in CRPC tissues or cell lines and inhibit or delay the occurrence of CRPC, and still others, such as miR-7, miR-19a, miR-125b, miR-221, and MALAT-1, are differentially expressed in the serum or tissue and can be used as potential biomarkers for the early diagnosis and prognosis of CRPC. This article presents an overview on the roles of ncRNAs in the occurrence, progression, diagnosis, and prognosis of CRPC and advances in their studies.
Humans
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Male
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MicroRNAs
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genetics
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Prostatic Neoplasms, Castration-Resistant
;
genetics
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RNA, Untranslated
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genetics
2.Transcriptional repression by androgen receptor: roles in castration-resistant prostate cancer.
Galina GRITSINA ; Wei-Qiang GAO ; Jindan YU
Asian Journal of Andrology 2019;21(3):215-223
Androgen receptor (AR), a hormonal transcription factor, plays important roles during prostate cancer progression and is a key target for therapeutic interventions. While androgen-deprivation therapies are initially successful in regressing prostate tumors, the disease ultimately comes back as castration-resistant prostate cancer (CRPC) or at the late stage as neuroendocrine prostate cancer (NEPC). CRPC remains largely dependent on hyperactive AR signaling in the milieu of low androgen, while NEPC is negative of AR expression but positive of many AR-repressed genes. Recent technological advances in genome-wide analysis of transcription factor binding sites have revealed an unprecedented set of AR target genes. In addition to its well-known function in activating gene expression, AR is increasingly known to also act as a transcriptional repressor. Here, we review the molecular mechanisms by which AR represses gene expression. We also summarize AR-repressed genes that are aberrantly upregulated in CRPC and NEPC and represent promising targets for therapeutic intervention.
Epigenetic Repression
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Humans
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Male
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Prostatic Neoplasms, Castration-Resistant/genetics*
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Receptors, Androgen/genetics*
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Transcriptional Activation
3.Enzalutamide and olaparib synergistically suppress castration-resistant prostate cancer progression by promoting apoptosis through inhibiting nonhomologous end joining pathway.
Hui-Yu DONG ; Pan ZANG ; Mei-Ling BAO ; Tian-Ren ZHOU ; Chen-Bo NI ; Lei DING ; Xu-Song ZHAO ; Jie LI ; Chao LIANG
Asian Journal of Andrology 2023;25(6):687-694
Recent studies revealed the relationship among homologous recombination repair (HRR), androgen receptor (AR), and poly(adenosine diphosphate-ribose) polymerase (PARP); however, the synergy between anti-androgen enzalutamide (ENZ) and PARP inhibitor olaparib (OLA) remains unclear. Here, we showed that the synergistic effect of ENZ and OLA significantly reduced proliferation and induced apoptosis in AR-positive prostate cancer cell lines. Next-generation sequencing followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed the significant effects of ENZ plus OLA on nonhomologous end joining (NHEJ) and apoptosis pathways. ENZ combined with OLA synergistically inhibited the NHEJ pathway by repressing DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and X-ray repair cross complementing 4 (XRCC4). Moreover, our data showed that ENZ could enhance the response of prostate cancer cells to the combination therapy by reversing the anti-apoptotic effect of OLA through the downregulation of anti-apoptotic gene insulin-like growth factor 1 receptor ( IGF1R ) and the upregulation of pro-apoptotic gene death-associated protein kinase 1 ( DAPK1 ). Collectively, our results suggested that ENZ combined with OLA can promote prostate cancer cell apoptosis by multiple pathways other than inducing HRR defects, providing evidence for the combined use of ENZ and OLA in prostate cancer regardless of HRR gene mutation status.
Male
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Humans
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Prostatic Neoplasms, Castration-Resistant/genetics*
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Drug Resistance, Neoplasm/genetics*
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Cell Line, Tumor
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Receptors, Androgen/genetics*
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Nitriles
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Apoptosis
4.Lineage plasticity-mediated therapy resistance in prostate cancer.
