The potential role of circular RNAs -regulated PI3K signaling in non-small cell lung cancer: Molecular insights and clinical perspective

Mafi A., Aghadavod E., Mazloomi S., Mousavi V.

Abstract: Polycystic ovary syndrome (PCOS) is a prevalent endocrine/metabolic disorder in women of reproductive age. PCOS is characterized by hyperandrogenism, polycystic ovary morphology, and ovulatory dysfunction/anovulation. It involves multiple effects in patients, including granulosa/theca cell hyperplasia, menstrual disturbances, infertility, acne, obesity, insulin resistance, and cardiovascular disorders. : Biochemical analyses and the results of RNA sequencing studies in recent years have shown a type of non-coding RNAs as a splicing product known as circular RNAs (circRNAs). Several biological functions have been identified in relation to circRNAs, including a role in miRNA sponge, protein sequestration, increased parental gene expression, and translation leading to polypeptides. These circular molecules are more plentiful and specialized than other types of RNAs. For this reason, they are referred to as potential biomarkers in different diseases. Evidence suggests that circRNAs may have regulatory potentials through different signaling pathways, such as the miRNA network. : Probably most experts in the field of obstetricians are not aware of circRNAs as a useful biomarker. Therefore, this review focused on the researches that have been done on the involvement of circRNAs in PCOS and summarized recent supportive evidence, and evaluated the circRNA association and mechanisms involved in PCOS.

Ragupathi A., Kim C., Jacinto E.

The mechanistic target of rapamycin, mTOR, controls cell metabolism in response to growth signals and stress stimuli. The cellular functions of mTOR are mediated by two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. Rapamycin and its analogs are currently used in the clinic to treat a variety of diseases and have been instrumental in delineating the functions of its direct target, mTORC1. Despite the lack of a specific mTORC2 inhibitor, genetic studies that disrupt mTORC2 expression unravel the functions of this more elusive mTOR complex. Like mTORC1 which responds to growth signals, mTORC2 is also activated by anabolic signals but is additionally triggered by stress. mTORC2 mediates signals from growth factor receptors and G-protein coupled receptors. How stress conditions such as nutrient limitation modulate mTORC2 activation to allow metabolic reprogramming and ensure cell survival remains poorly understood. A variety of downstream effectors of mTORC2 have been identified but the most well-characterized mTORC2 substrates include Akt, PKC, and SGK, which are members of the AGC protein kinase family. Here, we review how mTORC2 is regulated by cellular stimuli including how compartmentalization and modulation of complex components affect mTORC2 signaling. We elaborate on how phosphorylation of its substrates, particularly the AGC kinases, mediates its diverse functions in growth, proliferation, survival, and differentiation. We discuss other signaling and metabolic components that cross-talk with mTORC2 and the cellular output of these signals. Lastly, we consider how to more effectively target the mTORC2 pathway to treat diseases that have deregulated mTOR signaling.

Hedayati N., Babaei Aghdam Z., Rezaee M., Mousavi Dehmordi R., Alimohammadi M., Mafi A.

Abstract: The most prevalent and severe malignancy of the central nervous system within the brain is glioma. Glioma is a vascularized cancer, and angiogenesis is necessary for glioma growth, invasion, and recurrence. It is also believed that this factor is this factor to be accountable for therapy resistance in many cancers, including glioma. The process of angiogenesis, which plays a crucial role in both health and disease situations such as cancer, involves the creation of new blood vessels from pre-existing ones. Non-coding RNAs (ncRNAs) are unique molecules that have been found to possess a wide range of abilities to modify the expression of various genes. They carry out their gene-modulating roles at a variety of distinct levels, including post-transcriptional and post-translational levels. Long ncRNAs (lncRNAs) and circular RNAs (circRNAs) are a group of ncRNA that have attracted particular attention and are involved in the angiogenesis mechanism in cancer. Understanding the regulatory mechanisms of these RNAs in the angiogenesis process in gliomas provides unique fundamental information about the process of tumor-associated neovascularization. On the other hand, due to developments in the characterisation of lncRNAs and circRNAs, these novel structures may potentially be used in clinics as possible biomarkers for treatment strategies that target tumor angiogenesis. Throughout the review, new knowledge and views about the angioregulatory function of circRNAs and lncRNAs in gliomas have been presented. Additionally, we talk about the novel idea of ncRNA-based therapeutics for gliomas in the future.

