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Exosome confirmation from conditioned media isolates. (A) Transmission electron microscopy was performed to investigate size and structure of exosomes; (B) Western blotting was performed to assess the expression of common exosomes markers (TSG101 and PDC6I/Alix) in isolates from PC3, DU145, and 22Rv1 cell line variants.
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BACKGROUND
Docetaxel-resistance limits successful treatment of castration resistant prostate cancer. We previously demonstrated that extracellular vesicles (exosomes) may play a role in regulating docetaxel resistance. Here, we investigated intracellular and extracellular (exosomal) miRNAs related to docetaxel resistance.METHODS
Following global mi...
Contexts in source publication
Context 1
... vesicles, isolated from the conditioned medium of all cell line variants, were assessed by transmission electron microscopy to identify the pres- ence of vesicles of approximately 100 nm in diameter indicative of exosomes (Fig. 1A). TSG101 and PDC6I/ Alix proteins, considered to be important markers of successful isolation of exosomes [22,23], were detected by immunoblotting of isolates from the conditioned medium of all cell line variants (Fig. ...
Context 2
... electron microscopy to identify the pres- ence of vesicles of approximately 100 nm in diameter indicative of exosomes (Fig. 1A). TSG101 and PDC6I/ Alix proteins, considered to be important markers of successful isolation of exosomes [22,23], were detected by immunoblotting of isolates from the conditioned medium of all cell line variants (Fig. ...
Context 3
... >35C T were considered as "undetected." Setting the total number of miRNAs detected as an arbitrary 100%, the corresponding percentages of miRNAs detected in cells and exosomes are shown. The Prostate were no miRNAs identified as commonly up-regulated among the three cell line variants compared to their age-parent control cells and exosomes (Fig. ...
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The normal epithelial cell-specific-1 (NES1) gene, also named as KLK10, is recognised as a novel putative tumour suppressor in breast cancer, but few studies have focused on the function of KLK10 in human prostate cancer. Our study confirms that the expression of KLK10 in prostate cancer tissue and cell lines (PC3, DU145, and LNCaP clone FGC) is lo...
Citations
... [205] Further investigations identified that miRNAs, including miR-598, miR-34a, miR-146a, and miR-148a, can serve as potential biomarkers of drug resistance in PCa. [206] 2) lncRNA and circRNAs A investigation identified an active long non-coding RNA (lncRNA) named lncARSR (activated lncRNA in sunitinibresistant renal cell carcinoma) that can be integrated into EVs and transported to RCC-sensitive cells, thereby promoting sunitinib resistance. The clinical correlation of lncARSR in EVs with a diminished response to sunitinib implies its potential utility as a predictor of sunitinib resistance. ...
... [187] Furthermore, elevated levels of miR-1 were identified in the serum of enzalutamide-resistant PCa patients. [189] An RNA-Seq analysis of PC3 cells and plasma EVs samples from CRPC patients revealed 17 EVs mRNA phenotypes linked to the progres- [ 170] lncARSR (plasma) [ 96] miR-210 (plasma) [ 204] miR-1233 (plasma) [ 204] None PCa TUBB3mRNA (plasma) [ 208] AR-V7 (plasma) [ 187] YAP1(plasma) [ 189] CD44v8-10 mRNA (plasma) [ 184] miR-34a (tissue and urine) [ 206] CRPC miR-1290 (plasma) [ 205] miR-375 (plasma) [ 205] P-gp (plasma) [ 165] None sion of tumor resistance. Certain mRNA isoforms with high predictive potential for docetaxel response were suggested. ...
In spite of the therapeutic progress achieved in the treatment of urologic tumors, the persistence and intricate nature of tumor resistance significantly impact patient prognoses. Extracellular vesicles (EVs), actively secreted by diverse cell types, assume a crucial role in facilitating intercellular communication. These EVs facilitate the transfer of functional molecules, encompassing RNA, proteins, and lipids, to recipient cells. While these molecules participate in normal physiological processes, they also play a pivotal role in the pathogenesis of various diseases. Notably in the context of cancer, numerous investigations have substantiated the involvement of tumor‐derived EVs in the development of drug resistance. This review comprehensively explores the mechanisms underlying drug resistance in urologic cancers, elucidates the contributions of tumor‐derived EVs to drug resistance in urologic tumors, discusses advancements in targeting EVs to mitigate drug resistance in urologic tumors, and assesses the utility of EVs as biomarkers for drug resistance in urologic tumors.
