bims-mirpro 2023-07-02 papers

bims-mirpro

Biomed News

on MiRNA as biomarker in prostate cancer diagnosis and prognosis

Issue of 2023–07–02
nine papers selected by
Garima Jain, Banaras Hindu University

Biological and therapeutic viewpoints towards role of miR-218 in human cancers: Revisiting molecular interactions and future clinical translations.
Deregulation of miR-10b and miR-21 Correlate with Cancer Stem Cells Expansion through the Apoptotic Pathway in Prostate Cancer.
Non-coding RNAs: emerging roles in the characterization of immune microenvironment and immunotherapy of prostate cancer.
Stress, microRNAs, and stress-related psychiatric disorders: an overview.
Extracellular Vesicle MicroRNA in the Kidney.
Understanding the lncRNA/miRNA-NFκB regulatory network in diabetes mellitus: From function to clinical translation.
microRNAs in action: biogenesis, function and regulation.
In Silico Identification of a BRCA1:miR-29:DNMT3 Axis Involved in the Control of Hormone Receptors in BRCA1-Associated Breast Cancers.
Potential Diagnostic Biomarker Detection for Prostate Cancer Using Untargeted and Targeted Metabolomic Profiling.

Cell Signal. 2023 Jun 26. pii: S0898-6568(23)00200-0. [Epub ahead of print] 110786

Biological and therapeutic viewpoints towards role of miR-218 in human cancers: Revisiting molecular interactions and future clinical translations.

Mehrdad Hashemi, Sadaf Gholami, Rasoul Raesi, Sareh Sarhangi, Behnaz Mahmoodieh, Zeinab Khazaei Koohpar, Mohammad Ali Shekhi Beig Goharrizi, Mitra Behroozaghdam, Maliheh Entezari, Shokooh Salimimoghadam, Wenliang Zha, Mohsen Rashidi, Soheila Abdi, Afshin Taheriazam, Noushin Nabavi.

  Understanding the exact pathogenesis of cancer is difficult due to heterogenous nature of tumor cells and multiple factors that cause its initiation and development. Treatment of cancer is mainly based on surgical resection, chemotherapy, radiotherapy and their combination, while gene therapy has been emerged as a new kind of therapy for cancer. Post-transcriptional regulation of genes has been of interest in recent years and among various types of epigenetic factors that can modulate gene expression, short non-coding RNAs known as microRNAs (miRNAs) have obtained much attention. The stability of mRNA decreases by miRNAs to repress gene expression. miRNAs can regulate tumor malignancy and biological behavior of cancer cells and understanding their function in tumorigenesis can pave the way towards developing new therapeutics in future. One of the new emerging miRNAs in cancer therapy is miR-218 that increasing evidence highlights its anti-cancer activity, while a few studies demonstrate its oncogenic function. The miR-218 transfection is promising in reducing progression of tumor cells. miR-218 shows interactions with molecular mechanisms including apoptosis, autophagy, glycolysis and EMT, and the interaction is different. miR-218 induces apoptosis, while it suppresses glycolysis, cytoprotective autophagy and EMT. Low expression of miR-218 can result in development of chemoresistance and radio-resistance in tumor cells and direct targeting of miR-218 as a key player is promising in cancer therapy. LncRNAs and circRNAs are nonprotein coding transcripts that can regulate miR-218 expression in human cancers. Moreover, low expression level of miR-218 can be observed in human cancers such as brain, gastrointestinal and urological cancers that mediate poor prognosis and low survival rate.

Keywords:  Clinical application; Non-coding RNAs; Prognosis; Sponging; cancer gene therapy; miR-218

DOI:  https://doi.org/10.1016/j.cellsig.2023.110786
Asian Pac J Cancer Prev. 2023 Jun 01. pii: 90675. [Epub ahead of print]24(6): 2105-2119

Deregulation of miR-10b and miR-21 Correlate with Cancer Stem Cells Expansion through the Apoptotic Pathway in Prostate Cancer.