Pisignano G., Michael D.C., Visal T.H., Pirlog R., Ladomery M., Calin G.A.

AbstractTo date, thousands of highly abundant and conserved single-stranded RNA molecules shaped into ring structures (circRNAs) have been identified. CircRNAs are multifunctional molecules that have been shown to regulate gene expression transcriptionally and post-transcriptionally and exhibit distinct tissue- and development-specific expression patterns associated with a variety of normal and disease conditions, including cancer pathogenesis. Over the past years, due to their intrinsic stability and resistance to ribonucleases, particular attention has been drawn to their use as reliable diagnostic and prognostic biomarkers in cancer diagnosis, treatment, and prevention. However, there are some critical caveats to their utility in the clinic. Their circular shape limits their annotation and a complete functional elucidation is lacking. This makes their detection and biomedical application still challenging. Herein, we review the current knowledge of circRNA biogenesis and function, and of their involvement in tumorigenesis and potential utility in cancer-targeted therapy.

Fallone L., Walzer T., Marçais A.

CD8+ T cells and Natural Killer (NK) cells are cytotoxic lymphocytes important in the response to intracellular pathogens and cancer. Their activity depends on the integration of a large set of intracellular and environmental cues, including antigenic signals, cytokine stimulation and nutrient availability. This integration is achieved by signaling hubs, such as the mechanistic target of rapamycin (mTOR). mTOR is a conserved protein kinase that controls cellular growth and metabolism in eukaryotic cells and, therefore, is essential for lymphocyte development and maturation. However, our current understanding of mTOR signaling comes mostly from studies performed in transformed cell lines, which constitute a poor model for comprehending metabolic pathway regulation. Therefore, it is only quite recently that the regulation of mTOR in primary cells has been assessed. Here, we review the signaling pathways leading to mTOR activation in CD8+ T and NK cells, focusing on activation by cytokines. We also discuss how this knowledge can contribute to immunotherapy development, particularly for cancer treatment.

Araghi M., Mannani R., Heidarnejad maleki A., Hamidi A., Rostami S., Safa S.H., Faramarzi F., Khorasani S., Alimohammadi M., Tahmasebi S., Akhavan-Sigari R.

AbstractLung cancer continues to be the leading cause of cancer-related death worldwide. In the last decade, significant advancements in the diagnosis and treatment of lung cancer, particularly NSCLC, have been achieved with the help of molecular translational research. Among the hopeful breakthroughs in therapeutic approaches, advances in targeted therapy have brought the most successful outcomes in NSCLC treatment. In targeted therapy, antagonists target the specific genes, proteins, or the microenvironment of tumors supporting cancer growth and survival. Indeed, cancer can be managed by blocking the target genes related to tumor cell progression without causing noticeable damage to normal cells. Currently, efforts have been focused on improving the targeted therapy aspects regarding the encouraging outcomes in cancer treatment and the quality of life of patients. Treatment with targeted therapy for NSCLC is changing rapidly due to the pace of scientific research. Accordingly, this updated study aimed to discuss the tumor target antigens comprehensively and targeted therapy-related agents in NSCLC. The current study also summarized the available clinical trial studies for NSCLC patients.

Han D., Wang W., Jeon J.H., Shen T., Huang X., Yi P., Dong B., Yang F.

