Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The homeodomain-containing transcription factor NKX3.1 is a putative prostate tumor suppressor that is expressed in a largely prostate-specific and androgen-regulated manner. Loss of NKX3.1 protein expression is common in human prostate carcinomas and prostatic intraepithelial neoplasia (PIN) lesions and correlates with tumor progression. Disruption of the murine Nkx3.1 gene results in defects in prostate branching morphogenesis, secretions, and growth. To more closely mimic the pattern of NKX3.1 loss that occurs in human prostate tumors, we have used Cre- and loxP-mediated recombination to delete the Nkx3.1 gene in the prostates of adult transgenic mice. Conditional deletion of one or both alleles of Nkx3.1 leads to the development of preinvasive lesions that resemble PIN. The pattern of expression of several biomarkers (Ki-67, E-cadherin, and high-molecular-weight cytokeratins) in these PIN lesions resembled that observed in human cases of PIN. Furthermore, PIN foci in mice with conditional deletion of a single Nkx3.1 allele lose expression of the wild-type allele. Our results support the role of NKX3.1 as a prostate tumor suppressor and indicate a role for this gene in tumor initiation.
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PMID:Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia. 1183 15

A cascade of epigenetic events contributes to the selective growth advantage of cancer cells during tumor progression. PMEPA1 gene is an androgen-inducible negative regulator of cell growth in the prostate epithelium. During prostate cancer progression PMEPA1 gene transcription is reduced or lost prompting us to investigate the role of epigenetic events in this process. In LAPC4 cells harboring wild type androgen receptor decitabine (5-aza-2'-deoxycitidine) treatment resulted in increased expression of PMEPA1 along with other androgen-inducible genes, suggesting a role for DNA methylation in the repression of androgenic cell growth control signals in prostate cancer. In contrast, mutant androgen receptor expressing LNCaP cells were deficient in this response. Therefore, decitabine-induced expression of cell growth controlling genes such as NKX3.1 or PMEPA1 underlines the clinical applicability of decitabine in prostate tumors harboring wild type androgen receptor. Further analysis of DNA methylation within the PMEPA1 promoter downstream sequences suggests that methylation of SP1 binding sites may also contribute to the repression of PMEPA1 gene.
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PMID:A role for DNA methylation in regulating the growth suppressor PMEPA1 gene in prostate cancer. 1817 52

SOX4 is a critical developmental transcription factor in vertebrates and is required for precise differentiation and proliferation in multiple tissues. In addition, SOX4 is overexpressed in many human malignancies, but the exact role of SOX4 in cancer progression is not well understood. Here, we have identified the direct transcriptional targets of SOX4 using a combination of genome-wide localization chromatin immunoprecipitation-chip analysis and transient overexpression followed by expression profiling in a prostate cancer model cell line. We have also used protein-binding microarrays to derive a novel SOX4-specific position-weight matrix and determined that SOX4 binding sites are enriched in SOX4-bound promoter regions. Direct transcriptional targets of SOX4 include several key cellular regulators, such as EGFR, HSP70, Tenascin C, Frizzled-5, Patched-1, and Delta-like 1. We also show that SOX4 targets 23 transcription factors, such as MLL, FOXA1, ZNF281, and NKX3-1. In addition, SOX4 directly regulates expression of three components of the RNA-induced silencing complex, namely Dicer, Argonaute 1, and RNA Helicase A. These data provide new insights into how SOX4 affects developmental signaling pathways and how these changes may influence cancer progression via regulation of gene networks involved in microRNA processing, transcriptional regulation, the TGFbeta, Wnt, Hedgehog, and Notch pathways, growth factor signaling, and tumor metastasis.
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PMID:Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells. 1914 88

The NKX3-1 gene is a homeobox gene required for prostate tumor progression, but how it functions is unclear. Here, using chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq) we showed that NKX3-1 colocalizes with the androgen receptor (AR) across the prostate cancer genome. We uncovered two distinct mechanisms by which NKX3-1 controls the AR transcriptional network in prostate cancer. First, NKX3-1 and AR directly regulate each other in a feed-forward regulatory loop. Second, NKX3-1 collaborates with AR and FoxA1 to mediate genes in advanced and recurrent prostate carcinoma. NKX3-1- and AR-coregulated genes include those found in the "protein trafficking" process, which integrates oncogenic signaling pathways. Moreover, we demonstrate that NKX3-1, AR, and FoxA1 promote prostate cancer cell survival by directly upregulating RAB3B, a member of the RAB GTPase family. Finally, we show that RAB3B is overexpressed in prostate cancer patients, suggesting that RAB3B together with AR, FoxA1, and NKX3-1 are important regulators of prostate cancer progression. Collectively, our work highlights a novel hierarchical transcriptional regulatory network between NKX3-1, AR, and the RAB GTPase signaling pathway that is critical for the genetic-molecular-phenotypic paradigm in androgen-dependent prostate cancer.
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PMID:Integration of regulatory networks by NKX3-1 promotes androgen-dependent prostate cancer survival. 2208 57