Kamla Kant Shukla, Gautam Ram Choudhary, Shrimanjunath Sankanagoudar, Sanjeev Misra, Jeewan Ram Vishnoi, Puneet Pareek, Kiran Kumar Pilla, Sachchida N Pandey, Praveen Sharma.

   BACKGROUND: MicroRNAs are small, non-coding RNA molecules that regulate important cellular processes such as tumorigenesis, cell proliferation, and apoptosis. Cancer stem cells are a subset of cells that control metastasis and cell proliferation. In this study, we focus on the roles of miR-10b, miR-21 and correlate with cancer stem cells through the apoptotic pathway in different stages of prostate cancer (PCa).
METHODS: In total, 45 patients, each group with Benign prostatic hyperplasia (BPH), localised PCa, and metastatic PCa, were recruited. MicroRNA and gene expression were estimated through quantitative polymerase chain reaction. Flow cytometry was used to characterise prostate cancer stem cells (PCSCs), estimate reactive oxygen species (ROS), apoptosis and chemiluminescent immunoassay was used to estimate interleukin 6 (IL-6), tumour necrosis factor (TNF-α), prostate-specific antigen (PSA), and testosterone.
RESULTS: The fold change mean expressions of miR-21, miR-10b, Cytochrome C, and B-cell lymphoma 2 (BCL-2) were significantly upregulated in localised and metastatic PCa compared with BPH. In contrast, the mean fold change expressions of Bcl-2-associated X protein (BAX), Caspase-3, Caspase-9, and Second mitochondria-derived activator of caspase (SMAC) were lower in localised and metastatic PCa compared to BPH. The levels of IL-6, TNF-α, ROS, PSA and testosterone also showed a significant increase while apoptosis was decreased in both localized PCa and metastatic PCa as compared with BPH. In bioinformatics analyses, we found a similar pattern of miRNAs and gene expression in PCa databases. Our study also found a high expression of CD44+/CD24- and CD44+/CD133+ in localised and metastatic PCa compared with BPH.
CONCLUSION: Our findings suggest miR-10b and miR-21 promote PCSCs and may target apoptotic genes involved in PCa pathogenesis; these miRNAs could be used as diagnosis biomarkers of PCa. In PCa pathogenesis and PCSCs regulation, the interaction between these two players is crucial and will help develop new PCa therapeutic targets.

Keywords:  Diagnostic; Prostate cancer stem cell; apoptotic pathway mRNA expression; miRNAs expression

DOI:  https://doi.org/10.31557/APJCP.2023.24.6.2105
Biochem Pharmacol. 2023 Jun 24. pii: S0006-2952(23)00260-5. [Epub ahead of print] 115669

Non-coding RNAs: emerging roles in the characterization of immune microenvironment and immunotherapy of prostate cancer.

Feixiang Yang, Jiawei Li, Qintao Ge, Yuchen Zhang, Meng Zhang, Jun Zhou, Haitao Wang, Juan Du, Shenglin Gao, Chaozhao Liang, Jialin Meng.

  Prostate cancer is the most common tumor among men. Although the prognosis for early-stage prostate cancer is good, patients with advanced disease often progress to metastatic castration-resistant prostate cancer (mCRPC), which usually leads to death owing to resistance to existing treatments and lack of long-term effective therapy. In recent years, immunotherapy, especially immune checkpoint inhibitors (ICIs), has made great progress in the treatment of various solid tumors, including prostate cancer. However, the ICIs have only shown modest outcomes in mCRPC compared with other tumors. Previous studies have suggested that the suppressive tumor immune microenvironment (TIME) of prostate cancer leads to poor anti-tumor immune response and tumor resistance to immunotherapy. It has been reported that non-coding RNAs (ncRNAs) are capable of regulating upstream signaling at the transcriptional level, leading to a "cascade of changes" in downstream molecules. As a result, ncRNAs have been identified as an ideal class of molecules for cancer treatment. The discovery of ncRNAs provides a new perspective on TIME regulation in prostate cancer. ncRNAs have been associated with establishing an immunosuppressive microenvironment in prostate cancer through multiple pathways to modulate the immune escape of tumor cells which can promote resistance of prostate cancer to immunotherapy. Targeting these related ncRNAs presents an opportunity to improve the effectiveness of immunotherapy in this patient population.