Phosphoinositide-dependent kinase-1 (PDK1) is a master kinase of the protein A, G, and C (AGC) family kinases that play important roles in regulating cancer cell proliferation, survival, and metabolism. Besides phosphorylating/activating AKT at the cell membrane in a PI3K-dependent manner, PDK1 also exhibits constitutive activity on many other AGC kinases for tumor-promoting activity. In the latter case, PDK1 protein levels dominate its activity. We previously reported that MAPK4, an atypical MAPK, can PI3K-independently promote AKT activation and tumor growth. Here, using triple-negative breast cancer (TNBC) cell models, we demonstrate that MAPK4 can also enhance PDK1 protein synthesis, thus phosphorylate/activate PDK1 substrates beyond AKT. This new MAPK4-PDK1 axis alone lacks vigorous tumor-promoting activity but cooperates with our previously reported MAPK4-AKT axis to promote tumor growth. Besides enhancing resistance to PI3K blockade, MAPK4 also promotes cancer cell resistance to the more stringent PI3K and PDK1 co-blockade, a recently proposed therapeutic strategy. Currently, there is no MAPK4 inhibitor to treat MAPK4-high cancers. Based on the concerted action of MAPK4-AKT and MAPK4-PDK1 axis in promoting cancer, we predict and confirm that co-targeting AKT and PDK1 effectively represses MAPK4-induced cancer cell growth, suggesting a potential therapeutic strategy to treat MAPK4-high cancers.

Safaroghli-Azar A., Sanaei M., Pourbagheri-Sigaroodi A., Bashash D.

Lipid signaling is defined as any biological signaling action in which a lipid messenger binds to a protein target, converting its effects to specific cellular responses. In this complex biological pathway, the family of phosphoinositide 3-kinase (PI3K) represents a pivotal role and affects many aspects of cellular biology from cell survival, proliferation, and migration to endocytosis, intracellular trafficking, metabolism, and autophagy. While yeasts have a single isoform of phosphoinositide 3-kinase (PI3K), mammals possess eight PI3K types divided into three classes. The class I PI3Ks have set the stage to widen research interest in the field of cancer biology. The aberrant activation of class I PI3Ks has been identified in 30–50% of human tumors, and activating mutations in PIK3CA is one of the most frequent oncogenes in human cancer. In addition to indirect participation in cell signaling, class II and III PI3Ks primarily regulate vesicle trafficking. Class III PI3Ks are also responsible for autophagosome formation and autophagy flux. The current review aims to discuss the original data obtained from international research laboratories on the latest discoveries regarding PI3Ks-mediated cell biological processes. Also, we unravel the mechanisms by which pools of the same phosphoinositides (PIs) derived from different PI3K types act differently.

Bou Antoun N., Chioni A.

One of the leading causes of death worldwide, in both men and women, is cancer. Despite the significant development in therapeutic strategies, the inevitable emergence of drug resistance limits the success and impedes the curative outcome. Intrinsic and acquired resistance are common mechanisms responsible for cancer relapse. Several factors crucially regulate tumourigenesis and resistance, including physical barriers, tumour microenvironment (TME), heterogeneity, genetic and epigenetic alterations, the immune system, tumour burden, growth kinetics and undruggable targets. Moreover, transforming growth factor-beta (TGF-β), Notch, epidermal growth factor receptor (EGFR), integrin-extracellular matrix (ECM), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR), wingless-related integration site (Wnt/β-catenin), Janus kinase/signal transducers and activators of transcription (JAK/STAT) and RAS/RAF/mitogen-activated protein kinase (MAPK) signalling pathways are some of the key players that have a pivotal role in drug resistance mechanisms. To guide future cancer treatments and improve results, a deeper comprehension of drug resistance pathways is necessary. This review covers both intrinsic and acquired resistance and gives a comprehensive overview of recent research on mechanisms that enable cancer cells to bypass barriers put up by treatments, and, like “satellite navigation”, find alternative routes by which to carry on their “journey” to cancer progression.

Yao Z., Liu N., Lin H., Zhou Y.

El-Tanani M., Nsairat H., Aljabali A.A., Serrano-Aroca-Angel Á., Mishra V., Mishra Y., Naikoo G.A., Alshaer W., Tambuwala M.M.

