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Cancer is a broad name for a group of diseases in which abnormal cells grow out of control and are characterized by their complexity and recurrence. Although there has been progress in cancer therapy with the entry of precision medicine and immunotherapy, cancer incidence rates have increased globally. Non-coding RNAs in the form of circular RNAs (circRNAs) play crucial roles in the pathogenesis, clinical diagnosis, and therapy of different diseases, including cancer. According to recent studies, circRNAs appear to serve as accurate indicators and therapeutic targets for cancer treatment. However, circRNAs are promising candidates for cutting-edge cancer therapy because of their distinctive circular structure, stability, and wide range of capabilities; many challenges persist that decrease the applications of circRNA-based cancer therapeutics. Here, we explore the roles of circRNAs as a replacement for cancer therapy, highlight the main challenges facing circRNA-based cancer therapies, and discuss the key strategies to overcome these challenges to improve advanced innovative therapies based on circRNAs with long-term health effects.

Abstract Continued exploration of the androgen receptor (AR) is crucial, as it plays pivotal roles in diverse diseases such as prostate cancer (PCa), serving as a significant therapeutic focus. Therefore, the Department of Urology Dresden hosted an international meeting for scientists and clinical oncologists to discuss the newest advances in AR research. The 2nd International Androgen Receptor Symposium was held in Dresden, Saxony, Germany, from 26–27.04.2024, organised by Dr. Holger H.H. Erb. Following the format of the first meeting, more than 35 scientists from 8 countries attended the event to discuss recent developments, research challenges, and identification of venues in AR research. An important new feature was the involvement of PhD students and young investigators, acknowledging the high scientific quality of their work. The symposium included three covers: new advances from clinical research, basic and translational research, and novel strategies to target AR. Moreover, based on its increasing clinical relevance, a PSMA theranostic mini-symposium was added at the end of the AR symposium to allow the audience to discuss the newest advances in PSMA theranostic. This report focuses on the highlights and discussions of the meeting.

Abstract Background The androgen receptor (AR) is a drug target used to inhibit AR and prostate cancer (PCa) growth. Surprisingly, treatment with supraphysiological androgen level (SAL), used in bipolar androgen therapy, inhibits growth of PCa suggesting a tumor-suppressive activity by SAL. SAL was shown to induce cellular senescence in PCa. Methods RNA-seq and transcriptome analysis, ChIP-seq, human 3D PCa spheroids, mouse xenografted castration-resistant PCa, knockdown and overexpression, Co-immunoprecipitation (Co-IP), translocation analysis, immune detection, qRT-PCR, protein–protein interaction modelling. Results Here, mice xenografts with castration-resistant PCa tumors show that SAL inhibits cancer growth in vivo suggesting that SAL activates a tumor-suppressive mechanism. RNA-seq and ChIP-seq revealed the clock gene BHLHE40 is a novel direct AR target. Compared to adjacent human prostate tissues, the expression of BHLHE40 is reduced in PCa tumors and associated with reduced survival. Knockdown suggests that BHLHE40 mediates SAL-induced cellular senescence including tumor spheroids. Interestingly, a large overlap of differentially expressed gene sets was identified between BHLHE40 and SAL leading to the identification of four classes of SAL-BHLHE40 transcriptome landscapes. Co-IP and modelling suggest binding of BHLHE40 to AR and their co-translocation into nucleus by SAL treatment. Further, RNA-seq and ChIP-seq analysis indicate that the atypical tumor suppressive cyclin G2 emerged as a novel downstream target of BHLHE40 and a mediator of SAL-induced cellular senescence. Conclusions The data provide evidence of the tumor suppressive activity of SAL and a novel signaling by the AR-BHLHE40-CCNG2 axis for androgen-induced cellular senescence, linking circadian rhythm factor to androgen signaling as a novel tumor suppressive pathway.