... The researchers concluded that miR-1246 might be a great predictor of aggressive prostate cancer, resulting in an AUC of 0.926, 100% specificity, and 75% sensitivity [124]. Lastly, prostate cancer cell-derived miR-34a regulates multiple RNA targets that have been shown to possess a strong relationship with castration-resistant prostate cancer (CRPC) prognosis and progression [125]. Docetaxel is often the first line of treatment against CRPC; however, there is innate and acquired resistance to CRPC. ...
Liquid biopsy can detect circulating cancer cells or tumor cell-derived DNA at various stages of cancer. The fluid from these biopsies contains extracellular vesicles (EVs), such as apoptotic bodies, microvesicles, exomeres, and exosomes. Exosomes contain proteins and nucleic acids (DNA/RNA) that can modify the microenvironment and promote cancer progression, playing significant roles in cancer pathology. Clinically, the proteins and nucleic acids within the exosomes from liquid biopsies can be biomarkers for the detection and prognosis of cancer. We review EVs protein and miRNA biomarkers identified for select cancers, specifically melanoma, glioma, breast, pancreatic, hepatic, cervical, prostate colon, and some hematological malignancies. Overall, this review demonstrates that EV biomolecules have great potential to expand the diagnostic and prognostic biomarkers used in Oncology; ultimately, EVs could lead to earlier detection and novel therapeutic targets.
Clinical implications
EVs represent a new paradigm in cancer diagnostics and therapeutics. The potential use of exosomal contents as biomarkers for diagnostic and prognostic indicators may facilitate cancer management. Non-invasive liquid biopsy is helpful, especially when the tumor is difficult to reach, such as in pancreatic adenocarcinoma. Moreover, another advantage of using minimally invasive liquid biopsy is that monitoring becomes more manageable. Identifying tumor-derived exosomal proteins and microRNAs would allow a more personalized approach to detecting cancer and improving treatment.
... Of significance, miR-34a functions as a potent CSC suppressor by targeting key molecules essential for the survival and activities of CSCs [5,7]. In fact, extensive studies have shown that miR-34a exhibits anti-PCSC effects by targeting invasiveness and metastasis [9][10][11], stemness [12,13], epigenome [14,15], and cell survival [13,15,16]. Our earlier data revealed that systemic delivery of miR-34a reduced prostate tumor burden and lung metastasis by inhibiting PCSCs via targeting CD44 [11]. ...
Prostate cancer (PCa) remains a common cancer with high mortality in men due to its heterogeneity and the emergence of drug resistance. A critical factor contributing to its lethality is the presence of prostate cancer stem cells (PCSCs), which can self-renew, long-term propagate tumors, and mediate treatment resistance. MicroRNA-34a (miR-34a) has shown promise as an anti-PCSC therapeutic by targeting critical molecules involved in cancer stem cell (CSC) survival and functions. Despite extensive efforts, the development of miR-34a therapeutics still faces challenges, including non-specific delivery and delivery-associated toxicity. One emerging delivery approach is ligand-mediated conjugation, aiming to achieve specific delivery of miR-34a to cancer cells, thereby enhancing efficacy while minimizing toxicity. Folate-conjugated miR-34a (folate–miR-34a) has demonstrated promising anti-tumor efficacy in breast and lung cancers by targeting folate receptor α (FOLR1). Here, we first show that miR-34a, a TP53 transcriptional target, is reduced in PCa that harbors TP53 loss or mutations and that miR-34a mimic, when transfected into PCa cells, downregulated multiple miR-34a targets and inhibited cell growth. When exploring the therapeutic potential of folate–miR-34a, we found that folate–miR-34a exhibited impressive inhibitory effects on breast, ovarian, and cervical cancer cells but showed minimal effects on and targeted delivery to PCa cells due to a lack of appreciable expression of FOLR1 in PCa cells. Folate–miR-34a also did not display any apparent effect on PCa cells expressing prostate-specific membrane antigen (PMSA) despite the reported folate’s binding capability to PSMA. These results highlight challenges in the specific delivery of folate–miR-34a to PCa due to a lack of target (receptor) expression. Our study offers novel insights into the challenges and promises within the field and casts light on the development of ligand-conjugated miR-34a therapeutics for PCa.