The signalling system known as mammalian target of rapamycin (mTOR) is believed to be required for several biological activities involving cell proliferation. The serine-threonine kinase identified as mTOR recognises PI3K-AKT stress signals. It is well established in the scientific literature that the deregulation of the mTOR pathway plays a crucial role in cancer growth and advancement. This review focuses on the normal functions of mTOR as well as its abnormal roles in cancer development.

Rezaee M., Mohammadi F., Keshavarzmotamed A., Yahyazadeh S., Vakili O., Milasi Y.E., Veisi V., Dehmordi R.M., Asadi S., Ghorbanhosseini S.S., Rostami M., Alimohammadi M., Azadi A., Moussavi N., Asemi Z., et. al.

Breast cancer (BC) is the most common malignancy among women worldwide. Like many other cancers, BC therapy is challenging and sometimes frustrating. In spite of the various therapeutic modalities applied to treat the cancer, drug resistance, also known as, chemoresistance, is very common in almost all BCs. Undesirably, a breast tumor might be resistant to different curative approaches (e.g., chemo- and immunotherapy) at the same period of time. Exosomes, as double membrane-bound extracellular vesicles 1) secreted from different cell species, can considerably transfer cell products and components through the bloodstream. In this context, non-coding RNAs (ncRNAs), including miRNAs, long ncRNAs (lncRNAs), and circular RNAs (circRNAs), are a chief group of exosomal constituents with amazing abilities to regulate the underlying pathogenic mechanisms of BC, such as cell proliferation, angiogenesis, invasion, metastasis, migration, and particularly drug resistance. Thereby, exosomal ncRNAs can be considered potential mediators of BC progression and drug resistance. Moreover, as the corresponding exosomal ncRNAs circulate in the bloodstream and are found in different body fluids, they can serve as foremost prognostic/diagnostic biomarkers. The current study aims to comprehensively review the most recent findings on BC-related molecular mechanisms and signaling pathways affected by exosomal miRNAs, lncRNAs, and circRNAs, with a focus on drug resistance. Also, the potential of the same exosomal ncRNAs in the diagnosis and prognosis of BC will be discussed in detail.

Wu D., Li Y., Xu A., Tang W., Yu B.

Circular RNAs (circRNAs) have been shown to play a crucial role in cancer occurrence and progression. This present work investigated the link between hsa_circ_0008234 and colon cancer. Data retrieved from GSE172229 was used to compare the circRNA profiles of colon cancer and surrounding non-tumorous tissues. The amount of RNA and protein in the molecules was determined using quantitative real-time PCR (qRT-PCR) and Western blot analysis, respectively. The cell proliferation ability was assessed using CCK8, EdU, colon formation, and nude mice tumorigenesis tests. Cell invasion and migration abilities were evaluated using transwell wound healing and mice lung metastasis model. Hsa_circ_0008234 piqued our interest because bioinformatics and qRT-PCR analyses revealed that it is upregulated in colon cancer tissue. Cell phenotypic studies suggest that hsa_circ_0008234 may significantly increase colon cancer cell aggressiveness. Mice experiments revealed that inhibiting hsa_circ_0008234 significantly reduced tumor growth and metastasis. Moreover, the fluorescence in situ hybridization experiment demonstrated that hsa_circ_0008234 is primarily found in the cytoplasm, implying that it potentially functions via a competitive endogenous RNA pathway. These findings indicated that hsa_circ_0008234 may act as a “molecular sponge” for miR-338-3p, increasing the expression of miR-338-target 3p’s ETS1. In addition, the traditional oncogenic pathway PI3K/AKT/mTOR signaling was found to be the potential downstream pathway of the hsa_circ_0008234/miR-338-3p/ETS1 axis. In conclusion, hsa_circ_0008234 increases colon cancer proliferation, infiltration, and migration via the miR-338-3p/ETS1/PI3K/AKT axis; therefore, it could serve as a target and a focus for colon cancer therapy.

He F., Liu Q., Liu H., Pei Q., Zhu H.

Sun C., Guan H., Li J., Gu Y.

