MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression. Among these, miR-660, located on chromosome Xp11.23, is increasingly studied for its role in cancer due to its abnormal expression in various biological contexts. It is regulated by 8 competing endogenous RNAs (ceRNAs), which adds complexity to its function. miR- 660 targets 19 genes involved in 6 pathways such as PI3K/AKT/mTOR, STAT3, Wnt/β-catenin, p53, NF‑κB, and RAS, influencing cell cycle, proliferation, apoptosis, and invasion/migration. It also plays a role in resistance to chemotherapies like cisplatin, gemcitabine, and sorafenib in lung adenocarcinoma (LUAD), pancreatic ductal adenocarcinoma (PDAC), and hepatocellular carcinoma (HCC), thus highlighting its clinical importance. Additionally, leveraging liposomes as nanocarriers presents a promising avenue for enhancing cancer drug delivery. Our comprehensive study not only elucidates the aberrant expression patterns, biological functions, and regulatory networks of miR-660 and its ceRNAs but also delves into the intricate signaling pathways implicated. We envisage that our findings will furnish a robust framework and serve as a seminal reference for future investigations of miR-660, fostering advancements in cancer research and potentially catalyzing breakthroughs in cancer diagnosis and treatment paradigms.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignant tumor characterized by a poor prognosis. A prominent feature of PDAC is the rich and dense stroma present in the tumor microenvironment (TME), which significantly hinders drug penetration. Cancer-associated fibroblasts (CAFs), activated fibroblasts originating from various cell sources, including pancreatic stellate cells (PSCs) and mesenchymal stem cells (MSCs), play a critical role in PDAC progression and TME formation. MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules that are frequently involved in tumorigenesis and progression, exhibiting either oncolytic or oncogenic activity. Increasing evidence suggests that aberrant expression of miRNAs can mediate interactions between cancer cells and CAFs, thereby providing novel therapeutic targets for PDAC treatment. In this review, we will focus on the potential roles of miRNAs that target CAFs or CAFs-derived exosomes in PDAC progression, highlighting the feasibility of therapeutic strategies aimed at restoring aberrantly expressed miRNAs associated with CAFs, offering new pathways for the clinical management of PDAC.

Leukemia inhibitory factor (LIF) exerts an oncogenic function in several types of cancer, including hepatocellular carcinoma (HCC). However, small-molecule inhibitors of LIF haven't been established. Here, we identified that LIF was remarkably overexpressed in HCC by multi-omics approaches, indicating that inhibition of LIF would be a promising therapeutic strategy. Inhibiting LIF could suppress proliferation and metastasis by activating p38MAPK/p62-modulated mitophagy. Interestingly, we found that the natural small-molecule Cyclovirobuxine-D (CVB-D), was a new inhibitor of cytoplasmic LIF in HCC. We further validated LIF as a potential target of CVB-D through biotin-modified CVB-D-Probe utilizing mass spectrometry. Mechanistically, we showed that CVB-D could bind to LIF at Val145, thereby inducing mitophagy, accompanied by cell cycle arrest and inhibition of invasion and migration. Moreover, we demonstrated that CVB-D had a therapeutic potential by targeting LIF-modulated mitophagy in patient-derived xenograft (PDX) models, which would elucidate LIF as a druggable target and regulatory mechanisms and exploit CVB-D as the novel small-molecule inhibitor of LIF for future HCC drug discovery.

Noncoding RNAs (ncRNAs) are a class of RNA molecules with little or no protein-coding potential. Emerging evidence indicates that ncRNAs are frequently dysregulated and play pivotal roles in the pathogenesis of pancreatic cancer. Their aberrant expression can arise from chromosomal abnormalities, dysregulated transcriptional control, and epigenetic modifications. ncRNAs function as protein scaffolds or molecular decoys to modulate interactions between proteins and other biomolecules, thereby regulating gene expression and contributing to pancreatic cancer progression. In this review, we summarize the mechanisms underlying ncRNA dysregulation in pancreatic cancer, emphasize the biological significance of ncRNA-protein interactions, and highlight their clinical relevance. A deeper understanding of ncRNA-protein interactions is essential to elucidate molecular mechanisms and advance translational research in pancreatic cancer.

The tumor microenvironment (TME), a dynamic ecosystem which including immune cells, cancer-associated fibroblasts (CAFs), endothelial cells, pericytes and acellular components, is orchestrating cancer progression through crosstalk between malignant cells and stromal components and increasingly recognized as a therapeutic frontier. Within this intricate network, circular RNAs (circRNAs) have emerged as pivotal regulators due to their unique covalently closed structures, which confer exceptional stability and multifunctional capabilities. This regulation is mediated through multiple mechanisms, such as acting as microRNA (miRNA) sponges, interacting with proteins, and, in certain instances, encoding functional peptides. The interaction between circRNAs and the TME not only affects cancer growth and metastasis but also influences immune evasion and therapeutic resistance. Elucidating the mechanisms by which circRNAs orchestrate these interactions is essential for identifying novel diagnostic biomarkers and developing effective therapeutic strategies. Such insights are expected to bridge gaps in current cancer biology, offering promising avenues for precision oncology and ultimately improving clinical outcomes for cancer patients.