Abstract Background Prostate cancer (PCa) is a prevalent malignancy in men worldwide, ranking as the second leading cause of cancer-related death in Western countries. Various PCa hormone therapies, such as androgen receptor (AR)-antagonists or supraphysiological androgen level (SAL) reduce cancer cell proliferation. However, treated cells may influence the growth of neighboring cells through secreted exosomes in the tumor microenvironment (TME). Here, the change of protein content of exosomes secreted from PCa cells through treatment with different AR-antagonists or SAL has been analyzed. Methods Isolation of exosomes via ultracentrifugation of treated human PCa LNCaP cells with AR-agonist and various AR-antagonists; analysis of cellular senescence by detection of senescence associated beta galactosidase activity (SA β-Gal); Western blotting and immunofluorescence staining; Mass spectrometry (MS-spec) of exosomes and bioinformatic analyses to identify ligand-specific exosomal proteins. Growth assays to analyze influence of exosomes on non-treated cells. Results MS-spec analysis identified ligand-specific proteins in exosomes. One thousand seventy proteins were up- and 52 proteins downregulated by SAL whereas enzalutamide upregulated 151 proteins and downregulated 42 exosomal proteins. The bioinformatic prediction indicates an up-regulation of pro-proliferative pathways. AR ligands augment hub factors in exosomes that include AKT1, CALM1, PAK2 and CTNND1. Accordingly, functional assays confirmed that the isolated exosomes from AR-ligand treated cells promote growth of untreated PCa cells. Conclusion The data suggest that the cargo of exosomes is controlled by AR-agonist and -antagonists and distinct among the AR-antagonists. Further, exosomes promote growth that might influence the TME. This finding sheds light into the complex interplay between AR signaling and exosome-mediated communication between PCa cells.

Abstract Clustered regulatory interspaced short palindromic repeats (CRISPR) has changed biomedical research and provided entirely new models to analyze every aspect of biomedical sciences during the last decade. In the study of cancer, the CRISPR/CRISPR-associated protein (Cas) system opens new avenues into issues that were once unknown in our knowledge of the noncoding genome, tumor heterogeneity, and precision medicines. CRISPR/Cas-based gene-editing technology now allows for the precise and permanent targeting of mutations and provides an opportunity to target small non-coding RNAs such as microRNAs (miRNAs). However, the development of effective and safe cancer gene editing therapy is highly dependent on proper design to be innocuous to normal cells and prevent introducing other abnormalities. This study aims to highlight the cutting-edge approaches in cancer-gene editing therapy based on the CRISPR/Cas technology to target miRNAs in cancer therapy. Furthermore, we highlight the potential challenges in CRISPR/Cas-mediated miRNA gene editing and offer advanced strategies to overcome them.

ABSTRACTLong-term delivery is a successful strategy used to reduce the adverse effects of monoclonal antibody (mAb)-based treatments. Macroporous hydrogels and affinity-based strategies have shown promising results in sustained and localized delivery of the mAbs. Among the potential tools for affinity-based delivery systems, the de novo designed Ecoil and Kcoil peptides are engineered to form a high-affinity, heterodimeric coiled-coil complex under physiological conditions. In this study, we created a set of trastuzumab molecules tagged with various Ecoil peptides and evaluated their manufacturability and characteristics. Our data show that addition of an Ecoil tag at the C-termini of the antibody chains (light chains, heavy chains, or both) does not hinder the production of chimeric trastuzumab in CHO cells or affect antibody binding to its antigen. We also evaluated the influence of the number, length, and position of the Ecoil tags on the capture and release of Ecoil-tagged trastuzumab from macroporous dextran hydrogels functionalized with Kcoil peptide (the Ecoil peptide-binding partner). Notably, our data show that antibodies are released from the macroporous hydrogels in a biphasic manner; the first phase corresponding to the rapid release of residual, unbound trastuzumab from the macropores, followed by the affinity-controlled, slow-rate release of antibodies from the Kcoil-functionalized macropore surface.

Abstract Background Prostate cancer (PCa) is an age-related malignancy in men with a high incidence rate. PCa treatments face many obstacles due to cancer cell resistance and many bypassing mechanisms to escape therapy. According to the intricacy of PCa, many standard therapies are being used depending on PCa stages including radical prostatectomy, radiation therapy, androgen receptor (AR) targeted therapy (androgen deprivation therapy, supraphysiological androgen, and AR antagonists) and chemotherapy. Most of the aforementioned therapies have been implicated to induce cellular senescence. Cellular senescence is defined as a stable cell cycle arrest in the G1 phase and is one of the mechanisms that prevent cancer proliferation. Results In this review, we provide and analyze different mechanisms of therapy-induced senescence (TIS) in PCa and their effects on the tumor. Interestingly, it seems that different molecular pathways are used by cancer cells for TIS. Understanding the complexity and underlying mechanisms of cellular senescence is very critical due to its role in tumorigenesis. The most prevalent analyzed pathways in PCa as TIS are the p53/p21WAF1/CIP1, the p15INK4B/p16INK4A/pRb/E2F/Cyclin D, the ROS/ERK, p27Kip1/CDK/pRb, and the p27Kip1/Skp2/C/EBP β signaling. Despite growth inhibition, senescent cells are highly metabolically active. In addition, their secretome, which is termed senescence-associated secretory phenotype (SASP), affects within the tumor microenvironment neighboring non-tumor and tumor cells and thereby may regulate the growth of tumors. Induction of cancer cell senescence is therefore a double-edged sword that can lead to reduced or enhanced tumor growth. Conclusion Thus, dependent on the type of senescence inducer and the specific senescence-induced cellular pathway, it is useful to develop pathway-specific senolytic compounds to specifically targeting senescent cells in order to evict senescent cells and thereby to reduce SASP side effects.