Abstract Non-small cell lung cancer (NSCLC) accounts for 80% of total lung cancers, which are the main killer of cancer-related death worldwide. Circular RNA (circRNA) has been found to modulate NSCLC development. However, the role of circ_0000376 in NSCLC development has been underreported. The present work showed that circ_0000376 and 3-phos-phoinositide-dependent protein kinase-1 (PDPK1) expression were dramatically increased, but miR-545-3p was decreased in NSCLC tissues and cells. circ_0000376 expression was closely associated with lymph node metastasis, tumor-node-metastasis stage, and tumor size of NSCLC patients. circ_0000376 knockdown repressed NSCLC cell proliferation, migration, invasion, and glutaminolysis but induced cell apoptosis. Additionally, miR-545-3p bound to circ_0000376, and circ_0000376 regulated cell phenotypes by associating with miR-545-3p. MiR-545-3p also participated in NSCLC cell proliferation, migration, invasion, apoptosis, and glutaminolysis by targeting PDPK1. Further, circ_0000376 absence repressed tumor formation in vivo. Collectively, circ_0000376 regulated NSCLC cell tumor properties by the miR-545-3p/PDPK1 axis, suggesting that circ_0000376 could be employed as a therapeutic target for NSCLC.

Hashemi M., Gholamrezaei H., Ziyaei F., Asadi S., Naeini Z.Y., Salimian N., Enayat G., Sharifi N., Aliahmadi M., Rezaie Y.S., Khoushab S., Rahimzadeh P., Miri H., Abedi M., Farahani N., et. al.

Hashemi M., Fard A.A., pakshad B., Asheghabadi P.S., Hosseinkhani A., Hosseini A.S., Moradi P., Mohammadbeygi M., Najafi G., Farahzadi M., Khoushab S., Taheriazam A., Farahani N., Mohammadi M., Daneshi S., et. al.

Kahkesh S., Hedayati N., Rahimzadeh P., Farahani N., Khoozani M.F., Abedi M., Nabavi N., Naeimi B., Khoshnazar S.M., Alimohammadi M., Alaei E., mahmoodieh B.

Wang X., Chen Y., Ma C., Bi L., Su Z., Li W., Wang Z.

Shafieipour S., Zamanian Y., Hadipour E., Sinaei R., Khoshnazar S.M.

Abstract Background Colorectal carcinoma ranks as the second most prevalent neoplasm in females and the third most prevalent in males. Methods In this investigation, we examined the influence of alpha-pinene (ALP), classified as a monoterpene, on the proliferation of HT-29 human colorectal carcinoma cells via the PI3K/AKT signaling cascade. HT-29 cells were exposed to a range of ALP concentrations. The survival rate of the cells was assessed through the MTT assay; while, apoptotic events were evaluated using flow cytometry in conjunction with Annexin V/PI staining. Additionally, cell cycle dynamics were scrutinized through fluorescence-activated cell sorting. The expression levels of Bax, Bcl-2, Caspase-3, PI3K, and AKT at both the gene and protein levels were quantified employing real-time PCR and western blot techniques. Results ALP treatment led to a significant, dose-dependent decrease in cell viability, with prolonged exposure exacerbating cytotoxic effects. Apoptosis analysis showed that ALP significantly increased apoptotic cells after 24 h of treatment. Cell cycle analysis showed that ALP induces G2/M phase arrest and inhibits cell proliferation and DNA synthesis. Gene expression analysis revealed upregulation of pro-apoptotic genes Bax and caspase-3 and decreased anti-apoptotic gene Bcl-2. Furthermore, the administration of ALP led to a notable reduction in both the gene and protein expression levels of PI3K and Akt, suggesting a suppression of the PI3K/Akt signaling cascade. Conclusion ALP inhibits HT-29 colon cancer cell growth by reducing cell viability, inducing apoptosis, and blocking the PI3K/AKT pathway. These findings highlight ALP’s potential as a therapeutic candidate for colorectal cancer.

Shi M., Zhang R., Lyu H., Xiao S., Guo D., Zhang Q., Chen X., Tang J., Zhou C.