The tumor microenvironment (TME) is a complex and dynamic ecosystem that plays a critical role in cancer progression. It comprises various cell types, including immune cells, tumor cells, and stromal cells. Among these, cancer-associated fibroblasts (CAFs) represent a heterogeneous population with diverse origins, phenotypes, and functions. Activated CAFs secrete multiple factors that promote tumor growth, migration, angiogenesis, and contribute to chemoresistance. Additionally, CAFs secrete extracellular matrix (ECM) components, such as collagen, which form a physical barrier that hinders the penetration of chemotherapeutic and immunotherapeutic agents. This ECM also influences immune cell infiltration, impeding their ability to effectively target tumor cells. As a result, modulating the activity of CAFs has emerged as a promising strategy to enhance the efficacy of tumor immunotherapy. Nano-delivery systems, constructed from various nanomaterials with high targeting specificity and biocompatibility, offer a compelling approach to deliver therapeutic agents or immunomodulatory factors directly to CAFs. This modulation can alter CAF function, reduce their tumor-promoting effects, and thereby improve the outcomes of immunotherapy. This review provides an in-depth exploration of the origins, functions, and interactions of CAFs within the TME, particularly in the context of immune suppression. Furthermore, it discusses the potential applications of functional nanocarrifers in modulating CAFs and enhancing the effectiveness of tumor immunotherapy, highlighting the significant progress and potential of nanotechnology in this area.

Circular RNAs (circRNAs) have emerged as critical regulators in cancer biology, contributing to various cancer hallmarks, including cell proliferation, apoptosis, metastasis, and drug resistance. Defined by their covalently closed loop structure, circRNAs possess unique characteristics like high stability, abundance, and tissue-specific expression. These non-coding RNAs function through mechanisms such as miRNA sponging, interactions with RNA-binding proteins (RBPs), and modulating transcription and splicing. Advances in RNA sequencing and bioinformatics tools have enabled the identification and functional annotation of circRNAs across different cancer types. Clinically, circRNAs demonstrate high specificity and sensitivity in samples, offering potential as diagnostic and prognostic biomarkers. Additionally, therapeutic strategies involving circRNA mimics, inhibitors, and delivery systems are under investigation. However, their precise mechanisms remain unclear, and more clinical evidence is needed regarding their roles in cancer hallmarks. Understanding circRNAs will pave the way for novel diagnostic and therapeutic approaches, potentially improving patient outcomes.

Circular RNAs (circRNAs) are a class of novel RNA molecules featured by single-strand covalently closed circular structure, which not only are extensively found in eukaryotes and are highly conserved, but also conduct paramount roles in the occurrence and progression of pancreatic cancer (PC) through diverse mechanisms. As recent studies have demonstrated, circRNAs typically exhibit tissue-specific and cell specific expression patterns, with strong potential as biomarkers for disease diagnosis and prognosis. On the basis of their localization and specific interactions with DNA, RNA, and proteins, circRNAs are considered to possess specific biological functions by acting as microRNA (miRNA) sponges, RNA binding protein (RBP) sponges, transcriptional regulators, molecular scaffolds and translation templates. On that account, further addressing the technical difficulties in the detection and research of circRNAs and filling gaps in their biological knowledge will definitely push ahead this comparatively young research field and bring circRNAs to the forefront of clinical practice. Thus, this review systematically summarizes the biogenesis, function, molecular mechanisms, biomarkers and therapeutic targets of circRNAs in PC.

Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis, leading to a notably low five-year survival rate. This study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers, such as mutations in CDKN2A, KRAS, SMAD4, and TP53, along with the influence of cancer-associated fibroblasts (CAFs) on disease progression. In particular, we focused on the pivotal roles of signaling pathways such as the transforming growth factor-β and Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic strategies. This study provides new scientific perspectives on pancreatic cancer treatment, especially in the development of precision medicine and targeted therapeutic strategies, and demonstrates the importance of signaling pathway research in the development of effective therapeutic regimens. Future studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.

Cancer-associated fibroblasts (CAFs) play a key role in oxaliplatin resistance in pancreatic ductal adenocarcinoma (PDAC). However, the potential mechanisms by which CAFs promote chemotherapy resistance have not yet been explored. In this study, we found that circABCC4 (hsa_circ_0030582) was positively correlated with poor platinum-chemotherapeutic response and a shorter progression-free survival (PFS) time in late-stage PDAC patients. CircABCC4 enhanced the ability of CAFs to induce oxaliplatin resistance in pancreatic cancer cells through glycolysis reprogramming. Mechanistically, circABCC4 enhanced the interaction between PKM2 and KPNA2 to promote PKM2 nuclear translocation in CAFs, leading to the transcription of glycolysis-related genes. The glycolytic reprogramming of CAFs promoted the secretion of IL-8, which in turn enhanced DNA damage repair in pancreatic cancer. Blocking PKM2 nuclear translocation abolished circABCC4-driven oxaliplatin resistance of pancreatic cancer in vivo. Collectively, our study reveals a circRNA-mediated glycolysis reprogramming of CAFs to induce oxaliplatin resistance and highlights circABCC4 as a potential therapeutic target.

Cancer-associated fibroblasts (CAFs) are key components of tumor microenvironment and have been identified to be involved in modulating drug resistance in cancers by secreting molecules. Pancreatic cancer (PC) is a leading cause of cancer mortality with high aggressiveness. Gemcitabine (GEM) is one of primary antineoplastic drugs for PC. Collagen XVII (COL17A1) expression was found to be upregulated in GEM-resistant CAFs. Here, this study focused on investigating whether CAFs affected GEM resistance in PC by secreting COL17A1 and its associated mechanisms.

In total, 60 newly diagnosed PC patients only with GEM-based chemotherapy were recruited. Normal fibroblasts (NFs) and CAFs were isolated using fresh normal and resistant PC tissues. Human pancreatic duct epithelial (HPDE) cells were used for functional analyses. Levels of COL17A1 and Actinin Alpha 4 (ACTN4) were measured by using qRT-PCR and western blotting. Functional analyses were conducted using MTT, 5-ethynyl-2'-deoxyuridine, transwell, and sphere formation assays, respectively. The interaction between COL17A1 and ACTN4 was analyzed by Co-immunoprecipitation and immunofluorescence assays. Animal models were established for in vivo analysis.

