Analysis of miR-497/195 cluster identifies new therapeutic targets in cervical cancer.

OBJECTIVE: miR-497/195, located at 17p13.1, is a highly conserved miRNA cluster whose abnormal expression is a key regulator of carcinogenesis. We performed a comprehensive analysis of the miR-497/195 cluster to determine its prognostic utility and role in cervical cancer (CC) using publicly available datasets. RESULTS: In silico analysis and validation revealed that this cluster is downregulated in CC. A total of 60 target genes of miR-497/195 cluster were identified as differentially expressed between normal and CC samples. ShinyGO, STRING, CytoHubba, Timer 2.0, HPA, and HCMBD were used for functional enrichment, PPIN network construction, hub gene identification, immune infiltration correlation, histopathological expression, and determination of the metastatic potential of miR-497/195 cluster and their target genes. PPIN analysis identified CCNE1, CCNE2, ANLN, RACGAP1, KIF23, CHEK1, CDC25A, E2F7, CDK1, and CEP55 as the top 10 hub genes (HGs). Furthermore, the upregulation of RECK, ATD5, and BCL2, downregulation of OSBPL3, RCAN3, and HIST1H3H effected overall survival of CC patients. We identified 6 targets (TFAP2A, CLSPN, RASEF, HIST1H3H, AKT3, and ITPR1) of miR-497/195 cluster to influence metastasis. In addition, 8 druggable genes and 38 potential drugs were also identified. Our study identified miR-497/195 cluster target genes and pathways that could be used for prognostic and therapeutic applications in CC.

Multi-spectroscopic and in silico investigation of gambogic acid-calf thymus DNA interactions.

Gambogic acid (GA), a xanthanoid compound, is derived from Garcinia Hanbury gamboge resin. Studying GA's DNA binding and targeting processes is crucial to understanding its tumor-targeting potentiality. This study used spectroscopic and in silico methods to investigate the GA-calf thymus DNA-binding interaction. The results of the UV-visible absorbance spectroscopy revealed that GA binds to DNA and forms a complex. Investigation of fluorescence quenching using ethidium bromide-DNA revealed that GA displaced ethidium bromide, and the type of quenching was static in nature, as determined by Stern-Volmer plot data. Thermodynamic analysis of the DNA-GA complex revealed a spontaneous, favorable interaction involving hydrogen bonding and hydrophobic interactions. Quenching experiments with potassium iodide, Acridine orange, and NaCl verified GA's groove-binding nature and the presence of weak electrostatic interactions. The thermal melting temperature of DNA in its native and bound states with GA did not differ significantly (69.27° C to 71.25° C), validating the binding of GA to the groove region. Furthermore, the groove-binding nature of GA was confirmed by studying its interaction with ssDNA and DNA viscosity. The methods of DSC, FT-IR, and CD spectroscopy have not revealed any structural aberrations in DNA bound with GA. Molecular docking and modeling studies revealed that GA has a groove-binding nature with DNA, which is consistent with prior experimental results. Finally, the findings shed information by which GA attaches to DNA and provide insights into its recognized anticancer effects via topoisomerase inhibition causing DNA cleavage, inhibition of cell proliferation and apoptosis.Communicated by Ramaswamy H. Sarma.

A comprehensive review on the functional role of miRNA clusters in cervical cancer.

Cervical cancer (CC) poses a significant health threat in women globally. MicroRNA clusters (MCs), comprising multiple miRNA-encoding genes, are pivotal in gene regulation. Various factors, including circular RNA and DNA methylation, govern MC expression. Dysregulated MC expression correlates strongly with CC development via promoting the acquisition of cancer hallmarks. Certain MCs show promise for diagnosis, prognosis and therapy selection due to their distinct expression patterns in normal, premalignant and tumor tissues. This review explains the regulation and biological functions of MCs and highlights the clinical relevance of abnormal MC expression in CC.

Cervical cancer is a major global health concern, mostly caused by human papillomavirus infection, resulting in a high number of new cases and fatalities annually. This review examines the role of specific genetic variables known as microRNA clusters (MCs) in the development and progression of cervical cancer. The MCs harbor many microRNAs that control genes related to tumor proliferation, infiltration and dissemination. Understanding the functioning of these MCs can aid in early diagnosis of cervical cancer and predicting its patterns of behavior. We explore the potential benefits of assessing MC expression levels in cancer staging and prognosis, and the development of diagnostic tools and treatments. Targeting these molecular targets could provide interesting opportunities for future cancer treatments.

