Non-coding RNAs In Prostate Cancer Research Articles

Oncogenic Long Noncoding RNAs in Prostate Cancer, Osteosarcoma, and Metastasis

Prostate cancer (PC) is a common malignancy and is one of the leading causes of cancer-related death in men worldwide. Osteosarcoma (OS) is the most common bone cancer, representing 20-40% of all bone malignancy cases. Cancer metastasis is a process by which malignant tumor cells detach from the primary tumor site via a cascade of processes and migrate to secondary sites through the blood circulation or lymphatic system to colonize and form secondary tumors. PC has a specific affinity to the bone based on the "seed and soil" theory; once PC reach the bone, it becomes incurable. Several studies have identified long noncoding RNAs (lncRNAs) as potential targets for cancer therapy or as diagnostic and prognostic biomarkers. The dysregulation of various lncRNAs has been found in various cancer types, including PC, OS, and metastasis. However, the mechanisms underlying lncRNA oncogenic activity in tumor progression and metastasis are extremely complex and remain incompletely understood. Therefore, understanding oncogenic lncRNAs and their role in OS, PC, and metastasis and the underlying mechanism may help better manage and treat this malignancy. The aim of this review is to summarize current knowledge of oncogenic lncRNAs and their involvement in PC, OS, and bone metastasis.

Androgen Receptor-Related Non-coding RNAs in Prostate Cancer.

Prostate cancer (PCa) is the second leading cause of cancer-related death among men in the United States. Androgen receptor (AR) signaling is the dominant oncogenic pathway in PCa and the main strategy of PCa treatment is to control the AR activity. A large number of patients acquire resistance to Androgen deprivation therapy (ADT) due to AR aberrant activation, resulting in castration-resistant prostate cancer (CRPC). Understanding the molecular mechanisms underlying AR signaling in the PCa is critical to identify new therapeutic targets for PCa patients. The recent advances in high-throughput RNA sequencing (RNA-seq) techniques identified an increasing number of non-coding RNAs (ncRNAs) that play critical roles through various mechanisms in different diseases. Some ncRNAs have shown great potentials as biomarkers and therapeutic targets. Many ncRNAs have been investigated to regulate PCa through direct association with AR. In this review, we aim to comprehensively summarize recent findings of the functional roles and molecular mechanisms of AR-related ncRNAs as AR regulators or targets in the progression of PCa.

Long noncoding RNA LINC00963 induces NOP2 expression by sponging tumor suppressor miR-542-3p to promote metastasis in prostate cancer.

Metastatic disease caused by castration-resistant prostate cancer (CRPC) is the principal cause of prostate cancer (PCa)-related mortality. CRPC occurs within 2–3 years of initiation of androgen deprivation therapy (ADT), which is an important factor of influencing PCa metastasis. Recent studies have revealed that non-coding RNAs in PCa can enhance metastasis and progression, while the mechanisms are still unclear. In this study, we reported that the long noncoding RNA-LINC00963 was increased in CRPC tissues and promoted migration of PCa cells in vitro and their metastasis in vivo. High levels of LINC00963 significantly decreased tumor suppressor miR-542-3p, whose levels in metastasis tissues were low compared to those in non-metastasis tissues. LINC00963 promotes and miR-542-3p inhibits metastasis. Furthermore, the expression levels of LINC00963 and miR-542-3p were positively and negatively associated with the expression of NOP2. We demonstrated that NOP2 promoted PCa by activating the epithelial-mesenchymal transition (EMT) pathway. For specific mechanism, dual luciferase reporter assays showed that miR-542-3p directly binds to both 3'-untranslated region (UTR) of LINC00963 and NOP2 mRNA. Taken together, our results show that LINC00963 acts as an inducer of PCa metastasis by binding miR-542-3p, thereby promoting NOP2. This axis may have diagnostic and therapeutic potential for advanced PCa.

O20 - m6A-regulated long non-coding RNAs in prostate cancer

O20 - m6A-regulated long non-coding RNAs in prostate cancer

Long non-coding RNAs in prostate cancer: Functional roles and clinical implications.

Long noncoding RNAs (lncRNAs) are defined as RNA transcripts longer than 200 nucleotides that do not encode proteins. LncRNAs have been documented to exhibit aberrant expression in various types of cancer, including prostate cancer. Currently, screening for prostate cancer results in overdiagnosis. The consequent overtreatment of patients with indolent disease in the clinic is due to the lack of appropriately sensitive and specific biomarkers. Thus, the identification of lncRNAs as novel biomarkers and therapeutic targets for prostate cancer is promising. In the present review, we attempt to summarize the current knowledge of lncRNA expression patterns and mechanisms in prostate cancer. In particular, we focus on lncRNAs regulated by the androgen receptor and the specific molecular mechanism of lncRNAs in prostate cancer to provide a potential clinical therapeutic strategy for prostate cancer.

