Abstract:BackgroundProstate cancer is a common type of malignant tumor invading the male reproductive-urinary system, which has increasing incidence worldwide. Androgen receptor variant 7 (AR-V7) participates in regulating prostate cancer cell proliferation and gene expression. This study aimed to investigate the expression of AR-V7 in circulated tumor cells (CTCs) in patients with prostate cancer and to assess its correlation with drug sensitivity against enzalutamide or abiraterone.Material/MethodsBlood samples of pr… Show more
“…1D ). Enhanced levels of AR-V7 are associated with increased drug resistance 6 , 27 . Figure 1 Expression of AR-FL and AR-V7 in an isogenic model of enzalutamide resistance.…”
Most forms of castration-resistant prostate cancer (CRPC) are dependent on the androgen receptor (AR) for survival. While, enzalutamide provides a substantial survival benefit, it is not curative and many patients develop resistance to therapy. Although not yet fully understood, resistance can develop through a number of mechanisms, such as AR copy number gain, the generation of splice variants such as AR-V7 and mutations within the ligand binding domain (LBD) of the AR. circular RNAs (circRNAs) are a novel type of non-coding RNA, which can regulate the function of miRNA, and may play a key role in the development of drug resistance. circRNAs are highly resistant to degradation, are detectable in plasma and, therefore may serve a role as clinical biomarkers. In this study, AR-V7 expression was assessed in an isogenic model of enzalutamide resistance. The model consisted of age matched control cells and two sub-line clones displaying varied resistance to enzalutamide. circRNA profiling was performed on the panel using a high throughout microarray assay. Bioinformatic analysis identified a number of differentially expressed circRNAs and predicted five miRNA binding sites for each circRNA. miRNAs were stratified based on known associations with prostate cancer, and targets were validated using qPCR. Overall, circRNAs were more often down regulated in resistant cell lines compared with control (588
vs
. 278). Of particular interest was hsa_circ_0004870, which was down-regulated in enzalutamide resistant cells (p ≤ 0.05,
vs
. sensitive cells), decreased in cells that highly express AR (p ≤ 0.01,
vs
. AR negative), and decreased in malignant cells (p ≤ 0.01,
vs
. benign). The associated parental gene was identified as
RBM39
, a member of the U2AF65 family of proteins. Both genes were down-regulated in resistant cells (p < 0.05,
vs
. sensitive cells). This is one of the first studies to profile and demonstrate discrete circRNA expression patterns in an enzalutamide resistant cell line model of prostate cancer. Our data suggests that hsa_circ_0004870, through
RBM39
, may play a critical role in the development of enzalutamide resistance in CRPC.
“…1D ). Enhanced levels of AR-V7 are associated with increased drug resistance 6 , 27 . Figure 1 Expression of AR-FL and AR-V7 in an isogenic model of enzalutamide resistance.…”
Most forms of castration-resistant prostate cancer (CRPC) are dependent on the androgen receptor (AR) for survival. While, enzalutamide provides a substantial survival benefit, it is not curative and many patients develop resistance to therapy. Although not yet fully understood, resistance can develop through a number of mechanisms, such as AR copy number gain, the generation of splice variants such as AR-V7 and mutations within the ligand binding domain (LBD) of the AR. circular RNAs (circRNAs) are a novel type of non-coding RNA, which can regulate the function of miRNA, and may play a key role in the development of drug resistance. circRNAs are highly resistant to degradation, are detectable in plasma and, therefore may serve a role as clinical biomarkers. In this study, AR-V7 expression was assessed in an isogenic model of enzalutamide resistance. The model consisted of age matched control cells and two sub-line clones displaying varied resistance to enzalutamide. circRNA profiling was performed on the panel using a high throughout microarray assay. Bioinformatic analysis identified a number of differentially expressed circRNAs and predicted five miRNA binding sites for each circRNA. miRNAs were stratified based on known associations with prostate cancer, and targets were validated using qPCR. Overall, circRNAs were more often down regulated in resistant cell lines compared with control (588
vs
. 278). Of particular interest was hsa_circ_0004870, which was down-regulated in enzalutamide resistant cells (p ≤ 0.05,
vs
. sensitive cells), decreased in cells that highly express AR (p ≤ 0.01,
vs
. AR negative), and decreased in malignant cells (p ≤ 0.01,
vs
. benign). The associated parental gene was identified as
RBM39
, a member of the U2AF65 family of proteins. Both genes were down-regulated in resistant cells (p < 0.05,
vs
. sensitive cells). This is one of the first studies to profile and demonstrate discrete circRNA expression patterns in an enzalutamide resistant cell line model of prostate cancer. Our data suggests that hsa_circ_0004870, through
RBM39
, may play a critical role in the development of enzalutamide resistance in CRPC.
“…For instance, AR-V7 (also termed AR3) and AR-V3 have been described as constitutively active and are recurrently expressed in CRPC [ 129 , 130 , 136 , 138 , 139 ]. Furthermore, AR-V7 has been strongly associated with ARSI resistance (e.g., enzalutamide and abiraterone acetate), tumor growth, and poor patient prognosis [ 133 , 135 , 140 , 141 ]. Consequently, AR splice variants are central players in CRPC.…”
Section: Ecm Stiffness and Mechanisms Promoting Resistance To Ar-targ...mentioning
Despite advancements made in diagnosis and treatment, prostate cancer remains the second most diagnosed cancer among men worldwide in 2020, and the first in North America and Europe. Patients with localized disease usually respond well to first-line treatments, however, up to 30% develop castration-resistant prostate cancer (CRPC), which is often metastatic, making this stage of the disease incurable and ultimately fatal. Over the last years, interest has grown into the extracellular matrix (ECM) stiffening as an important mediator of diseases, including cancers. While this process is increasingly well-characterized in breast cancer, a similar in-depth look at ECM stiffening remains lacking for prostate cancer. In this review, we scrutinize the current state of literature regarding ECM stiffening in prostate cancer and its potential association with disease progression and castration resistance.
“…Using qualitative RT-PCR, Wang et al found that the expression of androgen receptor variant 7 (AR-V7) in CTCs from patients with prostate cancer was associated with drug resistance. e upregulation of AR-V7 led to the enhancement of cancer cell proliferation, suggesting poor patient prognosis [114]. Wei et al recruited 78 patients with stage I A2 -II A1 cervical cancer who had undergone radical hysterectomy by laparotomy or laparoscopy and selected 34 uterine fibroid patients and 32 healthy subjects as the positive control group and negative control group, respectively.…”
Circulating tumor cells (CTCs) play a crucial role in tumor recurrence and metastasis, and their early detection has shown remarkable benefits in clinical theranostics. However, CTCs are extremely rare, thus detecting them in the blood is very challenging. New CTC detection techniques are continuously being developed, enabling deeper analysis of CTC biology and potential clinical application. This article reviews current CTC detection techniques and their clinical application. CTCs have provided, and will continue to provide, important insights into the process of metastasis, which could lead to development of new therapies for different cancers.
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