Intermittent fasting in health and disease.

CONTEXT: Intermittent fasting, a new-age dietary concept derived from an age-old tradition, involves repetitive cycles of fasting/calorie restriction and eating. OBJECTIVE: We aim to take a deep dive into the biological responses to intermittent fasting, delineate the disease-modifying and cognitive effects of intermittent fasting, and also shed light on the possible side effects. METHODS: Numerous in vitro and in vivo studies were reviewed, followed by an in-depth analysis, and compilation of their implications in health and disease. RESULTS: Intermittent fasting improves the body's stress tolerance, which is further amplified with exercise. It impacts various pathological conditions like cancer, obesity, diabetes, cardiovascular disease, and neurodegenerative diseases. CONCLUSION: During dietary restriction, the human body experiences a metabolic switch due to the depletion of liver glycogen, which promotes a shift towards utilising fatty acids and ketones in the system, thereby significantly impacting adiposity, ageing and the immune response to various diseases.

Intermittent fasting (IF) comprises repetitive fasting and feeding cycles.There are many variations of IF schedules.Individuals practicing an appropriate IF pattern reap numerous health benefits.The possible side effects should be considered before commencing a new IF regimen.

Deciphering the role of MitomiRs in cancer: A comprehensive review.

MicroRNAs (miRNAs) are short non-coding RNAs that regulate many metabolic and signal transduction pathways. The role of miRNAs, usually found in the cytoplasm, in regulating gene expression and cancer progression has been extensively studied in the last few decades. However, very recently, miRNAs were found to localize in the mitochondria. MiRNAs that specifically localize in the mitochondria and the cytoplasmic miRNAs associated with mitochondria that directly or indirectly modulate specific mitochondrial functions are termed as "mitomiRs". Although it is not clear about the origin of mitomiRs that are situated within mitochondria (nuclear or mitochondrial origin), it is evident that they have specific functions in modulating gene expression and regulating important mitochondrial metabolic pathways. Through this review, we aim to delineate the mechanisms by which mitomiRs alter mitochondrial metabolic pathways and influence the initiation and progression of cancer. We further discuss the functions of particular mitomiRs, which have been widely studied in the context of mitochondrial metabolism and oncogenic signaling pathways. Based on the current knowledge, we can conclude that mitomiRs contribute significantly to mitochondrial function and metabolic regulation, and that dysregulation of mitomiRs can aid the proliferation of cancer cells. Therefore, the less explored area of mitomiRs' biology can be an important topic of research investigation in the future for targeting cancer cells.

Current Update on Nanotechnology-Based Approaches in Ovarian Cancer Therapy.

Ovarian cancer is one of the leading causes of cancer-related deaths among women. The drawbacks of conventional therapeutic strategies encourage researchers to look for alternative strategies, including nanotechnology. Nanotechnology is one of the upcoming domains of science that is rechanneled towards targeted cancer therapy and diagnosis. Nanocarriers such as dendrimers, liposomes, polymer micelles, and polymer nanoparticles present distinct surface characteristics in morphology, surface chemistry, and mode of action that help differentiate normal and malignant cells, which paves the way for target-specific drug delivery. Similarly, nanoparticles have been strategically utilized as efficacious vehicles to deliver drugs that alter the epigenetic modifications in epigenetic therapy. Some studies suggest that the use of specialized target-modified nanoparticles in siRNA-based nanotherapy prevents internalization and improves the antitumor activity of siRNA by ensuring unrestrained entry of siRNA into the tumor vasculature and efficient intracellular delivery of siRNA. Moreover, research findings highlight the significance of utilizing nanoparticles as depots for photosensitive drugs in photodynamic therapy. The applicability of nanoparticles is further extended to medical imaging. They serve as contrast agents in combination with conventional imaging modalities such as MRI, CT, and fluorescence-based imaging to produce vivid and enhanced images of tumors. Therefore, this review aims to explore and delve deeper into the advent of various nanotechnology-based therapeutic and imaging techniques that provide non-invasive and effective means to tackle ovarian cancers.

Landscape of Clinically Relevant Exosomal tRNA-Derived Non-coding RNAs.