CAF incubation promoted GEM resistance and enhanced the proliferation, invasion and stemness in GEM-resistant PC cells. COL17A1 was highly expressed in resistant CAFs and GEM-resistant PC cells, and CAF incubation could increase COL17A1 expression in resistant PC cells. Moreover, COL17A1 silencing in GEM-resistant PC cells or the incubation of COL17A1-decreased CAF with GEM-resistant PC cells could suppress GEM resistance and cell oncogenic phenotype progression. Mechanistically, COL17A1 interacted with ACTN4 protein, and the anticancer effects mediated by COL17A1-decreased CAFs in resistant PC cells were reversed by ACTN4 overexpression. In vivo assay also showed that COL17A1-decreased CAFs suppressed the growth and GEM resistance in PC by ACTN4.

CAFs-derived COL17A1 promoted GEM resistance and tumorigenesis in PC by interacting with ACTN4, suggesting a new method for overcoming GEM resistance in PC.

Circular RNA (circRNA), a subtype of noncoding RNA, has emerged as a significant focus in RNA research due to its distinctive covalently closed loop structure. CircRNAs play pivotal roles in diverse physiological and pathological processes, functioning through mechanisms such as miRNAs or proteins sponging, regulation of splicing and gene expression, and serving as translation templates, particularly in the context of various cancers. The hallmarks of cancer comprise functional capabilities acquired during carcinogenesis and tumor progression, providing a conceptual framework that elucidates the nature of the malignant transformation. Although numerous studies have elucidated the role of circRNAs in the hallmarks of cancers, their functions in the development of chemoradiotherapy resistance remain unexplored and the clinical applications of circRNA-based translational therapeutics are still in their infancy. This review provides a comprehensive overview of circRNAs, covering their biogenesis, unique characteristics, functions, and turnover mechanisms. We also summarize the involvement of circRNAs in cancer hallmarks and their clinical relevance as biomarkers and therapeutic targets, especially in thyroid cancer (TC). Considering the potential of circRNAs as biomarkers and the fascination of circRNA-based therapeutics, the "Ying-Yang" dynamic regulations of circRNAs in TC warrant vastly dedicated investigations.

Transcription factors (TFs) fulfill a critical role in the formation and maintenance of different cell types during the developmental process as well as disease. It is believed that cancer-associated fibroblasts (CAFs) are activation status of tissue-resident fibroblasts or derived from form other cell types via transdifferentiation or dedifferentiation. Despite a subgroup of CAFs exhibit anti-cancer effects, most of them are reported to exert effects on tumor progression, further indicating their heterogeneous origin.

This review aimed to summarize and review the roles of TFs in the reciprocal crosstalk between CAFs and tumor cells, discuss the emerging mechanisms, and their roles in cell-fate decision, cellular reprogramming and advancing our understanding of the gene regulatory networks over the period of cancer initiation and progression.

This manuscript delves into the key contributory factors of TFs that are involved in activating CAFs and maintaining their unique states. Additionally, it explores how TFs play a pivotal and multifaceted role in the reciprocal crosstalk between CAFs and tumor cells. This includes their involvement in processes such as epithelial-mesenchymal transition (EMT), proliferation, invasion, and metastasis, as well as metabolic reprogramming. TFs also have a role in constructing an immunosuppressive microenvironment, inducing resistance to radiation and chemotherapy, facilitating angiogenesis, and even 'educating' CAFs to support the malignancies of tumor cells. Furthermore, this manuscript delves into the current status of TF-targeted therapy and considers the future directions of TFs in conjunction with anti-CAFs therapies to address the challenges in clinical cancer treatment.

The innate ability to produce neurotrophic cytokines is a crucial component of retinal neuroprotection. Reduced levels of these cytokines accelerate neuronal cell death in the retina during injury but prolonged overexpression can lead to inflammation and retinal damage. It is therefore critical to find molecular targets that regulate the endogenous production of retinal neurotrophic factors. Outside of the eye, caveolins play essential roles in preconditioning, pro-survival signaling, and neuronal protection. They amplify the secretion of neuroprotective cytokines such as leukemia inhibitory factor (LIF), an important retinal neurotroph. We hypothesize that Caveolin-1 (Cav1) in the retina is required for retinal neuroprotection. This mini-review summarizes findings on the cytoprotective roles of Cav1 and how it may be required for retinal neuroprotection.

Although gemcitabine (GEM) is the cornerstone of the treatment of pancreatic cancer (PC), GEM resistance frequently arises. Circular RNA (circRNA) circ_0075829 is highly expressed in PC. However, whether circ_0075829 contributes to GEM resistance of PC is largely unknown. To generate GEM-resistant PC cells (BxPC-3/GR and SW1990/GR), we exposed GEM-sensitive PC cells to GEM. Circ_0075829, microRNA (miR)-326, and glutamic-oxaloacetic transaminase 1 (GOT1) were quantified by a qRT-PCR or western blot method. Cell survival and viability were gauged by MTS assay. Cell proliferation, apoptosis, invasion, and migration were assessed by EdU, flow cytometry, transwell, and wound-healing assays, respectively. Dual-luciferase reporter assays were used to verify the relationship between miR-326 and circ_0075829 or GOT1. Mouse xenografts were performed to evaluate the role of circ_0075829 in vivo. Our data showed that circ_0075829 was upregulated in GEM-resistant PC tissues and cells. Knockdown of circ_0075829 impeded the proliferation, invasion, migration, and glutamine metabolism, and promoted cell apoptosis and GEM sensitivity of GEM-resistant PC cells. Moreover, circ_0075829 silencing suppressed the tumorigenicity of SW1990/GR cells and sensitized them to the cytotoxic effect of GME in vivo. Mechanistically, circ_0075829 bound miR-326 and exerted regulatory effects by affecting miR-326 expression. GOT1 was a direct miR-326 target and a key downstream effector of miR-326. Furthermore, circ_0075829 modulated GOT1 expression via miR-326. Our findings establish a novel regulatory network, the circ_0075829/miR-326/GOT1 competing endogenous RNA (ceRNA) crosstalk, in the regulation of GEM resistance in PC.