Keywords:  immunotherapy; mCRPC; non-coding RNA; prostate cancer; tumor immune microenvironment； immune checkpoints

DOI:  https://doi.org/10.1016/j.bcp.2023.115669
Mol Psychiatry. 2023 Jun 30.

Stress, microRNAs, and stress-related psychiatric disorders: an overview.

Laura Musazzi, Jessica Mingardi, Alessandro Ieraci, Alessandro Barbon, Maurizio Popoli.

Stress is a major risk factor for psychiatric disorders. During and after exposure to stressors, the stress response may have pro- or maladaptive consequences, depending on several factors related to the individual response and nature of the stressor. However, the mechanisms mediating the long-term effects of exposure to stress, which may ultimately lead to the development of stress-related disorders, are still largely unknown. Epigenetic mechanisms have been shown to mediate the effects of the environment on brain gene expression and behavior. MicroRNAs, small non-coding RNAs estimated to control the expression of about 60% of all genes by post-transcriptional regulation, are a fundamental epigenetic mechanism. Many microRNAs are expressed in the brain, where they work as fine-tuners of gene expression, with a key role in the regulation of homeostatic balance, and a likely influence on pro- or maladaptive brain changes. Here we have selected a number of microRNAs, which have been strongly implicated as mediators of the effects of stress in the brain and in the development of stress-related psychiatric disorders. For all of them recent evidence is reported, obtained from rodent stress models, manipulation of microRNAs levels with related behavioral changes, and clinical studies of stress-related psychiatric disorders. Moreover, we have performed a bioinformatic analysis of the predicted brain-expressed target genes of the microRNAs discussed, and found a central role for mechanisms involved in the regulation of synaptic function. The complex regulatory role of microRNAs has suggested their use as biomarkers for diagnosis and treatment response, as well as possible therapeutic drugs. While, microRNA-based diagnostics have registered advancements, particularly in oncology and other fields, and many biotech companies have launched miRNA therapeutics in their development pipeline, the development of microRNA-based tests and drugs for brain disorders is comparatively slower.

DOI: https://doi.org/10.1038/s41380-023-02139-3
Compr Physiol. 2023 06 26. 13(3): 4833-4850

Extracellular Vesicle MicroRNA in the Kidney.

Sekyung Oh, Chang M Lee, Sang-H Kwon.

Most cells in our body release membrane-bound, nano-sized particles into the extracellular milieu through cellular metabolic processes. Various types of macromolecules, reflecting the physiological and pathological status of the producing cells, are packaged into such so-called extracellular vesicles (EVs), which can travel over a distance to target cells, thereby transmitting donor cell information. The short, noncoding ribonucleic acid (RNA) called microRNA (miRNA) takes a crucial part in EV-resident macromolecules. Notably, EVs transferring miRNAs can induce alterations in the gene expression profiles of the recipient cells, through genetically instructed, base-pairing interaction between the miRNAs and their target cell messenger RNAs (mRNAs), resulting in either nucleolytic decay or translational halt of the engaged mRNAs. As in other body fluids, EVs released in urine, termed urinary EVs (uEVs), carry specific sets of miRNA molecules, which indicate either normal or diseased states of the kidney, the principal source of uEVs. Studies have therefore been directed to elucidate the contents and biological roles of miRNAs in uEVs and moreover to utilize the gene regulatory properties of miRNA cargos in ameliorating kidney diseases through their delivery via engineered EVs. We here review the fundamental principles of the biology of EVs and miRNA as well as our current understanding of the biological roles and applications of EV-loaded miRNAs in the kidney. We further discuss the limitations of contemporary research approaches, suggesting future directions to overcome the difficulties to advance both the basic biological understanding of miRNAs in EVs and their clinical applications in treating kidney diseases. © 2023 American Physiological Society. Compr Physiol 13:4833-4850, 2023.