Long Non-coding RNAs in Prostate Cancer with Emphasis on Second Chromosome Locus Associated with Prostate-1 Expression.

Long non-coding RNAs (lncRNAs) are a class of RNA with transcripts longer than 200 nucleotides that lack functional open reading frames. They play various roles in human carcinoma, such as dysregulating gene expression in prostate cancer (PCa), which results in cancer initiation, development, and progression. The non-coding RNA SChLAP1 (second chromosome locus associated with prostate-1) is highly expressed in approximately 25% of PCas with higher prevalence in metastatic compared to localized PCa. Its expression is detectable non-invasively in PCa patient urine samples. Experimental data suggest that targeting SChLAP1 may represent a novel therapeutic application in PCa. This contribution focuses on the role of lncRNAs SChLAP1 expression in PCa diagnosis and prognosis.

The prognostic value of long noncoding RNAs in prostate cancer: a systematic review and meta-analysis.

The abnormally expressed LncRNAs played irreplaceable roles in the prognosis of prostate cancer (PCa). Therefore, we conducted this systematic review and meta-analysis to summarize the association between the expression of LncRNAs, prognosis and clinicopathology of PCa. 18 eligible studies were recruited into our analysis, including 18 on prognosis and 9 on clinicopathological features. Results indicated that aberrant expression of LncRNAs was significantly associated with biochemical recurrence-free survival (BCR-FS) (HR = 1.55, 95%CI: 1.01–2.37, P < 0.05), recurrence free survival (RSF) (HR = 3.07, 95%CI: 1.07–8.86, P < 0.05) and progression free survival (PFS) (HR = 2.34, 95%CI: 1.94–2.83, P < 0.001) in PCa patients. LncRNAs expression level was correlated with several vital clinical features, like tumor size (HR = 0.52, 95%CI: 0.28–0.95, P = 0.03), distance metastasis (HR = 4.55, 95%CI: 2.26–9.15, P < 0.0001) and histological grade (HR = 6.23, 95% CI: 3.29–11.82, P < 0.00001). Besides, down-regulation of PCAT14 was associated with the prognosis of PCa [over survival (HR = 0.77, 95%CI: 0.63–0.95, P = 0.01), BCR-FS (HR = 0.61, 95%CI: 0.48–0.79, P = 0.0001), prostate cancer-specific survival (HR = 0.64, 95%CI: 0.48–0.85, P = 0.002) and metastasis-free survival (HR = 0.61, 95%CI: 0.50-0.74, P < 0.00001)]. And, the increased SChLAP1 expression could imply the worse BCR-FS (HR = 2.54, 95%CI: 1.82-3.56, P < 0.00001) and correlate with Gleason score (< 7 vs ≥ 7) (OR = 4.11, 95% CI: 1.94-8.70, P = 0.0002). Conclusively, our present work demonstrated that LncRNAs transcription level might be potential prognostic markers in PCa.

Abstract B14: PVT1-derived non-coding RNAs in prostate cancer in men of African ancestry