Abstract The Cyclin-dependent kinase (CDK) class of serine/threonine kinases has crucial roles in the regulation of cell cycle transition and is mainly involved in the pathogenesis of cancers. The expression of CDKs is controlled by a complex regulatory network comprised of genetic and epigenetic mechanisms, which are dysregulated during the progression of cancer. The abnormal activation of CDKs results in uncontrolled cancer cell proliferation and the induction of cancer stem cell characteristics. The levels of CDKs can be utilized to predict the prognosis and treatment response of cancer patients, and further understanding of the function and underlying mechanisms of CDKs in human tumors would pave the way for future cancer therapies that effectively target CDKs. Defects in the regulation of cell cycle and mutations in the genes coding cell-cycle regulatory proteins lead to unrestrained proliferation of cells leading to formation of tumors. A number of treatment modalities have been designed to combat dysregulation of cell cycle through affecting expression or activity of CDKs. However, effective application of these methods in the clinical settings requires recognition of the role of CDKs in the progression of each type of cancer, their partners, their interactions with signaling pathways and the effects of suppression of these kinases on malignant features. Thus, we designed this literature search to summarize these findings at cellular level, as well as in vivo and clinical levels.

Abstract Exosomes are naturally occurring nanosized particles that aid intercellular communication by transmitting biological information between cells. Exosomes have therapeutic efficacy that can transfer their contents between cells as natural carriers. In addition, the exosomal contents delivered to the recipient pathological cells significantly inhibit cancer progression. However, exosome-based tumor treatments are inadequately precise or successful, and various challenges should be adequately overcome. Here, we discuss the significant challenges that exosomes face as drug carriers used for therapeutic targets and strategies for overcoming these challenges in order to promote this new incoming drug carrier further and improve future clinical outcomes. We also present techniques for overcoming these challenges.

Abstract ING genes belong to family of tumor suppressor genes with regulatory functions on cell proliferation, apoptosis, and cellular senescence. These include a family of proteins with 5 members (ING1-5), which are downregulated in human malignancies and/or affected by pathogenic mutations. ING proteins are highly evolutionarily conserved proteins containing several domains through which bind to chromatin structures by exerting their effects as readers of histone modification marks, and also binding to proteins like p53 involved in biological processes such as cell cycle regulation. Further, they are known as subunits of histone acetylation as well as deacetylation complexes and so exert their regulatory roles through epigenetic mechanisms. Playing role in restriction of proliferative but also invasive potentials of normal cells, INGs are particularly involved in cancer development and progression. However, additional studies and experimental confirmation are required for these models. This paper highlights the potential impact that INGs may have on the development of human cancer and explores what new information has recently arise on the functions of ING genes.

Abstract Naturally, in somatic cells chromosome ends (telomeres) shorten during each cell division. This process ensures to limit proliferation of somatic cells to avoid malignant proliferation; however, it leads to proliferative senescence. Telomerase contains the reverse transcriptase TERT, which together with the TERC component, is responsible for protection of genome integrity by preventing shortening of telomeres through adding repetitive sequences. In addition, telomerase has non-telomeric function and supports growth factor independent growth. Unlike somatic cells, telomerase is detectable in stem cells, germ line cells, and cancer cells to support self-renewal and expansion. Elevated telomerase activity is reported in almost all of human cancers. Increased expression of hTERT gene or its reactivation is required for limitless cellular proliferation in immortal malignant cells. In hormonally regulated tissues as well as in prostate, breast and endometrial cancers, telomerase activity and hTERT expression are under control of steroid sex hormones and growth factors. Also, a number of hormones and growth factors are known to play a role in the carcinogenesis via regulation of hTERT levels or telomerase activity. Understanding the role of hormones in interaction with telomerase may help finding therapeutical targets for anticancer strategies. In this review, we outline the roles and functions of several steroid hormones and growth factors in telomerase regulation, particularly in hormone regulated cancers such as prostate, breast and endometrial cancer.