Alexandra M BLEE ; Haojie HUANG
Asian Journal of Andrology 2019;21(3):241-248
Therapy resistance is a significant challenge for prostate cancer treatment in clinic. Although targeted therapies such as androgen deprivation and androgen receptor (AR) inhibition are effective initially, tumor cells eventually evade these strategies through multiple mechanisms. Lineage reprogramming in response to hormone therapy represents a key mechanism that is increasingly observed. The studies in this area have revealed specific combinations of alterations present in adenocarcinomas that provide cells with the ability to transdifferentiate and perpetuate AR-independent tumor growth after androgen-based therapies. Interestingly, several master regulators have been identified that drive plasticity, some of which also play key roles during development and differentiation of the cell lineages in the normal prostate. Thus, further study of each AR-independent tumor type and understanding underlying mechanisms are warranted to develop combinational therapies that combat lineage plasticity in prostate cancer.
Androgen Antagonists/therapeutic use*
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Androgen Receptor Antagonists/therapeutic use*
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Gene Expression Regulation, Neoplastic
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Humans
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Male
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Prostatic Neoplasms/genetics*
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Prostatic Neoplasms, Castration-Resistant/genetics*
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Receptors, Androgen/drug effects*
5.The regulatory pathways leading to stem-like cells underlie prostate cancer progression.
Chun-Jung LIN ; U-Ging LO ; Jer-Tsong HSIEH
Asian Journal of Andrology 2019;21(3):233-240
Prostate cancer (PCa) is the most common cause of malignancy in males and the third leading cause of cancer mortality in the United States. The standard care for primary PCa with local invasive disease mainly is surgery and radiation. For patients with distant metastases, androgen deprivation therapy (ADT) is a gold standard. Regardless of a favorable outcome of ADT, patients inevitably relapse to an end-stage castration-resistant prostate cancer (CRPC) leading to mortality. Therefore, revealing the mechanism and identifying cellular components driving aggressive PCa is critical for prognosis and therapeutic intervention. Cancer stem cell (CSC) phenotypes characterized as poor differentiation, cancer initiation with self-renewal capabilities, and therapeutic resistance are proposed to contribute to the onset of CRPC. In this review, we discuss the role of CSC in CRPC with the evidence of CSC phenotypes and the possible underlying mechanisms.
Androgen Antagonists/therapeutic use*
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Cell Differentiation/genetics*
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Disease Progression
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Humans
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Male
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Neoplastic Stem Cells/pathology*
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Prostatic Neoplasms/pathology*
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Prostatic Neoplasms, Castration-Resistant/pathology*
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Signal Transduction/genetics*
6.Identification of PTPRR and JAG1 as key genes in castration-resistant prostate cancer by integrated bioinformatics methods.
Ji-Li WANG ; Yan WANG ; Guo-Ping REN
Journal of Zhejiang University. Science. B 2020;21(3):246-255
To identify novel genes in castration-resistant prostate cancer (CRPC), we downloaded three microarray datasets containing CRPC and primary prostate cancer in Gene Expression Omnibus (GEO). R packages affy and limma were performed to identify differentially expressed genes (DEGs) between primary prostate cancer and CRPC. After that, we performed functional enrichment analysis including gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway. In addition, protein-protein interaction (PPI) analysis was used to search for hub genes. Finally, to validate the significance of these genes, we performed survival analysis. As a result, we identified 53 upregulated genes and 58 downregulated genes that changed in at least two datasets. Functional enrichment analysis showed significant changes in the positive regulation of osteoblast differentiation pathway and aldosterone-regulated sodium reabsorption pathway. PPI network identified hub genes like cortactin-binding protein 2 (CTTNBP2), Rho family guanosine triphosphatase (GTPase) 3 (RND3), protein tyrosine phosphatase receptor-type R (PTPRR), Jagged1 (JAG1), and lumican (LUM). Based on PPI network analysis and functional enrichment analysis, we identified two genes (PTPRR and JAG1) as key genes. Further survival analysis indicated a relationship between high expression of the two genes and poor prognosis of prostate cancer. In conclusion, PTPRR and JAG1 are key genes in the CRPC, which may serve as promising biomarkers of diagnosis and prognosis of CRPC.