Sayaf H., Salimian N., Mohammadi M., Ahmadi P., Gholamzad A., Babashah S., Entezari M., Farahani N., Montazeri M., Hashemi M.

Li X., Wang X., Yu F., Li Z., Chen D., Qi Y., Lu Z., Liu Y., Chen D., Wu Y.

Wang C., Lv T., Jin B., Li Y., Fan Z.

Abstract Colorectal cancer (CRC) is one of the most common tumors in the digestive system, and the majority of patients are found to be in advanced stages, which is a burden to human health all over the world. Moreover, in recent years, CRC has been progressively becoming younger, with an increasing incidence mainly among patients <50 years old. Despite the increase in awareness of CRC and the continuous improvement of medical treatment nowadays, the challenge of CRC still needs to be conquered. By now, the pathogenesis of CRC is complex and not fully understood. With the deepening of research, it has been revealed that PPARs, as a transcription factor, are inextricably linked to CRC. This article outlines the mechanisms by which PPARs are involved in CRC development. An in-depth understanding of the pathways related to PPARs may provide new ways of developing effective therapies for CRC with PPARs as potential targets.

Qin X., Niu R., Tan Y., Huang Y., Ren W., Zhou W., Wu H., Zhang J., Xu M., Zhou X., Guan H., Zhu X., Chen Y., Cao K.

Abstract Background It is well-established that understanding the mechanism of prostate cancer (PCa)-associated metastasis is paramount for improving its prognosis. Metastasis is known to involve the communication between tumor-associated macrophages (TAMs) and tumor cells. Exosomes are crucial in mediating this intercellular communication within the tumor microenvironment. Nonetheless, the role of exosomal proteins in PCa metastasis is not yet fully understood. Here, we investigated the mechanisms of prostate cancer-derived exosomal PSM-E on regulating macrophage M2 polarization to suppress tumor invasion and metastasis. Methods PSM-E levels in exosomes were detected by transmission electron microscopy and Western blotting analysis. The diagnostic value of urine-derived exosomal PSM-E in PCa were evaluated by LC-MS/MS, correlation analysis, and ROC curves analysis. The mechanisms underlying the inhibitory effect of exosomal PSM-E on the M2 polarization of macrophages was investigated by co-IP, IHC staining, and PCa tumorigenesis model, etc. Results We revealed that exosomal PSM-E is upregulated in exosomes derived from the serum and urine of PCa patients. Clinically, an elevated exosomal PSM-E expression in urine is significantly correlated with an advanced pathological tumor stage and a high Gleason score. Our research also revealed that exosomal PSM-E inhibits prostate cancer cell proliferation, invasion, and metastasis by suppressing macrophage polarization in vitro and in vivo. Furthermore, we provided compelling evidence that exosomal PSM-E inhibits M2 polarization of macrophages by recruiting RACK1 and suppressing the FAK and ERK signaling pathways, consequently suppressing PCa invasion and metastasis. Furthermore, we found that the protease-associated domain of PSM-E and the fourth tryptophan-aspartate repeat of RACK1 are crucial for the interaction between PSM-E and RACK1. Conclusions Notably, exosomes carrying PSM-E from PCa urine could potentially serve as a biomarker for PCa, and targeting exosomal PSM-E may represent a strategy for preventing tumor progression in this patient population.

Sen O., Sarkar P., Das S., Giri N.K., Sarkar S., Jana S., Nandi G., Manna S.