Long non-coding RNAs (lncRNAs) are regulatory transcripts with essential roles in the pathogenesis of almost all types of cancers, including prostate cancer. They can act as either oncogenic lncRNAs or tumor suppressor ones in prostate cancer. Small nucleolar RNA host genes are among the mostly assessed oncogenic lncRNAs in this cancer. PCA3 is an example of oncogenic lncRNAs that has been approved as a diagnostic marker in prostate cancer. A number of well-known oncogenic lncRNAs in other cancers such as DANCR, MALAT1, CCAT1, PVT1, TUG1 and NEAT1 have also been shown to act as oncogenes in prostate cancer. On the other hand, LINC00893, LINC01679, MIR22HG, RP1-59D14.5, MAGI2-AS3, NXTAR, FGF14-AS2 and ADAMTS9-AS1 are among lncRNAs that act as tumor suppressors in prostate cancer. LncRNAs can contribute to the pathogenesis of prostate cancer via modulation of androgen receptor (AR) signaling, ubiquitin–proteasome degradation process of AR or other important signaling pathways. The current review summarizes the role of lncRNAs in the evolution of prostate cancer with an especial focus on their importance in design of novel biomarker panels and therapeutic targets.

Abstract DANCR is an RNA gene located on chr4. This gene has several splice variants. Up-regulation of DANCR has been reported in many types of cancers. This lncRNA is mainly located in the cytoplasm and regulates genes expression at post-transcriptional level. In fact, it acts as a molecular sponge for a variety of miRNAs, including miR-874-3P, miR-335, miR-149, miR-4319, miR-758-3p, miR-216a-5p, miR-874-3p, miR-33a-5p, miR-335-5p, miR-145-3p, miR-665, miR-345-5p and miR-125b-5p. DANCR also regulates activity of PI3K/AKT/NF-κB, Wnt/β-catenin, ERK/SMAD, MAPK, IL-6/JAK1/STAT3, Smad2/3, p53, FAK/PI3K/AKT/GSK3β/Snail pathways. In the current narrative review article, we summarize the roles of DANCR in the carcinogenesis, with an especial emphasis on its role in the development of osteosarcoma and lung, liver, pancreatic and colorectal cancers.

Abstract G-quadruplexes are secondary helical configurations established between guanine-rich nucleic acids. The structure is seen in the promoter regions of numerous genes under certain situations. Predicted G-quadruplex-forming sequences are distributed across the genome in a non-random way. These structures are formed in telomeric regions of the human genome and oncogenic promoter G-rich regions. Identification of mechanisms of regulation of stability of G-quadruplexes has practical significance for understanding the molecular basis of genetic diseases such as cancer. A number of non-coding RNAs such as H19, XIST, FLJ39051 (GSEC), BC200 (BCYRN1), TERRA, pre-miRNA-1229, pre-miRNA-149 and miR-1587 have been found to contain G-quadraplex-forming regions or affect configuration of these structures in target genes. In the current review, we outline the recent research on the interaction between G-quadruplexes and non-coding RNAs, other RNA transcripts and DNA molecules.

Abstract CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats-associated protein 9) shows the opportunity to treat a diverse array of untreated various genetic and complicated disorders. Therapeutic genome editing processes that target disease-causing genes or mutant genes have been greatly accelerated in recent years as a consequence of improvements in sequence-specific nuclease technology. However, the therapeutic promise of genome editing has yet to be explored entirely, many challenges persist that increase the risk of further mutations. Here, we highlighted the main challenges facing CRISPR/Cas9-based treatments and proposed strategies to overcome these limitations, for further enhancing this revolutionary novel therapeutics to improve long-term treatment outcome human health.