DOI: https://doi.org/10.1002/cphy.c220023
Diabetes Res Clin Pract. 2023 Jun 25. pii: S0168-8227(23)00567-3. [Epub ahead of print]202 110804

Understanding the lncRNA/miRNA-NFκB regulatory network in diabetes mellitus: From function to clinical translation.

Parisa Hoorzad, Fatemehsadat Mousavinasab, Pouya Tofigh, Elham Mazaheri Kalahroud, Seyed Mohsen Aghaei-Zarch, Ali Salehi, Mehdi Fattahi, Binh Nguyen Le.

  Diabetes mellitus (DM) and its significant ramifications make out one of the primary reasons behind morbidity worldwide. Noncoding RNAs (ncRNAs), such as microRNAs and long noncoding RNAs, are involved in regulating manifold biological processes, including diabetes initiation and progression. One of the established pathways attributed to DM development is NF-κB signaling. Neurons, β cells, adipocytes, and hepatocytes are among the metabolic tissues where NF-κB is known to produce a range of inflammatory chemokines and cytokines. The direct or indirect role of ncRNAs such as lncRNAs and miRNAs on the NF-κB signaling pathway and DM development has been supported by many studies. As a result, effective diabetes treatment and preventive methods will benefit from a comprehensive examination of the interplay between NF-κB and ncRNAs. Herein, we provide a concise overview of the role of NF-κB-mediated signaling pathways in diabetes mellitus and its consequences. The reciprocal regulation of ncRNAs and the NF-κB signaling pathway in diabetes is then discussed, shedding light on the pathogenesis of the illness and its possible therapeutic interventions.

Keywords:  Diabetes mellitus; NF-κB; lncRNAs; miRNAs

DOI:  https://doi.org/10.1016/j.diabres.2023.110804
Nat Rev Genet. 2023 Jun 28.

microRNAs in action: biogenesis, function and regulation.

Renfu Shang, Seungjae Lee, Gayan Senavirathne, Eric C Lai.

Ever since microRNAs (miRNAs) were first recognized as an extensive gene family >20 years ago, a broad community of researchers was drawn to investigate the universe of small regulatory RNAs. Although core features of miRNA biogenesis and function were revealed early on, recent years continue to uncover fundamental information on the structural and molecular dynamics of core miRNA machinery, how miRNA substrates and targets are selected from the transcriptome, new avenues for multilevel regulation of miRNA biogenesis and mechanisms for miRNA turnover. Many of these latest insights were enabled by recent technological advances, including massively parallel assays, cryogenic electron microscopy, single-molecule imaging and CRISPR-Cas9 screening. Here, we summarize the current understanding of miRNA biogenesis, function and regulation, and outline challenges to address in the future.

DOI: https://doi.org/10.1038/s41576-023-00611-y
Int J Mol Sci. 2023 Jun 08. pii: 9916. [Epub ahead of print]24(12):

In Silico Identification of a BRCA1:miR-29:DNMT3 Axis Involved in the Control of Hormone Receptors in BRCA1-Associated Breast Cancers.

Manuela Santarosa, Davide Baldazzi, Michela Armellin, Roberta Maestro.