Circular RNAs (circRNAs) are endogenous covalently closed single-stranded RNAs produced by reverse splicing of pre-mRNA. Emerging evidence suggests that circRNAs contribute to cancer progression by modulating the oncogenic STAT3 signaling pathway, which plays key roles in human malignancies. STAT3 signaling-related circRNAs expression appears to be extensively dysregulated in diverse cancer types, where they function either as tumor suppressors or oncogenes. However, the biological effects of STAT3 signaling-related circRNAs and their associations with cancer have not been systematically studied before. Given this, shedding light on the interaction between circRNAs and STAT3 signaling pathway in human malignancies may provide several novel insights into cancer therapy. In this review, we provide a comprehensive introduction to the molecular mechanisms by which circRNAs regulate STAT3 signaling in cancer progression, and the crosstalk between STAT3 signaling-related circRNAs and other signaling pathways. We also further discuss the role of the circRNA/STAT3 axis in cancer chemotherapy sensitivity.

Osteosarcoma (OS) is a primary malignancy of bone. The emergence of chemoresistance represents a persistent barrier to effective cancer patient care. This analysis sought to examine hsa_circ_0078767 as a mediator of doxorubicin (DOX) resistance in OS.

Levels of hsa_circ_0078767, miR-188-3p, and glutathione peroxidase 4 (GPX4) in OS clinical tissue samples and cell lines were evaluated by quantitative polymerase chain reaction (qPCR) and Western blotting. Associations between hsa_circ_0078767 levels in clinical samples and patient overall survival were assessed with Kaplan-Meier curves. CCK-8 assays were utilized as a means of examining DOX half-inhibitory concentration (IC50) values. RNA immunoprecipitation and pull-down, as well as reporter assays, investigated interactions between hsa_circ_0078767, miR-188-3p, and GPX4 within OS cells exhibiting DOX resistance.

OS patient tissues and cell lines resistant to DOX exhibited elevated hsa_circ_0078767 and GPX4 expression together with a reduction in miR-188-3p levels. Inhibiting hsa_circ_0078767 expression contributed to a profound decrease in the ability of OS tumors to resist DOX. Mechanistically, it was determined that hsa_circ_0078767 can enhance DOX chemoresistance through its ability to bind and sequester miR-188-3p, which otherwise negatively modulates GPX4 to enhance chemosensitivity. Accordingly, the sequestration of miR-188-3p by hsa_circ_0078767 led to the derepression and upregulation of GPX4.

Hsa_circ_0078767 was found to modulate miR-188-3p/GPX4 signaling to enhance OS cell resistance to DOX treatment and facilitate disease progression. As such, hsa_circ_0078767 may represent a valuable biomarker or target for use in the context of OS patient management.

Despite the ongoing advances in interventional strategies (surgery, chemotherapy, radiotherapy, and immunotherapy) for managing pancreatic ductal adenocarcinoma (PDAC), the development of therapy refractory phenotypes remains a significant challenge. Resistance to various therapeutic modalities in PDAC emanates from a combination of inherent and acquired factors and is attributable to cancer cell-intrinsic and -extrinsic mechanisms. The critical determinants of therapy resistance include oncogenic signaling and epigenetic modifications that drive cancer cell stemness and metabolic adaptations, CAF-mediated stromagenesis that results in ECM deposition altered mechanotransduction, and secretome and immune evasion. We reviewed the current understanding of these multifaceted mechanisms operating in the PDAC microenvironment, influencing the response to chemotherapy, radiotherapy, and immunotherapy regimens. We then describe how the lessons learned from these studies can guide us to discover novel therapeutic regimens to prevent, delay, or revert resistance and achieve durable clinical responses.

Pancreatic adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer deaths by 2030 and this is mostly due to therapy failure. Limited treatment options and resistance to standard-of-care (SoC) therapies makes PDAC one of the cancer types with poorest prognosis and survival rates [1,2]. Pancreatic tumors are renowned for their poor response to therapeutic interventions including targeted therapies, chemotherapy and radiotherapy. Herein, we review hallmarks of therapy resistance in PDAC and current strategies aiming to tackle escape mechanisms and to re-sensitize cancer cells to therapy. We will further provide insights on recent advances in the field of drug discovery, nanomedicine, and disease models that are setting the ground for future research.