Prostate cancer (PCa) bone metastases have long been believed to be osteoblastic because of bone remodeling leading to the formation of new bone. However, recent studies have shown increased osteolytic activity in the beginning stages of PCa bone metastases, suggesting that targeting both osteolytic and osteoblastic mediators would likely inhibit bone remodeling and PCa bone metastasis. In this study, we found that PCa cells could stimulate differentiation of osteoclasts and osteoblasts through the up-regulation of RANKL, RUNX2 and osteopontin, promoting bone remodeling. Interestingly, we found that formulated isoflavone and 3,3'-diindolylmethane (BR-DIM) were able to inhibit the differentiation of osteoclasts and osteoblasts through the inhibition of cell signal transduction in RANKL, osteoblastic, and PCa cell signaling. Moreover, we found that isoflavone and BR-DIM down-regulated the expression of miR-92a, which is known to be associated with RANKL signaling, EMT and cancer progression. By pathway and network analysis, we also observed the regulatory effects of isoflavone and BR-DIM on multiple signaling pathways such as AR/PSA, NKX3-1/Akt/p27, MITF, etc. Therefore, isoflavone and BR-DIM with their multi-targeted effects could be useful for the prevention of PCa progression, especially by attenuating bone metastasis mechanisms.
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PMID:Targeting bone remodeling by isoflavone and 3,3'-diindolylmethane in the context of prostate cancer bone metastasis. 2241 75

We present a meta-analysis of somatic copy number alterations (CNAs) from 11 publications that examined 662 prostate cancer patient samples, which were derived from 546 primary and 116 advanced tumors. Normalization, segmentation, and identification of corresponding CNAs for meta-analysis was achieved using established commercial software. Unsupervised analysis identified five genomic subgroups in which approximately 90% of the samples were characterized by abnormal profiles with gains of 8q. The most common loss was 8p (NKX3.1). The CNA distribution in other genomic subgroups was characterized by losses at 2q, 3p, 5q, 6q, 13q, 16q, 17p, 18q, and PTEN (10q), and acquisition of 21q deletions associated with the TMPRSS2-ERG fusion rearrangement. Parallel analysis of advanced and primary tumors in the cohort indicated that genomic deletions of PTEN and the gene fusion were enriched in advanced disease. A supervised analysis of the PTEN deletion and the fusion gene showed that PTEN deletion was sufficient to impose higher levels of CNA. Moreover, the overall percentage of the genome altered was significantly higher when PTEN was deleted, suggesting that this important genomic subgroup was likely characterized by intrinsic chromosomal instability. Predicted alterations in expression levels of candidate genes in each of the recurrent CNA regions characteristic of each subgroup showed that signaling networks associated with cancer progression and genome stability were likely to be perturbed at the highest level in the PTEN deleted genomic subgroup.
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PMID:Recurrent copy number alterations in prostate cancer: an in silico meta-analysis of publicly available genomic data. 2543 80

The oxidative stress response is a cellular defense mechanism that protects cells from oxidative damage and cancer development. The exact molecular mechanism by which reactive oxygen species (ROS) contribute to DNA damage and increase genome instability in prostate cancer merits further investigation. Here, we aimed to determine the effects of NKX3.1 loss on antioxidant defense in response to acute and chronic inflammation in an in vitro model. Oxidative stress-induced DNA damage resulted in increased H2AX((S139)) phosphorylation (a hallmark of DNA damage), along with the degradation of the androgen receptor (AR), p53 and NKX3.1, upon treatment with conditioned medium (CM) obtained from activated macrophages or H2O2. Furthermore, the expression and stability of SIRT1 were increased by CM treatment but not by H2O2 treatment, although the level of ATM((S1981)) phosphorylation was not changed compared with controls. Moreover, the deregulated antioxidant response resulted in upregulation of the pro-oxidant QSCN6 and the antioxidant GPX2 and downregulation of the antioxidant GPX3 after CM treatment. Consistently, the intracellular ROS level increased after chronic treatment, leading to a dose-dependent increase in the ability of LNCaP cells to tolerate oxidative damage. These data suggest that the inflammatory microenvironment is a major factor contributing to DNA damage and the deregulation of the oxidative stress response, which may be the underlying cause of the increased genetic heterogeneity during prostate tumor progression.
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PMID:Inflammation contributes to NKX3.1 loss and augments DNA damage but does not alter the DNA damage response via increased SIRT1 expression. 2570 29