Computational Biology/methods*
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Gene Ontology
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Humans
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Jagged-1 Protein/genetics*
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Male
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Prognosis
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Prostatic Neoplasms, Castration-Resistant/mortality*
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Protein Interaction Maps
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Receptor-Like Protein Tyrosine Phosphatases, Class 7/genetics*
7.Scaffold protein MAPK8IP2 expression is a robust prognostic factor in prostate cancer associated with AR signaling activity.
Jian HUANG ; Wang LIU ; Bi-Yun LIN ; Jean C LI ; Jane LU ; Ben-Yi LI
Asian Journal of Andrology 2023;25(2):198-207
Mitogen-activated protein kinase-8-interacting protein 2 (MAPK8IP2) is a scaffold protein that modulates MAPK signal cascades. Although MAPK pathways were heavily implicated in prostate cancer progression, the regulation of MAPK8IP2 expression in prostate cancer is not yet reported. We assessed MAPK8IP2 gene expression in prostate cancer related to disease progression and patient survival outcomes. MAPK8IP2 expression was analyzed using multiple genome-wide gene expression datasets derived from The Cancer Genome Atlas (TCGA) RNA-sequence project and complementary DNA (cDNA) microarrays. Multivariable Cox regressions and log-rank tests were used to analyze the overall survival outcome and progression-free interval. MAPK8IP2 protein expression was evaluated using the immunohistochemistry approach. The quantitative PCR and Western blot methods analyzed androgen-stimulated MAPK8IP2 expression in LNCaP cells. In primary prostate cancer tissues, MAPK8IP2 mRNA expression levels were significantly higher than those in the case-matched benign prostatic tissues. Increased MAPK8IP2 expression was strongly correlated with late tumor stages, lymph node invasion, residual tumors after surgery, higher Gleason scores, and preoperational serum prostate-specific antigen (PSA) levels. MAPK8IP2 upregulation was significantly associated with worse overall survival outcomes and progression-free intervals. In castration-resistant prostate cancers, MAPK8IP2 expression strongly correlated with androgen receptor (AR) signaling activity. In cell culture-based experiments, MAPK8IP2 expression was stimulated by androgens in AR-positive prostate cancer cells. However, MAPK8IP2 expression was blocked by AR antagonists only in androgen-sensitive LNCaP but not castration-resistant C4-2B and 22RV1 cells. These results indicate that MAPK8IP2 is a robust prognostic factor and therapeutic biomarker for prostate cancer. The potential role of MAPK8IP2 in the castration-resistant progression is under further investigation.
Male
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Humans
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Androgens/therapeutic use*
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Receptors, Androgen/genetics*
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Prognosis
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Mitogen-Activated Protein Kinase 8/therapeutic use*
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Cell Line, Tumor
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Prostatic Neoplasms/pathology*
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Prostatic Neoplasms, Castration-Resistant/drug therapy*
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Gene Expression Regulation, Neoplastic
8.Regulatory effect of Skp2 on the expression and transactivation of the androgen receptor in the progression of castration-resistant prostate cancer.
Yi-ting SONG ; Kai-jie WU ; Xin-yang WANG ; Yong-gang NA ; Chuan-min YIN
National Journal of Andrology 2016;22(2):122-127
OBJECTIVETo determine the expression of Skp2 in different prostate cancer (PCa) cell lines and tissues, and explore its influence on the androgen receptor (AR) signaling pathway and development of castration-resistant prostate cancer (CRPC).
METHODSThe expression levels of Skp2 and AR in different PCa cell lines were detected by Western blot. After knockdown of Skp2 in the C4-2 and 22RV1 cells transfected with shRNA, the expressions of AR and P27 were determined and the activity of ARR3-Luc measured by dual-luciferase reporter gene assay following treatment with dihydrotestosterone (DHT). The expressions of AR and Skp2 in human naïve PCa or CRPC specimens were detected by immunohistochemical staining followed by analysis of their differences and correlation.