Abstract Prostate cancer (PCa) is the most common non-skin cancer and the second leading cause of cancer-related death for men in the U.S. Males of African Ancestry (MoAA) have a higher incidence of PCa, compared to Caucasian males (CM). In fact, African ancestry is a confirmed, non-modifiable risk factor for PCa with a 2.5 fold greater risk of lethal PCa in MoAA compared to CM. Discovery of biomarkers with diagnostic, prognostic, and therapeutic applications are necessary to address this profound health disparity. The chromosomal region 8q24 is associated with aggressive PCa in MoAA and variants of this region have been identified to interact with the PVT1 non-coding gene in PCa. PVT1 is located at 8q24 and is transcribed into a long non-coding RNA that has been implicated in PCa. In previous work where we identified at least 12 exons of PVT1, we observed that exon 9 of PVT1 is significantly upregulated in aggressive PCa cell lines derived from MoAA and that silencing expression of PVT1 exon 9 induces apoptosis and cell cycle arrest in aggressive PCa cells derived from MoAA. PVT1 also encodes six annotated microRNAs and we have reported that one of them, miR-1207-3p, has prognostic value in PCa, is differentially expressed in the prostate tumor tissues of MoAA versus CM, and directly binds to the 3' UTR of Fibronectin type III domain containing 1 (FNDC1) to regulate a novel FNDC1/fibronectin (FN1)/androgen receptor (AR) pathway upregulated in metastatic PCa. To further identify racially differentiated cancer-risk factors in the PVT1 locus, we scanned for signatures of population differentiation and positive natural selection using the latest (Release GRCh38) full-genome variability panel from the 1000 Genomes Project. A string of 75 single-nucleotide polymorphisms (SNPs) in a 26-kb region spanning PVT1 exons 4A and 4B consistently show the highest level of genetic differentiation (Fst ~ 0.25) between the African and non-African populations. Nucleotide sequences in the 26-kb region fall into two major phylogenetic clades, including a clade present in all human populations (“Cosmopolitan Clade”), and another clade present nearly exclusively in non-African populations. To investigate the biological functions of the 26-kb element and its potential role in cancer, we examined the expression of PVT1 exons 4A and 4B in a panel of eight PCa cell lines modeling various clinical characteristics, and found that PVT1 exons 4A and 4B are overexpressed in PCa cell lines derived from aggressive PCa in MoAA. Functional studies upon silencing of PVT1 exons 4A and 4B showed an inhibition of cell proliferation when PVT1 exon 4B was silenced in aggressive PCa cells derived from MoAA. To discover all the molecular targets of miR-1207-3p, we designed and synthesized a novel synthetic biotinylated miR-1207-3p duplex and a novel synthetic biotinylated scramble duplex as control, and then we proceeded to validate these novel tools. Our data show that the novel synthetic biotinylated miR-1207-3p duplex directly binds to the 3' UTR of FNDC1 and inhibits the FNDC1/FN1/AR pathway. Wound healing assays revealed that our synthetic biotinylated miR-1207-3p duplex significantly inhibits cellular migration in PCa cells derived from MoAA by up to 40% when compared with the scramble duplex. Furthermore, Annexin V staining analysis demonstrated that our synthetic biotinylated miR-1207-3p duplex increased apoptosis by nearly 2-fold in PCa cells derived from MoAA compared to scramble duplex. These results show that our synthetic biotinylated miR-1207-3p duplex significantly inhibits migration and induces apoptosis. These data demonstrate the importance of PVT1-derived non-coding RNAs in PCa in MoAA, and provide the basis for larger studies to evaluate prognostic, diagnostic, and therapeutic applications of miR-1207-3p, PVT1 exon 9, PVT1 exon 4A and PVT1 exon 4B in PCa. Note: This abstract was not presented at the conference. Citation Format: Adeodat Ilboudo, Dibash Das, Michelle Naidoo, Lia Di, Weigang Qiu, Olorunseun Ogunwobi. PVT1-derived non-coding RNAs in prostate cancer in men of African ancestry. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B14.

Noncoding RNA for personalized prostate cancer treatment: utilizing the 'dark matters' of the genome.

Prostate cancer is the most commonly diagnosed cancer in men in western countries, with significant health impact. Clinically, it is complicated with the lack of biomarkers and effective treatments for aggressive disease, particularly castration-resistant prostate cancer. Although we have gained much insight into the biology of prostate cancer through studying protein-coding genes, they represent only a small fraction of our genome. Therefore, it is essential for us to investigate noncoding RNAs, which comprise the majority of our transcriptome, in order to achieve a better understanding of prostate cancer and move toward personalized medicine. In this article, we will address recent advancements in our knowledge of noncoding RNAs, and discuss the clinical potentials and challenges of different types of noncoding RNAs in prostate cancer.

Deciphering the function of non-coding RNAs in prostate cancer.

The advent of next-generation sequencing methods is fuelling the discovery of multiple non-coding RNA transcripts with direct implication in cell biology and homeostasis. This new layer of biological regulation seems to be of particular importance in human pathogenesis, including cancer. The aberrant expression of ncRNAs is a feature of prostate cancer, as they promote tumor-suppressive or oncogenic activities, controlling multicellular events leading to carcinogenesis and tumor progression. From the small RNAs involved in the RNAi pathway to the long non-coding RNAs controlling chromatin remodeling, alternative splicing, and DNA repair, the non-coding transcriptome represents the significant majority of transcriptional output. As such, ncRNAs appear as exciting new diagnostic, prognostic, and therapeutic tools. However, additional work is required to characterize the RNA species, their functions, and their applicability to clinical practice in oncology. In this review, we summarize the most important features of ncRNA biology, emphasizing its relevance in prostate carcinogenesis and its potential for clinical applications.

Long noncoding RNAs in prostate cancer: overview and clinical implications.

Prostate cancer is the second most common cause of cancer mortality among men in the United States. While many prostate cancers are indolent, an important subset of patients experiences disease recurrence after conventional therapy and progresses to castration-resistant prostate cancer (CRPC), which is currently incurable. Thus, there is a critical need to identify biomarkers that will distinguish indolent from aggressive disease, as well as novel therapeutic targets for the prevention or treatment of CRPC. In recent years, long noncoding RNAs (lncRNAs) have emerged as an important class of biological molecules. LncRNAs are polyadenylated RNA species that share many similarities with protein-coding genes despite the fact that they are noncoding (not translated into proteins). They are usually transcribed by RNA polymerase II and exhibit the same epigenetic signatures as protein-coding genes. LncRNAs have also been implicated in the development and progression of variety of cancers, including prostate cancer. While a large number of lncRNAs exhibit tissue- and cancer-specific expression, their utility as diagnostic and prognostic biomarkers is just starting to be explored. In this review, we highlight recent findings on the functional role and molecular mechanisms of lncRNAs in the progression of prostate cancer and evaluate their use as potential biomarkers and therapeutic targets.