Exosomes are extra-cellular vesicles that are < 150 nm that is formed by invagination of the plasma membrane and are released as vesicles. These contain proteins, RNA, and DNA as their cargo. In recent times, the non-coding RNA (ncRNA) present within exosomes has been studied extensively in the context of sorting, localization, and their potential as biomarkers. For example, miR-1246, miR-1290, miR-21, and miR-23a are exosomal biomarkers of cancer, and YBX1 (Y-Box Binding Protein 1) is attributed to exosomal RNA sorting. Transfer RNA-derived fragments are a class of small ncRNAs that were discovered in 2009. They are classified as tRFs (tRNA-derived fragments) and tsRNAs (tRNA halves). Interestingly, these tRNA-derived ncRNAs are emerging as biomarkers in various diseases, and these are found in exosomes. To date, the literature has covered only the biomarker potential of plasma/serum tRNA-derived ncRNAs. Hence, in the current review, we discuss the exosomal tRNA-derived fragments that are clinically relevant in pathological conditions.

The role of tumor-educated platelets in ovarian cancer: A comprehensive review and update.

Platelets have recently surfaced as critical players in cancer metastasis and the local and systemic responses to tumor growth. The emerging concept of "Tumor-educated platelets (TEPs)" comprises the exchange of biomolecules between tumor cells and platelets, thereby leading to the "education" of platelets. Increased platelet numbers have long been associated with cancer patients' tumor metastasis and poor clinical prognosis. However, it is very recently that researchers have delved deeper into the tumor-microenvironment and probed the mechanism of interactions between tumor cells and platelets. Designing strategies to target the TEPs and the communications between platelets and tumor cells can prove to be a promising breakthrough in cancer therapy. Through this review, we aim to analyze the recent developments in this field and discuss the characteristics of TEPs, focusing on ovarian cancer-associated TEPs and their characteristics, the interplay between ovarian cancer-associated TEPs and cancer cells, and the purview of TEP-targeted cancer diagnosis and therapy, including platelet biomarkers and inhibitors.

Deregulated miRNA clusters in ovarian cancer: Imperative implications in personalized medicine.

Ovarian cancer (OC) is one of the most common and fatal types of gynecological cancer. OC is usually detected at the advanced stages of the disease, making it highly lethal. miRNAs are single-stranded, small non-coding RNAs with an approximate size ranging around 22 nt. Interestingly, a considerable proportion of miRNAs are organized in clusters with miRNA genes placed adjacent to one another, getting transcribed together to result in miRNA clusters (MCs). MCs comprise two or more miRNAs that follow the same orientation during transcription. Abnormal expression of the miRNA cluster has been identified as one of the key drivers in OC. MC exists both as tumor-suppressive and oncogenic clusters and has a significant role in OC pathogenesis by facilitating cancer cells to acquire various hallmarks. The present review summarizes the regulation and biological function of MCs in OC. The review also highlights the utility of abnormally expressed MCs in the clinical management of OC.

LncRNA-miRNA-mRNA regulatory axes in endometrial cancer: a comprehensive overview.

INTRODUCTION: Recent research on tumorigenesis and progression has opened up an array of novel molecular mechanisms in the form of interactions between cellular non-coding RNAs (long non-coding RNA[lncRNA]/microRNA [miRNA]) and coding transcripts that regulate health and disease. Endometrial cancer (EC) is a prominent gynecological malignancy with a high incidence rate and poorly known etiology and prognostic factors that hinder the success of disease management. The emerging role of lncRNA-miRNA-mRNA interactions and their dysregulation in the pathophysiology of EC has been elucidated in many recent studies. METHODS: A thorough literature review was conducted to explore information about lncRNA-miRNA-mRNA axes in EC. RESULTS: Several lncRNAs act as molecular sponges that sequester various tumor suppressor miRNAs to inhibit their function, leading to the dysregulation of their target mRNA transcripts that contribute to the EC regulation. CONCLUSIONS: This review summarizes these networks of molecular mechanisms and their contribution to different aspects of endometrial carcinogenesis, leading to a better conceptualization of the molecular pathways that underlie the disease and helping establish novel diagnostic biomarkers and therapeutic intervention points to aid the curative intent of EC.

Comparative expression analysis of tRF-3001a and tRF-1003 with corresponding miRNAs (miR-1260a and miR-4521) and their network analysis with breast cancer biomarkers.