Chemotherapy resistance has been a great challenge in pancreatic ductal adenocarcinoma(PDAC) treatments. Current first-line chemotherapy regimens for PDAC include gemcitabine-based regimens such as AG regimen (albumin paclitaxel and gemcitabine), fluorouracil-based regiments such as FOLFIRINOX regimen ((5-fluorouracil5-FU), oxaliplatin, Irinotecan) and platinum-based regimens for patients with BRCA mutations. large amounts of work have been done on exploring the mechanism underlying resistance of gemcitabine-based and platinum-based regimens, while little research has been achieved on the mechanism of FOLFIRINOX regimens resistance. Hence, we identified Polypeptide N-Acetylgalactosaminyltransferase 5, (GALNT5) as a vital regulator and a potential therapeutic target in FOLFIRINOX regimens resistance. Colony formation assays and flow cytometry assays were performed to explore the roles of GALNT5 in cell proliferation and apoptosis in PDAC treated with FOLFIRINOX. IC50 alterations were calculated in GALNT5 knockdown and overexpressed cell lines. RNA-seq followed by GSEA (gene set enrichment analysis) was displayed to explore the potential mechanism. WB (western blotting), real-time PCR, and IF (immunofluorescence) were performed to validate relative pathways. The mouse orthotopic xenograft PDAC model was established to examine GALNT5 functions in vivo. GALNT5 was highly expressed in PDAC tissues and predicted poor prognosis in PDAC. Upregulation of GALNT5 in PDAC cells conferred FOLFIRINOX resistance on PDAC by inhibiting DNA damage. Moreover, GALNT5 interacted with MYH9, thus participating in the activation of the NOTCH pathways, resulting in hampering FOI-induced DNA damage. Functions of GALNT5 promoting FOLFIRINOX resistance were validated in vivo. In this study, we found that aberrantly overexpressed GALNT5 in PDAC took part in the activation of the NOTCH pathway by interacting with MYH9, thus inhibiting the DDR to achieve FOLFIRINOX resistance and causing poor prognosis. We identified GALNT5 as a potential therapeutic target for PDAC patients resistant to FOLFIRINOX chemotherapy.

The pleiotropic effect of cancer-associated fibroblasts (CAFs) on tumour progression depends on the environment. circFARP1 is critical for CAFs-induced gemcitabine (GEM) resistance in pancreatic cancer. Its specific role and mechanism in non-small cell lung cancer (NSCLC) have not been reported yet. We prepared a cancer-associated fibroblasts-conditioned medium (CAF-CM) to incubate the A549 cells. Quantitative real-time polymerase chain reaction was used to detect RNA levels. We detected protein expression by immunohistochemistry, immunocytochemistry, western blot and immunofluorescence. We also detected the targeting impact between circFARP1, miR-338-3p and SRY-box transcription factor 4 (SOX4) by using dual-luciferase reporter and RNA pull-down assays. We determined cell proliferation, migration and invasion capabilities through Cell Counting Kit-8 and transwell assays. In addition, we measured tumour volume and weight in vivo by establishing a xenograft tumour model. CircFARP1 levels were remarkably high in the CAFs. The transfection experiments found that circFARP1 downregulation in CAFs caused migration, proliferation and invasion inhibition of CAFs and A549 cells, whereas inhibiting miR-38-3p or overexpressing SOX4 in CAFs could significantly reverse the inhibition. In vivo study in nude mice confirmed that CAFs could promote NSCLC tumour growth and knockdown of circFARP1 could inhibit tumour growth of NSCLC, whereas miR-38-3p downregulation or SOX4 overexpression could significantly reverse the inhibition. circFARP1 promotes NSCLC development by stimulating miR-338-3p/SOX4 signalling axis to regulate CAFs.

Pancreatic cancer is a devastating malignancy with a high mortality rate, poor prognosis, and limited treatment options. The tumor microenvironment (TME) plays a crucial role in tumor progression and therapy resistance. Multiple subpopulations of cancer-associated fibroblasts (CAFs) within the TME can switch between different states, exhibiting both antitumorigenic and protumorigenic functions in pancreatic cancer. It seems that targeting fibroblast-related proteins and other stromal components is an appealing approach to combat pancreatic cancer. This study employed single-cell transcriptome sequencing to identify MME (Membrane Metalloendopeptidase)-expressing CAFs in pancreatic cancer. Systematic screening was conducted based on tumor differentiation, lymph node metastasis, and T-stage parameters to identify and confirm the existence of a subpopulation of fibroblasts termed MME+CAFs. Subsequent analyses included temporal studies, exploration of intercellular communication patterns focusing on the hypoxia signaling pathway, and investigation of MME+CAF functions in the pancreatic cancer microenvironment. The pathway enrichment analysis and clinical relevance revealed a strong association between high MME expression and glycolysis, hypoxia markers, and pro-cancer inflammatory pathways. The role of MME+CAFs was validated through in vivo and in vitro experiments, including high-throughput drug screening to evaluate potential targeted therapeutic strategies. Single-cell transcriptome sequencing revealed tumor-associated fibroblasts with high MME expression, termed MME+CAF, exhibiting a unique end-stage differentiation function in the TME. MME+CAF involvement in the hypoxia signaling pathway suggested the potential effects on pancreatic cancer progression through intercellular communication. High MME expression was associated with increased glycolysis, hypoxia markers (VEGF), and pro-cancer inflammatory pathways in pancreatic cancer patients, correlating with lower survival rates, advanced disease stage, and higher oncogene mutation rates. Animal experiments confirmed that elevated MME expression in CAFs increases tumor burden, promotes an immunosuppressive microenvironment, and enhances resistance to chemotherapy and immunotherapy. The developed MME+CAF inhibitor IOX2 (a specific prolyl hydroxylase-2 (PHD2) inhibitor), combined with AG (Paclitaxel + Gemcitabine) and anti-PD1 therapy, demonstrated promising antitumor effects, offering a translational strategy for targeting MME in CAFs of pancreatic cancer. The study findings highlighted the significant role of MME+CAF in pancreatic cancer progression by shaping the TME and influencing key pathways. Targeting MME presented a promising strategy to combat the disease, with potential implications for therapeutic interventions aimed at disrupting MME+CAF functions and enhancing the efficacy of pancreatic cancer treatments.

Circular RNAs (circRNAs) can influence a variety of biological functions and act as a significant role in the progression and recurrence of glioblastoma (GBM). However, few coding circRNAs have been discovered in cancer, and their role in GBM is still unknown. The aim of this study was to identify coding circRNAs and explore their potential roles in the progression and recurrence of GBM.