Genomic loss of chromosome (chr) 8p21 region, containing prostate-specific NKX3.1 gene, is a frequent alteration of the prostate cancer (PCa) oncogenome. We propose a novel, paradigm shifting hypothesis that this frequently deleted locus is also associated with a cluster of microRNA genes- miR-3622a/b- that are lost in PCa and play an important mechanistic role in progression and metastasis. In this study, we demonstrate the role of miR-3622b in prostate cancer. Expression analyses in a cohort of PCa clinical specimens and cell lines show that miR-3622b expression is frequently lost in prostate cancer. Low miR-3622b expression was found to be associated with tumor progression and poor biochemical recurrence-free survival. Further, our analyses suggest that miR-3622b expression is a promising prostate cancer diagnostic biomarker that exhibits 100% specificity and 66% sensitivity. Restoration of miR-3622b expression in PCa cell lines led to reduced cellular viability, proliferation, invasiveness, migration and increased apoptosis. miR-3622b overexpression in vivo induced regression of established prostate tumor xenografts pointing to its therapeutic potential. Further, we found that miR-3622b directly represses Epidermal Growth Factor Receptor (EGFR). In conclusion, our study suggests that miR-3622b plays a tumor suppressive role and is frequently downregulated in prostate cancer, leading to EGFR upregulation. Importantly, miR-3622b has associated diagnostic, prognostic and therapeutic potential. Considering the association of chr8p21 loss with poor prognosis, our findings are highly significant and support a novel concept that associates a long standing observation of frequent loss of a chromosomal region with a novel miRNA in prostate cancer.
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PMID:Novel tumor suppressor microRNA at frequently deleted chromosomal region 8p21 regulates epidermal growth factor receptor in prostate cancer. 2761 43

The lysine demethylase 3A (KDM3A, JMJD1A or JHDM2A) controls transcriptional networks in a variety of biological processes such as spermatogenesis, metabolism, stem cell activity, and tumor progression. We matched transcriptomic and ChIP-Seq profiles to decipher a genome-wide regulatory network of epigenetic control by KDM3A in prostate cancer cells. ChIP-Seq experiments monitoring histone 3 lysine 9 (H3K9) methylation marks show global histone demethylation effects of KDM3A. Combined assessment of histone demethylation events and gene expression changes presented major transcriptional activation suggesting that distinct oncogenic regulators may synergize with the epigenetic patterns by KDM3A. Pathway enrichment analysis of cells with KDM3A knockdown prioritized androgen signaling indicating that KDM3A plays a key role in regulating androgen receptor activity. Matched ChIP-Seq and knockdown experiments of KDM3A in combination with ChIP-Seq of the androgen receptor resulted in a gain of H3K9 methylation marks around androgen receptor binding sites of selected transcriptional targets in androgen signaling including positive regulation of KRT19, NKX3-1, KLK3, NDRG1, MAF, CREB3L4, MYC, INPP4B, PTK2B, MAPK1, MAP2K1, IGF1, E2F1, HSP90AA1, HIF1A, and ACSL3. The cancer systems biology analysis of KDM3A-dependent genes identifies an epigenetic and transcriptional network in androgen response, hypoxia, glycolysis, and lipid metabolism. Genome-wide ChIP-Seq data highlights specific gene targets and the ability of epigenetic master regulators to control oncogenic pathways and cancer progression.
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PMID:The histone demethylase KDM3A regulates the transcriptional program of the androgen receptor in prostate cancer cells. 2841 60

The most frequent alteration in the prostate oncogenome is loss of chromosome (chr) 8p21 that has been associated with loss of NKX3.1 homeobox gene. Chr8p21 deletions increase significantly with tumor grade and are associated with poor prognosis in prostate cancer (PCa), suggesting critical involvement of this region in tumor progression. Recent studies suggest that apart from NKX3.1, this region harbors alternative tumor suppressors that are yet undefined. We proposed a novel, paradigm shifting hypothesis that this locus is associated with a miRNA gene cluster-miR-3622a/b- that plays a crucial suppressive role in PCa. Here we demonstrate the crucial role of miR-3622a in prostate cancer epithelial-to-mesenchymal transition (EMT). MicroRNA expression profiling in microdissected human PCa clinical tissues showed that miR-3622a expression is widely downregulated and is significantly correlated with poor survival outcome and tumor progression. To understand the functional significance of miR-3622a, knockdown and overexpression was performed using non-transformed prostate epithelial and PCa cell lines, respectively, followed by functional assays. Our data demonstrate that endogenous miR-3622a expression is vital to maintain the epithelial state of normal and untransformed prostate cells. miR-3622a expression inhibits EMT, progression and metastasis of PCa in vitro and in vivo. Further, we found that miR-3622a directly targets EMT effectors ZEB1 and SNAI2. In view of these data, we propose that frequent loss of miR-3622a at chr8p21 region leads to induction of EMT states that in turn, promotes PCa progression and metastasis. This study has potentially significant implications in the field of prostate cancer as it identifies an important miRNA component of a frequently lost chromosomal region with critical roles in prostate carcinogenesis which is a highly significant step towards understanding the mechanistic involvement of this locus. Also, our study indicates that miR-3622a is a novel PCa biomarker and potential drug target for developing therapeutic regimens against advanced PCa.
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PMID:A novel microRNA regulator of prostate cancer epithelial-mesenchymal transition. 2849 63


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