BACKGROUND: MicroRNAs and tRFs (tRNA-derived fragments) are small non-coding RNAs that are promising breast cancer (BC) biomarkers. miRNA sequences are found within tRFs. For example, miR-1260a and miR-4521 sequences are found within tRF-3001a and tRF-1003, respectively. No study has addressed the biomarker potential of these tRF-miRNA pairs in BC or their association with other BC miRNA biomarkers. METHODS AND RESULTS: Real-time PCR was performed to examine the expression of miR-1260a-tRF-3001a and miR-4521-tRF-1003 pairs in plasma of BC patients. miR-4521 and miR-1260a showed no change in plasma of breast cancer patients (n = 19). On the contrary, both the corresponding tRFs (tRF-1003 and tRF-3001a) were down-regulated. Also, we performed miRNA/mRNA network analysis for miR-1260a and miR-4521 with top degree BC biomarkers miR-16-5p and miR-93-5p. We found that they shared nine target genes. Moreover, miR-16-5p was down-regulated, and miR-93-5p was up-regulated in the same sample set. Survival analysis plotted using clinical data from Kaplan-Meier Plotter showed that all four miRNAs and 8/9 target gene expressions could predict the survival of BC patients. CONCLUSIONS: Our cohort analyses suggest that tRF-3001a and tRF-1003 serve as better biomarkers than their miRNA counterparts in addition to miR-93-5p and miR-16-5p. Also, they form a significant miRNA/mRNA biomarker cluster.

Breast cancer fibroblasts and cross-talk.

The breast tumor microenvironment is one of the crucial elements supporting breast cancer tumor progression and metastasis. The fibroblasts are the chief cellular component of the stromal microenvironment and are pathologically activated and differentiated into breast cancer-associated fibroblasts (CAFs). The catabolic phenotype of breast CAFs arises due to metabolic reprogramming of these fibroblasts under pseudo-hypoxic conditions. The metabolic intermediates and ATP produced by the breast CAFs are exploited by the neighboring cancer cells for energy generation. The growth factors, cytokines, and chemokines secreted by the CAFs help fuel tumor growth, invasion, and dissemination. Moreover, the interplay between breast CAFs and cancer cells, mediated by the growth factors, ROS, metabolic intermediates, exosomes, and catabolite transporters, aids in building a favorable microenvironment that promotes cancer cell proliferation, tumor progression, and metastasis. Therefore, identifying effective means to target the reprogrammed metabolism of the breast CAFs and the cross-communication between CAFs and cancer cells serve as promising strategies to develop anti-cancer therapeutics. Henceforth, the scope of the present review ranges from discussing the underlying characteristics of breast CAFs, mechanisms of metabolic reprogramming in breast CAFs, and the nature of interactions between breast CAFs and cancer cells to studying the intricacies of reprogrammed metabolism targeted cancer therapy.

Long Non-coding RNA NEAT1 as an Emerging Biomarker in Breast and Gynecologic Cancers: a Systematic Overview.

Long non-coding RNAs (lncRNAs) are emerging regulators of cellular pathways, especially in cancer development. Among the lncRNAs, nuclear paraspeckle assembly transcript 1 (NEAT1) forms a scaffold for a nuclear body; the paraspeckle and aberrant expression of NEAT1 have been reported in breast and gynecologic cancers (ovarian, cervical, endometrial, and vulvar). Abundantly expressed NEAT1 in breast and gynecologic cancers generally contribute to tumor development by sponging its corresponding tumor-suppressive microRNAs or interacting with various regulatory proteins. The distinct expression of NEAT1 and its contribution to tumorigenic pathways make it a promising therapeutic target in breast and gynecologic cancers. Herein, we summarize the functions and molecular mechanisms of NEAT1 in human breast, ovarian, cervical, endometrial, and vulvar cancers. Furthermore, we emphasize its critical role in the formation of paraspeckle development and its functions. Conclusively, NEAT1 is a considerable biomarker with a bright prospect and can be therapeutically targeted to manage breast and gynecologic cancers.

A synergy of estradiol with leptin modulates the long non-coding RNA NEAT1/ mmu-miR-204-5p/IGF1 axis in the uterus of high-fat-diet-induced obese ovariectomized mice.