Integrative Analysis of Normal Long Intergenic Non-Coding RNAs in Prostate Cancer.

Recently, large numbers of normal human tissues have been profiled for non-coding RNAs and more than fourteen thousand long intergenic non-coding RNAs (lincRNAs) are found expressed in normal human tissues. The functional roles of these normal lincRNAs (nlincRNAs) in the regulation of protein coding genes in normal and disease biology are yet to be established. Here, we have profiled two RNA-seq datasets including cancer and matched non-neoplastic tissues from 12 individuals from diverse demography for both coding genes and nlincRNAs. We find 130 nlincRNAs significantly regulated in cancer, with 127 regulated in the same direction in the two datasets. Interestingly, according to Illumina Body Map, significant numbers of these nlincRNAs display baseline null expression in normal prostate tissues but are specific to other tissues such as thyroid, kidney, liver and testis. A number of the regulated nlincRNAs share loci with coding genes, which are either co-regulated or oppositely regulated in all cancer samples studied here. For example, in all cancer samples i) the nlincRNA, TCONS_00029157, and a neighboring tumor suppressor factor, SIK1, are both down regulated; ii) several thyroid-specific nlincRNAs in the neighborhood of the thyroid-specific gene TPO, are both up-regulated; and iii) the TCONS_00010581, an isoform of HEIH, is down-regulated while the neighboring EZH2 gene is up-regulated in cancer. Several nlincRNAs from a prostate cancer associated chromosomal locus, 8q24, are up-regulated in cancer along with other known prostate cancer associated genes including PCAT-1, PVT1, and PCAT-92. We observe that there is significant bias towards up-regulation of nlincRNAs with as high as 118 out of 127 up-regulated in cancer, even though regulation of coding genes is skewed towards down-regulation. Considering that all reported cancer associated lincRNAs (clincRNAs) are biased towards up-regulation, we conclude that this bias may be functionally relevant.

Long noncoding RNAs in prostate cancer: mechanisms and applications

A large proportion of the control of gene expression in humans is mediated by noncoding elements in the genome. Long noncoding RNAs (lncRNAs) have emerged as a new class of pivotal regulatory components, orchestrating extensive cellular processes and connections. LncRNAs play various roles from chromatin modification to alternative splicing and post-transcriptional processing and are involved in almost all aspects of eukaryotic regulation. LncRNA-based mechanisms modulate cell fates during development, and their dysregulation underscores many human disorders, especially cancer, through chromosomal translocation, deletion, and nucleotide expansions. Recent studies demonstrate that multiple prostate cancer risk loci are associated with lncRNAs and that ectopic expression of these transcripts triggers a cascade of cellular events driving tumor initiation and progression. The recent increased rate of discovery of lncRNAs has been leveraged for application in clinical strategies such as novel biomarkers and therapeutic targets. Despite this potential, many issues remain to be addressed in this fast-growing field.

Noncoding RNAs in Prostate Cancer: The Long and the Short of It

As the leading culprit in cancer incidence for American men, prostate cancer continues to pose significant diagnostic, prognostic, and therapeutic tribulations for clinicians. The vast spectrum of disease behavior warrants better molecular classification to facilitate the development of more robust biomarkers that can identify the more aggressive and clinically significant tumor subtypes that require treatment. The untranslated portion of the human transcriptome, namely noncoding RNAs (ncRNA), is emerging as a key player in cancer initiation and progression and boasts many attractive features for both biomarker and therapeutic research. Genetic linkage studies show that many ncRNAs are located in cancer-associated genomic regions that are frequently deleted or amplified in prostate cancer, whereas aberrant ncRNA expression patterns have well-established links with prostate tumor cell proliferation and survival. The dysregulation of pathways controlled by ncRNAs results in a cascade of multicellular events leading to carcinogenesis and tumor progression. The characterization of RNA species, their functions, and their clinical applicability is a major area of biologic and clinical importance. This review summarizes the growing body of evidence, supporting a pivotal role for ncRNAs in the pathogenesis of prostate cancer. We highlight the most promising ncRNA biomarkers for detection and risk stratification and present the state-of-play for RNA-based personalized medicine in treating the "untreatable" prostate tumors.

Expression of prostate cancer related long non-coding RNAs in prostate cancer and its biological function

Expression of prostate cancer related long non-coding RNAs in prostate cancer and its biological function