  Germline inactivating mutations in the BRCA1 gene lead to an increased lifetime risk of ovarian and breast cancer (BC). Most BRCA1-associated BC are triple-negative tumors (TNBC), aggressive forms of BC characterized by a lack of expression of estrogen and progesterone hormone receptors (HR) and HER2. How BRCA1 inactivation may favor the development of such a specific BC phenotype remains to be elucidated. To address this question, we focused on the role of miRNAs and their networks in mediating BRCA1 functions. miRNA, mRNA, and methylation data were retrieved from the BRCA cohort of the TCGA project. The cohort was divided into a discovery set (Hi-TCGA) and a validation set (GA-TCGA) based on the platform used for miRNA analyses. The METABRIC, GSE81002, and GSE59248 studies were used as additional validation data sets. BCs were differentiated into BRCA1-like and non-BRCA1-like based on an established signature of BRCA1 pathway inactivation. Differential expression of miRNAs, gene enrichment analysis, functional annotation, and methylation correlation analyses were performed. The miRNAs downregulated in BRCA1-associated BC were identified by comparing the miRNome of BRCA1-like with non-BRCA1-like tumors from the Hi-TCGA discovery cohort. miRNAs:gene-target anticorrelation analyses were then performed. The target genes of miRNAs downregulated in the Hi-TCGA series were enriched in the BRCA1-like tumors from the GA-TCGA and METABRIC validation data sets. Functional annotation of these genes revealed an over-representation of several biological processes ascribable to BRCA1 activity. The enrichment of genes related to DNA methylation was particularly intriguing, as this is an aspect of BRCA1 functions that has been poorly explored. We then focused on the miR-29:DNA methyltransferase network and showed that the miR-29 family, which was downregulated in BRCA1-like tumors, was associated with poor prognosis in these BCs and inversely correlated with the expression of the DNA methyltransferases DNMT3A and DNMT3B. This, in turn, correlated with the methylation extent of the promoter of HR genes. These results suggest that BRCA1 may control the expression of HR via a miR-29:DNMT3:HR axis and that disruption of this network may contribute to the receptor negative phenotype of tumors with dysfunctional BRCA1.

Keywords:  BRCA1; DNA methylation; DNMT3A; DNMT3B; breast cancer; estrogen receptor; miR-29b; miR-29c; microRNA; progesterone receptor

DOI:  https://doi.org/10.3390/ijms24129916
Curr Issues Mol Biol. 2023 Jun 08. 45(6): 5036-5051

Potential Diagnostic Biomarker Detection for Prostate Cancer Using Untargeted and Targeted Metabolomic Profiling.

Diana Nitusca, Carmen Socaciu, Andreea Iulia Socaciu, Ioan Ovidiu Sirbu, Razvan Bardan, Alin Adrian Cumpanas, Edward Seclaman, Catalin Marian.

  Prostate cancer (PCa) remains one of the leading causes of cancer mortality in men worldwide, currently lacking specific, early detection and staging biomarkers. In this regard, modern research focuses efforts on the discovery of novel molecules that could represent potential future non-invasive biomarkers for the diagnosis of PCa, as well as therapeutic targets. Mounting evidence shows that cancer cells express an altered metabolism in their early stages, making metabolomics a promising tool for the discovery of altered pathways and potential biomarker molecules. In this study, we first performed untargeted metabolomic profiling on 48 PCa plasma samples and 23 healthy controls using ultra-high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-[ESI+]-MS) for the discovery of metabolites with altered profiles. Secondly, we selected five molecules (L-proline, L-tryptophan, acetylcarnitine, lysophosphatidylcholine C18:2 and spermine) for the downstream targeted metabolomics and found out that all the molecules, regardless of the PCa stage, were decreased in the PCa plasma samples when compared to the controls, making them potential biomarkers for PCa detection. Moreover, spermine, acetylcarnitine and L-tryptophan had very high diagnostic accuracy, with AUC values of 0.992, 0.923 and 0.981, respectively. Consistent with other literature findings, these altered metabolites could represent future specific and non-invasive candidate biomarkers for PCa detection, which opens novel horizons in the field of metabolomics.

Keywords:  biomarkers; diagnosis; metabolomics; prostate cancer

DOI:  https://doi.org/10.3390/cimb45060320