Obesity increases the risk of developing cancers for both males and females. This study investigated potential crosstalk between estradiol and leptin signaling pathways within the endometrium of high-fat-diet-induced obese ovariectomized mice to gain insight into possible links between obesity and endometrial cancer. We administered 17-ß estradiol (0.2 µg/mouse subcutaneously) and/or recombinant mouse leptin (1 µg/g Bwt intraperitoneally.,) for 20 h to high-fat-diet-induced obese ovariectomized mice. The uterine tissues of experimental animals after treatments were studied by histological, immunohistochemical, quantitative real-time PCR (gene/miRNAs), and methylation-specific PCR analyses. Quantitative real-time PCR analysis revealed significantly increased expression of Cyclin d1, Esr1, Igf1, Igfbp2, Vegf, Oct4, and Pgr after estradiol and leptin co-treatment. Methylation-specific PCR results indicated that the hormonal dependent transcriptional regulation of Vegf, Igf1, and Pgr is independent of promoter methylation. The decreased expression of mmu- miR-204-5p after estradiol and leptin treatments correlated with the increased expression of long non-coding RNA Neat1. Insilico analysis confirmed the interaction of Neat1 and mmu- miR-204-5p and gene targets of mmu-miR-204-5p, including Igf1 were analyzed in this study. Immunohistochemical analyses revealed subcellular localization and increased expression of ESR, VEGF, phospho-Estrogen Receptor-α (pTyr537), and LEPR proteins following estradiol and leptin exposure. Overall, the data from our in vivo studies suggest the regulation of Neat1-mmu-miR-204-5p- Igf1 axis and associated gene expression changes in uterine tissue after estradiol and leptin co-treatment. In humans, long-term exposure to estradiol and leptin can alter endometrial homeostasis through the NEAT1-miR-204-5p-Igf1 axis and favor carcinogenic pathways, which provide mechanistic insight into the obesity-associated endometrial cancer.

Small nucleolar RNA and its potential role in breast cancer - A comprehensive review.

Small Nucleolar RNAs (snoRNAs) are known for their canonical functions, including ribosome biogenesis and RNA modification. snoRNAs act as endogenous sponges that regulate miRNA expression. Thus, precise snoRNA expression is critical for fine-tuning miRNA expression. snoRNAs processed into miRNA-like sequences play a crucial role in regulating the expression of protein-coding genes similar to that of miRNAs. Recent studies have linked snoRNA deregulation to breast cancer (BC). Inappropriate snoRNA expression contributes to BC pathology by facilitating breast cells to acquire cancer hallmarks. Since snoRNAs show significant differential expression in normal and cancer conditions, measuring snoRNA levels could be useful for BC prognosis and diagnosis. The present article provides a comprehensive overview of the role of snoRNAs in breast cancer pathology. More specifically, we have discussed the regulation, biological function, signaling pathways, and clinical utility of abnormally expressed snoRNAs in BC. Besides, we have also discussed the role of snoRNA host genes in breast tumorigenesis and emerging and future research directions in the field of snoRNA and cancer.

Regulation of processing bodies: From viruses to cancer epigenetic machinery.

Processing bodies (PBs) are 100-300 nm cytoplasmic messenger ribonucleoprotein particle (mRNP) granules that regulate eukaryotic gene expression. These cytoplasmic compartments harbor messenger RNAs (mRNAs) and several proteins involved in mRNA decay, microRNA silencing, nonsense-mediated mRNA decay, and splicing. Though membrane-less, PB structures are maintained by RNA-protein and protein-protein interactions. PB proteins have intrinsically disordered regions and low complexity domains, which account for its liquid to liquid phase separation. In addition to being dynamic and actively involved in the exchange of materials with other mRNPs and organelles, they undergo changes on various cellular cues and environmental stresses, including viral infections. Interestingly, several PB proteins are individually implicated in cancer development, and no study has addressed the effects on PB dynamics after epigenetic modifications of cancer-associated PB genes. In the current review, we summarize modulations undergone by P bodies or P body components upon viral infections. Furthermore, we discuss the selective and widely investigated PB proteins that undergo methylation changes in cancer and their potential as biomarkers.

Liquid biopsy in ovarian cancer.

Ovarian cancer is typically diagnosed at an advanced stage and poses a significant challenge to treatment and recovery. Relapsed ovarian cancer and chemoresistance of ovarian tumor cells are other clinical challenges. Liquid biopsy is an essential non-invasive diagnostic test that evaluates circulating tumor cells and tumor DNA, as well as other blood markers that may be useful in guiding precision medicine. Although liquid biopsy is not a routinely used diagnostic test, the potential applications in the diagnosis and prognosis in ovarian cancer are rapidly growing. This review explores recent studies examining the clinical potential of circulating tumor cells, cell-free microRNA, exosomes, tumor DNA, and other analytes as a source of liquid biopsy biomarkers in ovarian cancer diagnosis, prognosis and response to treatment.