LncRNA prostate androgen-regulated transcript 1 (PART1) is an important lncRNA in the carcinogenesis whose role has been firstly unraveled in prostate cancer. Expression of this lncRNA is activated by androgen in prostate cancer cells. In addition, this lncRNA has a role in the pathogenesis intervertebral disc degeneration, myocardial ischemia-reperfusion injury, osteoarthritis, osteoporosis and Parkinson’s disease. Diagnostic role of PART1 has been assessed in some types of cancers. Moreover, dysregulation of PART1 expression is regarded as a prognostic factor in a variety of cancers. The current review provides a concise but comprehensive summary of the role of PART1 in different cancers and non-malignant disorders.

Senescence is defined as a gradual weakening of functional features of a living organism. Cellular senescence is a process that is principally aimed to remove undesirable cells by prompting tissue remodeling. This process is also regarded as a defense mechanism induced by cellular damage. In the course of oncogenesis, senescence can limit tumor progression. However, senescence participates in the pathoetiology of several disorders such as fibrotic disorders, vascular disorders, diabetes, renal disorders and sarcopenia. Recent studies have revealed contribution of different classes of non-coding RNAs in the cellular senescence. Long non-coding RNAs, microRNAs and circular RNAs are three classes of these transcripts whose contributions in this process have been more investigated. In the current review, we summarize the available literature on the impact of these transcripts in the cellular senescence.

This study synthesized a La2O3@snowflake-like Cu2S composite to fabricate an electrochemical sensor for sensitively simultaneous detection of diclofenac and chlorzoxazone exploiting an easy hydrothermal approach, followed by analysis with XRD, FE-SEM, and EDX methods. According to voltammetric studies, the electrocatalytic diclofenac and chlorzoxazone oxidations on the electrode modified with La2O3@SF-L Cu2S composites were increased, with greater oxidation currents, as well as the oxidation potential was significantly decreased due to synergetic impact of La2O3@SF-L Cu2S composites when compared with the pure SF-L Cu2S NS-modified electrode. The differential pulse voltammetry findings showed wide straight lines (0.01–900.0 μM) for La2O3 NP@SF-L Cu2S NS-modified electrode with a limit of detection (LOD) of 1.7 and 2.3 nM for the detection of diclofenac and chlorzoxazone, respectively. In addition, the limit of quantification was calculated to be 5.7 and 7.6 nM for diclofenac and chlorzoxazone, respectively. The diffusion coefficient was calculated to be 1.16 × 10−5and 8.4 × 10−6 cm2/s for diclofenac and chlorzoxazone oxidation on the modified electrode, respectively. Our proposed electrode was examined for applicability by detecting diclofenac and chlorzoxazone in real specimens.

Calcium binding proteins (CBP) are a group of proteins mediating the effects of calcium on cellular functions. These proteins can regulate calcium levels inside the cells and contribute in several cellular functions through transporting this ion across cell membranes or decoding related signals. Recent studies have shown that several non-coding RNAs interact with CBPs to affect their expression or activity. The interactions between these transcripts and CBPs have implications in the pathoetiology of human disorders, including both neoplastic and non-neoplastic conditions. In the current review, we describe the interactions between three classes of non-coding RNAs (long non-coding RNAs, circular RNAs, and microRNAs) and a number of CBPs, particularly CAB39, S100A1, S100A4, S100A7 and S100P. This kind of interaction has been verified in different pathological contexts such as drug-induced cardiotoxicity, osteoblasts cytotoxicity, acute lung injury, myocardial ischemia/reperfusion injury, proliferative diabetic retinopathy, glomerulonephritis, as well as a wide array of neoplastic conditions.

Programmed cell death (PDCD) family of proteins includes at least 12 members, function of seven of them being more investigated. These members are PDCD1, PDCD2, PDCD4, PDCD5, PDCD6, PDCD7 and PDCD10. Consistent with the important roles of these proteins in the regulation of apoptosis, dysregulation of PDCDs is associated with diverse disorders ranging from intervertebral disc degeneration, amyotrophic lateral sclerosis, immune thrombocytopenia, type 1 diabetes, congenital hypothyroidism, Alzheimer’s disease to different types of cancers. More recently, the interaction between non-coding RNAs and different members of PDCD family is being discovered. In the current study, we described the functional interactions between PDCDs and two classes of non-coding RNAs, namely microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). miR-21 and miR-183 are two miRNAs whose interactions with PDCDs have been assessed in different contexts. The lncRNAs interaction with PDCDs is mainly assessed in the context of neoplasia indicating the role of MALAT1, MEG3, SNHG14 and LINC00473 in this process.