RESULTSThe Skp2 protein expression level was significantly higher in the C4-2 or 22RV1 cells than in the LNCaP cells. DHT treatment increased the expression of Skp2 in the C4-2 cells, but knock-down of Skp2 significantly up-regulated the expression of the well-known downstream protein P27 and down-regulated that of AR. Consistently, DHT treatment increased the activity of ARR3-Luc, while knockdown of Skp2 remarkably decreased it in the C4-2 and 22RV1 cells (P < 0.05). In addition, significantly higher expressions of Skp2 and AR were observed in the CRPC than in the naïve specimens (P < 0.05), with a positive correlation between the two proteins (r = 0.658 1, P < 0.05).
CONCLUSIONSkp2 can enhance the expression and transcription activity of the AR protein in CRPC cells or tissues and is promising to be a critical molecular therapeutic target.
Androgens ; pharmacology ; Cell Line, Tumor ; Dihydrotestosterone ; pharmacology ; Disease Progression ; Gene Knockdown Techniques ; Humans ; Male ; Neoplasm Proteins ; genetics ; metabolism ; Prostatic Neoplasms, Castration-Resistant ; metabolism ; Receptors, Androgen ; genetics ; metabolism ; S-Phase Kinase-Associated Proteins ; physiology ; Transcriptional Activation ; Up-Regulation
9.Correlation between the expression of Pim-1 and androgen-deprivation therapy for prostate cancer.
Jiang WANG ; Chang-yi QUAN ; Wen-liang CHANG ; Zhi-qun SHANG ; Ning JIANG ; Bo LI ; Yuan-jie NIU
National Journal of Andrology 2015;21(9):775-781
OBJECTIVETo investigate the expression of the Pim-1 gene in the LNCaP cells of the animal model of orthotopically implanted prostate cancer by surgical castration simulating androgen-deprivation therapy.
METHODSWe equally allocated 32 male BALBc-nu mice into 4 groups, androgen-dependent prostate cancer (ADPC), androgen-deprivation therapy (ADT) , castration-resistant prostate cancer (CRPC) and blank control, and established the models of orthotopically implanted tumor using human prostate cancer LNCaP cells. We detected and ,compared the expressions of Pim-1, PSA, and androgen receptor (AR) in the tumor tissues of different groups by RT-PCR. qRT-PCR, ELSIA and immunohistochemistry.
RESULTSThe relative gray scales in the ADPC and CRPC groups were 0.59 ± 0.01 and 1.14 ± 0.02, with statistically significant differences from 0.62 ± 0.03 in the ADT group (P < 0.05), and the Δ Ct values of Pim-1 were 6.15 ± 0.34 and 4.56 ± 0.23 in the former two groups, also with significant differences from 5.11 ± 0.21 in the latter (P < 0.05). The results of 2-ΔΔ Ct relative quantification analysis showed that the amplification products of Pim-1 in the ADT and CRPC groups increased 2.05 and 3.01 times respectively that of the ADPC group. The concentration of PSA was significantly higher in the ADPC ([480 ± 25] pg/ml) and CRPC ([870 ± 23] pg/ml) than in the ADT ([170 ± 32] pg/ml) and blank control groups (0 µg/L) (P < 0.01). The mean optical densities of Pim-1 and AR proteins were 0.017 ± 0.002 and 0.032 ± 0.009 in the ADPC group and 0.024 ± 0.002 and 0.040 ± 0.011 in the CRPC group, both with significant differences from those in the ADT group (0.018 ± 0.001 and 0.019 ± 0.006) (P < 0.01).
CONCLUSIONPim-1 is highly expressed in nude mice with prostate cancer receiving androgen-deprivation therapy and plays an important role in the progression and metastasis of prostate cancer.
Androgen Antagonists ; therapeutic use ; Animals ; Disease Progression ; Gene Expression ; Heterografts ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasms, Hormone-Dependent ; metabolism ; Prostate-Specific Antigen ; metabolism ; Prostatic Neoplasms, Castration-Resistant ; genetics ; metabolism ; therapy ; Proto-Oncogene Proteins c-pim-1 ; metabolism ; Receptors, Androgen ; metabolism