... miR-34a is selected as a potential predictive biomarker for docetaxel response. 30 It was proven that PC cells with miR-375 overexpression are resistant to docetaxel in the study conducted by Yuan Wang et al. In vivo in PC xenograft tumors in mice, using both qRT-PCR and Western blot, miR-375 transfection causes significant reduction of SEC23A and YAP1 mRNA expression and protein (also relevant in clinical samples in PC patients) which is the cause of docetaxel resistance. ...
... There is growing evidence that resistance can develop via the delivery of o cosome-shuttled miRNA [9,10,[27][28][29]. MicroRNA is a non-coding RNA molecule that ...
... There is growing evidence that resistance can develop via the delivery of oncosomeshuttled miRNA [9,10,[27][28][29]. MicroRNA is a non-coding RNA molecule that is involved in the post-transcriptional regulation of gene expression by binding to mRNA and silencing genes, as well as under some circumstances, such as starvation, activating genes [30][31][32]. ...
... Numerous studies conducted microarray analyses and RT-PCR of miRNA content from oncosomes isolated from the conditioned media of chemoresistant, radioresistant, and sensitive cancer cells that showed differentially expressed miRNAs as well as an exclusive set of miRNAs in each group [10,28,[36][37][38]. Further experiments with transfections of selected deregulated oncosome-derived miRNA mimics and inhibitors confirmed their involvement with the development of resistance [27,39]. ...
Resistance to chemo- or radiotherapy is the main obstacle to consistent treatment outcomes in oncology patients. A deeper understanding of the mechanisms driving the development of resistance is required. This review focuses on secretory factors derived from chemo- and radioresistant cancer cells, cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), and cancer stem cells (CSCs) that mediate the development of resistance in unexposed cells. The first line of evidence considers the experiments with conditioned media (CM) from chemo- and radioresistant cells, CAFs, MSCs, and CSCs that elevate resistance upon the ionizing radiation or anti-cancer drug exposure of previously untreated cells. The composition of CM revealed factors such as circular RNAs; interleukins; plasminogen activator inhibitor; and oncosome-shuttled lncRNAs, mRNAs, and miRNAs that aid in cellular communication and transmit signals inducing the chemo- and radioresistance of sensitive cancer cells. Data, demonstrating that radioresistant cancer cells become resistant to anti-neoplastic drug exposure and vice versa, are also discussed. The mechanisms driving the development of cross-resistance between chemotherapy and radiotherapy are highlighted. The secretion of resistance-mediating factors to intercellular fluid and blood brings attention to its diagnostic potential. Highly stable serum miRNA candidates were proposed by several studies as prognostic markers of radioresistance; however, clinical studies are needed to validate their utility. The ability to predict a treatment response with the help of the miRNA resistance status database will help with the selection of an effective therapeutic strategy. The possibility of miRNA-based therapy is currently being investigated with ongoing clinical studies, and such approaches can be used to alleviate resistance in oncology patients.
... Namely, in patients with advanced NSCLC undergoing immunotherapy, dynamic changes of plasma EV PD-L1 were significantly associated with survival, recently underlining even a better prediction for durable response than tissue PD-L1 [298]. Likewise, EV-associated miRNAs and long non-coding RNAs have received global attention in the longitudinal monitoring of systemic treatments in melanoma, breast and prostate cancer [299][300][301]. Further, a dynamic increase in plasmaderived EV KRAS or EGFR mutations seemed to be reliably suggestive of disease progression in pancreatic and lung cancer, respectively [302,303]. ...