CircSPECC1 was screened via circRNAs microarray of primary and recurrent GBM samples. To ascertain the characteristics and coding ability of circSPECC1, we conducted a number of experiments. Afterward, through in vivo and in vitro experiments, we investigated the biological functions of circSPECC1 and its encoded novel protein (SPECC1-415aa) in GBM, as well as their effects on TMZ sensitivity.

By analyzing primary and recurrent GBM samples via circRNAs microarray, circSPECC1 was found to be a downregulated circRNA with coding potential in recurrent GBM compared with primary GBM. CircSPECC1 suppressed the proliferation, migration, invasion, and colony formation abilities of GBM cells by encoding a new protein known as SPECC1-415aa. CircSPECC1 restored TMZ sensitivity in TMZ-resistant GBM cells by encoding the new protein SPECC1-415aa. The m6A reader protein IGF2BP1 can bind to circSPECC1 to promote its expression and stability. Mechanistically, SPECC1-415aa can bind to ANXA2 and competitively inhibit the binding of ANXA2 to EGFR, thus resulting in the inhibition of the phosphorylation of EGFR (Tyr845) and its downstream pathway protein AKT (Ser473). In vivo experiments showed that the overexpression of circSPECC1 could combine with TMZ to treat TMZ-resistant GBM, thereby restoring the sensitivity of TMZ-resistant GBM to TMZ.

CircSPECC1 was downregulated in recurrent GBM compared with primary GBM. The m6A reader protein IGF2BP1 could promote the expression and stability of circSPECC1. The sequence of SPECC1-415aa, which is encoded by circSPECC1, can inhibit the binding of ANXA2 to EGFR by competitively binding to ANXA2 and inhibiting the phosphorylation of EGFR and AKT, thereby restoring the sensitivity of TMZ-resistant GBM cells to TMZ.

Cancer-associated fibroblasts (CAFs) are a diverse stromal cell population within the tumour microenvironment, where they play fundamental roles in cancer progression and patient prognosis. Multiple lines of evidence have identified that CAFs are critically involved in shaping the structure and function of the tumour microenvironment with numerous functions in regulating tumour behaviours, such as metastasis, invasion, and epithelial-mesenchymal transition (EMT). CAFs can interact extensively with cancer cells by producing extracellular vesicles (EVs), multiple secreted factors, and metabolites. Notably, CAF-derived EVs have been identified as critical mediators of cancer therapy resistance, and constitute novel therapy targets and biomarkers in cancer management. This review aimed to summarize the biological roles and detailed molecular mechanisms of CAF-derived EVs in mediating cancer resistance to chemotherapy, targeted therapy agents, radiotherapy, and immunotherapy. We also discussed the therapeutic potential of CAF-derived EVs as novel targets and clinical biomarkers in cancer clinical management, thereby providing a novel therapeutic strategy for enhancing cancer therapy efficacy and improving patient prognosis.

Circular RNAs (circRNAs) lack the 5'-end methylated guanine cap structure and 3' polyadenylate tail structure, classifying it as a non-coding RNA. With the extensive investigation of circRNA, its role in regulating cell death has garnered significant attention in recent years, establishing it as a recognized participant in cancer's biological processes. Autophagy, an essential pathway in programmed cell death (PCD), involves the formation of autophagosomes using lysosomes to degrade cellular contents under the regulation of various autophagy-related (ATG) genes. Numerous studies have demonstrated that circRNA can modulate the biological activity of cancer cells by influencing the autophagy pathway, exhibiting a dualistic role in suppressing or promoting carcinogenesis. In this review, we comprehensively analyze how autophagy-related circRNA impacts the progression of gastrointestinal cancer (GIC). Additionally, we discuss drug resistance phenomena associated with autophagy regulation in GIC. This review offers valuable insights into exploring potential biological targets for prognosis and treatment strategies related to GIC.

Due to resistance to gemcitabine (GEM), patients with pancreatic cancer (PC) usually have poor prognosis and low survival rate. The purpose of our research was to explore the impact of exosome PPP3CB on GEM resistance in PC, and concurrently analyze the regulatory role of the miR-298/STAT3 signaling pathway.

Exosomes isolated from PC cells were verified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting (WB). The interaction between PPP3CB and miR-298 was verified using dual-luciferase reporter gene assay, followed by evaluation of cell growth and death using CCK8 assay, EdU staining, and flow cytometry.

Increased PPP3CB expression was observed in GEM-resistant PC cells. Exosomes from PC cells and GEM-resistant PC cells were successfully extracted by ultra-high speed centrifugation. Confocal microscopy showed internalization of fluorescein amide (FAM)-labeled GEM-resistant exosomes by PC cells. PPP3CB enhanced the proliferation of GEM-resistant PC cells and inhibited their apoptosis, whereas down-regulation of PPP3CB promoted the death of PC cells and inhibited the proliferation of GEM-resistant PC cells, and enhance the susceptibility of PC cells to GEM. Additionally, PPP3CB positively regulated STAT3 expression in PC cells by down-regulating miR-298, thus promoting the growth and inhibiting the death of PC cells.

PC cell-derived exosome PPP3CB enhances STAT3 expression by downregulating miR-298, stimulating cell growth, and suppressing cell death, thereby increasing the resistance of PC cells to GEM.