AbstractLung cancer has become the leading cause of cancer‐related deaths, surpassing all other forms of cancer. Among lung cancers, non‐small cell lung cancer (NSCLC) accounts for approximately 85% of cases. The use of tobacco, genetic traits, and radiation exposure are amongst the major reasons of lung cancer. The ongoing research in the medical field has considered the efficacy of nanocarriers in targeting various cancer cells. Among several biomaterials, lipid‐based nanocarriers have gained special attention due to their excellent compatibility, improved targeting efficacy, and encapsulation ability of diverse therapeutic agents. Phospholipids are naturally occurring amphiphilic moieties found in all living creatures. The presence of phospholipids in biomembrane aids the permeability of phospholipid‐based drug carrier. It can also facilitate targeting of therapeutic agents to cancer microenvironment without degrading the encapsulated drug. Phospholipids can be employed to develop conjugated nanocarriers and vesicular nanoformulation that can result in prolonged circulatory half‐life and controlled release of drugs. Phospholipids are also suitable biomaterials to attach a ligand for tissue‐specific targeting. Recent researches have reported effective targeting of chemotherapeutic agents, genes, and vaccines through phospholipid‐based nanocarriers to lung cancer cells. This review focuses on the rationality and applications of phospholipid‐based nanocarriers in lung cancer therapy.

Helen H., Gunawan M.C., Halim P., Dinata M.R., Ahmed A., Dalimunthe A., Marianne M., Ribeiro R.I., Hasibuan P.A., Nurkolis F., Hey-hawkins E., Park M.N., Harahap U., Kim S., Kim B., et. al.

Pancreatic cancer (PC) is a complex malignancy, distinguished by its aggressive characteristics and unfavorable prognosis. Recent developments in understanding the molecular foundations of this disease have brought attention to the noteworthy involvement of microRNAs (miRNAs) in disease development, advancement, and treatment resistance. The anticancer capabilities of flavonoids, which are a wide range of phytochemicals present in fruits and vegetables, have attracted considerable interest because of their ability to regulate miRNA expression. This review provides the effects of flavonoids on miRNA expression in PC, explains the underlying processes, and explores the possible therapeutic benefits of flavonoid-based therapies. Flavonoids inhibit PC cell proliferation, induce apoptosis, and enhance chemosensitivity via the modulation of miRNAs involved in carcinogenesis. Additionally, this review emphasizes the significance of certain miRNAs as targets of flavonoid action. These miRNAs have a role in regulating important signaling pathways such as the phosphoinositide-3-kinase-protein kinase B/Protein kinase B (Akt), mitogen activated protein kinase (MAPK), Janus kinase/signal transducers and activators of transcription (JAK/STAT), and Wnt/β-catenin pathways. This review aims to consolidate current knowledge on the interaction between flavonoids and miRNAs in PC, providing a comprehensive analysis of how flavonoid-mediated modulation of miRNA expression could influence cancer progression and therapy. It highlights the use of flavonoid nanoformulations to enhance stability, increase absorption, and maximize anti-PC activity, improving patient outcomes. The review calls for further research to optimize the use of flavonoid nanoformulations in clinical trials, leading to innovative treatment strategies and more effective approaches for PC.

Mafi A., Hedayati N., Milasi Y.E., Kahkesh S., Daviran M., Farahani N., Hashemi M., Nabavi N., Alimohammadi M., Rahimzadeh P., Taheriazam A.

5-Fluorouracil (5-FU) is a well-known chemotherapy drug extensively used in the treatment of breast cancer. It works by inhibiting cancer cell proliferation and inducing cell death through direct incorporation into DNA and RNA via thymidylate synthase (TS). Circular RNAs (circRNAs), a novel family of endogenous non-coding RNAs (ncRNAs) with limited protein-coding potential, contribute to 5-FU resistance. Their identification and targeting are crucial for enhancing chemosensitivity. CircRNAs can regulate tumor formation and invasion by adhering to microRNAs (miRNAs) and interacting with RNA-binding proteins, regulating transcription and translation. MiRNAs can influence enzymes responsible for 5-FU metabolism in cancer cells, affecting their sensitivity or resistance to the drug. In the context of 5-FU resistance, circRNAs can target miRNAs and regulate biological processes such as cell proliferation, cell death, glucose metabolism, hypoxia, epithelial-to-mesenchymal transition (EMT), and drug efflux. This review focuses on the function of circRNAs in 5-FU resistance, discussing the underlying molecular pathways and biological mechanisms. It also presents recent circRNA/miRNA-targeted cancer therapeutic strategies for future clinical application.