Tissue-based biopsy is the present main tool to explore the molecular landscape of cancer, but it also has many limits to be frequently executed, being too invasive with the risk of side effects. These limits and the ability of cancer to constantly evolve its genomic profile, have recently led to the need of a less invasive and more accurate alternative, such as liquid biopsy. By searching Circulating Tumor Cells and residues of their nucleic acids or other tumor products in body fluids, especially in blood, but also in urine, stools and saliva, liquid biopsy is becoming the future of clinical oncology. Despite the current lack of a standardization for its workflows, that makes it hard to be reproduced, liquid biopsy has already obtained promising results for cancer screening, diagnosis, prognosis, and risk of recurrence.
Through a more accessible molecular profiling of tumors, it could become easier to identify biomarkers predictive of response to treatment, such as EGFR mutations in non-small cell lung cancer and KRAS mutations in colorectal cancer, or Microsatellite Instability and Mismatch Repair as predictive markers of pembrolizumab response.
By monitoring circulating tumor DNA in longitudinal repeated sampling of blood we could also predict Minimal Residual Disease and the risk of recurrence in already radically resected patients.
In this review we will discuss about the current knowledge of limitations and strengths of the different forms of liquid biopsies for its inclusion in normal cancer management, with a brief nod to their newest biomarkers and its future implications.
... High amounts of miRNA21 and EGFRvIII were also found in exosomes harvested from the serum of glioblastoma individuals(Junqueira- Neto et al. 2019). Another study reported a decreased level of exosomal miR34a and miR148a in urine samples of PCa individuals differentiate from benign prostate hyperplasia(Corcoran et al. 2014). Additionally, several InRNAs are also crucial as non-invasive biomarkers for the detection of tumor progression. ...
Precision medicine and omics technologies play a critical role in the development and implementation of existing biostatistics and bioinformatics approaches. Investments in the development of data mining algorithms and their application to health data are increasing rapidly. It is possible to reveal the relationships between omic levels in order to evaluate all the omic data obtained in the field of biostatistics and bioinformatics, to determine the biomarkers for the diagnosis and treatment of diseases, to provide detailed disease pathophysiology and personalized treatment options. However, there are many challenges to overcome in identifying relationships in big data, such as high dimensionality, heterogeneity, and highly correlated genomic features. Numerous methods using statistics, machine learning and artificial intelligence tools to address these issues are currently being developed and investigated for omic data analysis.KeywordsBioinformaticsBiomarker discoveryBiostatisticsMachine learningPrecision medicine
... High amounts of miRNA21 and EGFRvIII were also found in exosomes harvested from the serum of glioblastoma individuals (Junqueira-Neto et al. 2019). Another study reported a decreased level of exosomal miR34a and miR148a in urine samples of PCa individuals differentiate from benign prostate hyperplasia (Corcoran et al. 2014). Additionally, several InRNAs are also crucial as non-invasive biomarkers for the detection of tumor progression. ...
Cancer is a fatal illness that kills millions of people each year. Considering the heterogeneity of the disease, conventional therapies, like radiotherapy and chemotherapy, have limited effectiveness. There can be a variety of genetic factors that contribute to the development of tumors, and certain patients may exhibit different proteins than others. As a result of this inherent variability, cancer is well suited to the ever-expanding practice of personalized and precision medicine. The acquisition of precision medicine data is being conducted in many ways in an effort to better understand cancer molecular differences. Over the past decade, the number of druggable molecular mutations that can be detected in tumors has increased dramatically, providing significant information on tumor diagnosis, prognosis, and survival benefits in several cancer types with biomarker-matching therapies. With the advent of liquid biopsy and the rise of targeted therapies for a variety of tumors, precision oncology is revolutionizing. A summary of precision medicine in cancer treatment and approaches to tailoring individual treatments for different cancer types is presented in this chapter. We describe the clinical applications of liquid biopsy components to assess the blood-based biomarkers that facilitate cancer diagnosis. Additionally, we review various targeted therapies and specific diagnostic tests for different cancers in order to develop personalized medicine, emphasizing the updated information about various tumors to aid the elucidation of results and improve the effectiveness of targeted therapies. Moreover, we elaborate on the experiences gained from basket and umbrella clinical trials for tumor treatment using precision medicine trial designs, suggesting future individualized tumor treatment.KeywordsPrecision medicineLiquid biopsyBiomarkerTargeted therapyBasket trialUmbrella trialOncology
... Of the several miRNAs that were either up-or downregulated, only miR-34a had clinical significance. Further experiments proved that it regulates the expression of BCL-2, which may take part in docetaxel resistance [193]. Cancer-associated fibroblasts (CAFs) promote the metastasis of PCa after androgen deprivation therapy through the transfer of exosomal miR-146a-5p to PCa cells. ...