An increasing number of circRNAs have been found to be involved in the development of gastric cancer. However, the function of circ_0003789 in regulating gastric cancer progression is unclear. Here, we aimed to investigate the expression, function and molecular mechanism of circ_0003789 in gastric cancer pathogenesis. Circ_0003789, miR-429 and ZFP36 ring finger protein like 2 (ZFP36L2) mRNA were quantified by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was illustrated by 5-Ethynyl-2'-deoxyuridine (Edu), cell counting kit-8 (CCK-8) and colony formation assays. Apoptosis was determined by flow cytometry. Protein level was detected by Western blotting assay. Xenograft assays were used for functional analysis of circ_0003789 in vivo. The relationship between miR-429 and circ_0003789 or ZFP36L2 was predicted by starbase3.0 online database and identified by dual luciferase reporter assay. The expression levels of circ_0003789 and ZFP36L2 were significantly upregulated in gastric cancer tissues and cells, while the expression of miR-429 was downregulated. Downregulation of circ_0003789 inhibited gastric cancer cell growth and invasion and promoted apoptosis in vitro. Circ_0003789 acted as a sponge of miR-429. Moreover, miR-429 silencing by miR-429 inhibitors attenuated the effects of circ_0003789 interference on cell growth, apoptosis and invasion. ZFP36L2 was targeted by miR-429, and the effects of miR-429 on cell growth, invasion and apoptosis were attenuated by ZFP36L2 overexpression. Circ_0003789 could enhance ZFP36L2 expression by interacting with miR-429. Silencing of circ_0003789 inhibited tumor growth in vivo. Circ_0003789 regulates tumor progression in gastric cancer through miR-429/ZFP36L2 axis. This finding implies that circ_0003789 may be a therapeutic target for gastric cancer.

We have reviewed the literature for circular RNAs (circRNAs) with efficacy in preclinical pancreatic-cancer related in vivo models. The identified circRNAs target chemoresistance mechanisms (n=5), secreted proteins and transmembrane receptors (n=15), transcription factors (n=9), components of the signaling- (n=11), ubiquitination- (n=2), autophagy-system (n=2), and others (n=9). In addition to identifying targets for therapeutic intervention, circRNAs are potential new entities for treatment of pancreatic cancer. Up-regulated circRNAs can be inhibited by antisense oligonucleotides (ASO), small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs) or clustered regularly interspaced short-palindromic repeats-CRISPR associated protein (CRISPR-CAS)-based intervention. The function of down-regulated circRNAs can be reconstituted by replacement therapy using plasmids or virus-based vector systems. Target validation experiments and the development of improved delivery systems for corresponding agents were examined.

Keloids are pathological scar tissue resulting from skin trauma or spontaneous formation, often accompanied by itching and pain. Although GNAS antisense RNA 1 (GNAS-AS1) shows abnormal upregulation in keloids, the underlying molecular mechanism is unclear. The levels of genes and proteins in clinical tissues from patients with keloids and human keloid fibroblasts (HKFs) were measured using quantitative reverse transcription PCR, western blot and enzyme-linked immunosorbent assay. The features of HKFs, including proliferation and migration, were evaluated using cell counting kit 8 and a wound healing assay. The colocalization of GNAS-AS1 and miR-196a-5p in HKFs was measured using fluorescence in situ hybridization. The relationships among GNAS-AS1, miR-196a-5p and C-X-C motif chemokine ligand 12 (CXCL12) in samples from patients with keloids were analysed by Pearson correlation analysis. Gene interactions were validated by chromatin immunoprecipitation and luciferase reporter assays. GNAS-AS1 and CXCL12 expression were upregulated and miR-196a-5p expression was downregulated in clinical tissues from patients with keloids. GNAS-AS1 knockdown inhibited proliferation, migration, and extracellular matrix (ECM) accumulation of HKFs, all of which were reversed by miR-196a-5p downregulation. Signal transducer and activator of transcription 3 (STAT3) induced GNAS-AS1 transcription through GNAS-AS1 promoter interaction, and niclosamide, a STAT3 inhibitor, decreased GNAS-AS1 expression. GNAS-AS1 positively regulated CXCL12 by sponging miR-196-5p. Furthermore, CXCL12 knockdown restrained STAT3 phosphorylation in HKFs. Our findings revealed a feedback loop of STAT3/GNAS-AS1/miR-196a-5p/CXCL12/STAT3 that promoted HKF proliferation, migration and ECM accumulation and affected keloid progression.

Pancreatic ductal adenocarcinoma (PDAC) is a solid organ malignancy with a high mortality rate. Statistics indicate that its incidence has been increasing as well as the associated deaths. Most patients with PDAC show poor response to therapies making the clinical management of this cancer difficult. Stromal cells in the tumor microenvironment (TME) contribute to the development of resistance to therapy in PDAC cancer cells. Cancer-associated fibroblasts (CAFs), the most prevalent stromal cells in the TME, promote a desmoplastic response, produce extracellular matrix proteins and cytokines, and directly influence the biological behavior of cancer cells. These multifaceted effects make it difficult to eradicate tumor cells from the body. As a result, CAF-targeting synergistic therapeutic strategies have gained increasing attention in recent years. However, due to the substantial heterogeneity in CAF origin, definition, and function, as well as high plasticity, majority of the available CAF-targeting therapeutic approaches are not effective, and in some cases, they exacerbate disease progression. This review primarily elucidates on the effect of CAFs on therapeutic efficiency of various treatment modalities, including chemotherapy, radiotherapy, immunotherapy, and targeted therapy. Strategies for CAF targeting therapies are also discussed.