Exosomes are extracellular vesicles that originate from endosomes and are released by all cells irrespective of their origin or type. They play an important role in cell communication and can act in an autocrine, endocrine, or paracrine fashion. They are 40–150 nm in diameter and have a similar composition to the cell of origin. An exosome released by a particular cell is unique since it carries information about the state of the cell in pathological conditions such as cancer. miRNAs carried by cancer-derived exosomes play a multifaceted role by taking part in cell proliferation, invasion, metastasis, epithelial–mesenchymal transition, angiogenesis, apoptosis, and immune evasion. Depending on the type of miRNA that it carries as its cargo, it can render cells chemo- or radiosensitive or resistant and can also act as a tumor suppressor. Since the composition of exosomes is affected by the cellular state, stress, and changes in the environment, they can be used as diagnostic or prognostic biomarkers. Their unique ability to cross biological barriers makes them an excellent choice as vehicles for drug delivery. Because of their easy availability and stability, they can be used to replace cancer biopsies, which are invasive and expensive. Exosomes can also be used to follow the progression of diseases and monitor treatment strategies. A better understanding of the roles and functions of exosomal miRNA can be used to develop noninvasive, innovative, and novel treatments for cancer.
... Our results showed that the knockdown of JMJD2A increased the expression of miR-34a, significantly decreased cell viability and significantly increased apoptosis; confirming our hypothesis. Wang et al. showed that miR-34a inhibited the growth of CRPC xenografts by suppressing the proliferation of CRPC cells PC-3 and promoting apoptosis [27]. Similarly, our in vivo results showed that miR-34a was significantly elevated in the shJMJD2A group and was associated with significant tumor growth inhibition. ...
Background
To investigate underlying mechanism of JMJD2A in regulating cytoskeleton remodeling in castration-resistant prostate cancer (CRPC) resistant to docetaxel.
Methods
Tissue samples from CRPC patients were collected, and the expression of JMJD2A, miR-34a and cytoskeleton remodeling-related proteins were evaluated by qPCR, western blot and immunohistochemistry, and pathological changes were observed by H&E staining. Further, JMJD2A, STMN1 and TUBB3 were knocked down using shRNA in CRPC cell lines, and cell viability, apoptosis and western blot assays were performed. The interaction between miR-34a/STMN1/β3-Tubulin was analyzed with dual-luciferase reporter and co-immunoprecipitation assays.
Results
In clinical experiment, the CRPC-resistant group showed higher expression of JMJD2A, STMN1, α-Tubulin, β-Tubulin and F-actin, and lower expression of miR-34a and β3-Tubulin compared to the sensitive group. In vitro experiments showed that JMJD2A could regulate cytoskeletal remodeling through the miR-34a/STMN1/β3-Tubulin axis. The expression of miR-34a was elevated after knocking down JMJD2A, and miR-34a targeted STMN1. The overexpression of miR-34a was associated with a decreased expression of STMN1 and elevated expression of β3-Tubulin, which led to the disruption of the microtubule network, decreased cancer cell proliferation, cell cycle arrest in the G0/G1 phase, and increased apoptosis.
Conclusion
JMJD2A promoted docetaxel resistance in prostate cancer cells by regulating cytoskeleton remodeling through the miR-34a/STMN1/β3-Tubulin axis.