CircRNAs are covalently closed, single-stranded RNA that form continuous loops and play a crucial role in the initiation and progression of tumors. Cancer stem cells (CSCs) are indispensable for cancer development; however, the regulation of cancer stem cell-like properties in gastric cancer (GC) and its specific mechanism remain poorly understood. We elucidate the specific role of Circ-0075305 in GC stem cell properties. Circ-0075305 associated with chemotherapy resistance was identified by sequencing GC cells. Subsequent confirmation in both GC tissues and cell lines revealed that patients with high expression of Circ-0075305 had significantly better overall survival (OS) rates than those with low expression, particularly when treated with postoperative adjuvant chemotherapy for GC. In vitro and in vivo experiments confirmed that overexpression of Circ-0075305 can effectively reduce stem cell-like properties and enhance the sensitivity of GC cells to Oxaliplatin compared with the control group. Circ-0075305 promotes RPRD1A expression by acting as a sponge for corresponding miRNAs. The addition of LF3 (a β-catenin/TCF4 interaction antagonist) confirmed that RPRD1A inhibited the formation of the TCF4-β-catenin transcription complex through competitive to β-catenin and suppressed the transcriptional activity of stem cell markers such as SOX9 via the Wnt/β-catenin signaling pathway. This leads to the downregulation of stem cell-like property-related markers in GC. This study revealed the underlying mechanisms that regulate Circ-0075305 in GCSCs and suggests that its role in reducing β-catenin signaling may serve as a potential therapeutic candidate.

Circular RNA (circRNA) was first observed in the cytoplasm of eukaryotic cells in 1979, but it was not characterized in detail until 2012, when high‑throughput sequencing technology was more advanced and available. Consequently, the mechanism of circRNA formation and its biological function have been progressively elucidated by researchers. circRNA is abundant in eukaryotic cells and exhibits a certain degree of organization, timing and disease‑specificity. Additionally, it is poorly degradable, meeting the characteristics of an ideal clinical biomarker. In the present review, the recent research progress of circRNAs in digestive tract malignant tumors was primarily discussed. This included the roles, biological functions and clinical significance of circRNA, providing references for its research value and clinical potential in gastrointestinal cancer.

Pancreatic cancer is one of the most lethal malignancies. Even though many substantial improvements in the survival rates for other major cancer forms were made, pancreatic cancer survival rates have remained relatively unchanged since the 1960s. Even more, no standard classification system for pancreatic cancer is based on cellular biomarkers. This review will discuss and provide updates about the role of stem cells in the progression of PC, the genetic changes associated with it, and the promising biomarkers for diagnosis.

The search process used PubMed, Cochrane Library, and Scopus databases to identify the relevant and related articles. Articles had to be published in English to be considered.

The increasing number of studies in recent years has revealed that the diversity of cancer-associated fibroblasts is far greater than previously acknowledged, which highlights the need for further research to better understand the various cancer-associated fibroblast subpopulations. Despite the huge diversity in pancreatic cancer, some common features can be noted to be shared among patients. Mutations involving CDKN2, P53, and K-RAS can be seen in a big number of patients, for example. Similarly, some patterns of genes and biomarkers expression and the level of their expression can help in predicting cancer behavior such as metastasis and drug resistance. The current trend in cancer research, especially with the advancement in technology, is to sequence everything in hopes of finding disease-related mutations.

Optimizing pancreatic cancer treatment requires clear classification, understanding CAF roles, and exploring stroma reshaping approaches.

Stroke is a major cause of death and severe disability, and there remains a substantial need for the development of therapeutic agents for neuroprotection in acute ischemic stroke (IS) to protect the brain against damage before and during recanalization. Caveolin-1 (CAV1), an integrated protein that is located at the caveolar membrane, has been reported to exert neuroprotective effects during IS. Nevertheless, the mechanism remains largely unknown. Here, we explored the upstream modifiers of CAV1 in IS.

E3 ubiquitin ligases of CAV1 that are differentially expressed in IS were screened using multiple databases. The transcription factor responsible for the dysregulation of E3 ubiquitin-protein ligase synoviolin (SYVN1) in IS was predicted and verified. Genetic manipulations by lentiviral vectors were applied to investigate the effects of double-strand-break repair protein rad21 homolog (RAD21), SYVN1, and CAV1 in a middle cerebral artery occlusion (MCAO) mouse model and mouse HT22 hippocampal neurons induced by oxygen-glucose deprivation (OGD).

SYVN1 was highly expressed in mice with MCAO, and knockdown of SYVN1 alleviated IS injury in mice, as evidenced by limited infarction volume, the lower water content in the brain, and repressed apoptosis and inflammatory response. RAD21 inhibited the transcription of SYVN1, thereby reducing the ubiquitination modification of CAV1. Overexpression of RAD21 elicited a neuroprotective role as well in mice with MCAO and HT22 induced with OGD, which was overturned by SYVN1.

Transcriptional repression of SYVN1 by RAD21 alleviates IS in mice by reducing ubiquitination modification of CAV1.

The gastrointestinal tract can be affected by a number of diseases that pancreatic cancer (PC) is a malignant manifestation of them. The prognosis of PC patients is unfavorable and because of their diagnosis at advanced stage, the treatment of this tumor is problematic. Owing to low survival rate, there is much interest towards understanding the molecular profile of PC in an attempt in developing more effective therapeutics. The conventional therapeutics for PC include surgery, chemotherapy and radiotherapy as well as emerging immunotherapy. However, PC is still incurable and more effort should be performed. The molecular landscape of PC is an underlying factor involved in increase in progression of tumor cells. In the presence review, the newest advances in understanding the molecular and biological events in PC are discussed. The dysregulation of molecular pathways including AMPK, MAPK, STAT3, Wnt/β-catenin and non-coding RNA transcripts has been suggested as a factor in development of tumorigenesis in PC. Moreover, cell death mechanisms such as apoptosis, autophagy, ferroptosis and necroptosis demonstrate abnormal levels. The EMT and glycolysis in PC cells enhance to ensure their metastasis and proliferation. Furthermore, such abnormal changes have been used to develop corresponding pharmacological and nanotechnological therapeutics for PC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a very poor prognosis. Despite advancements in treatment strategies, PDAC remains recalcitrant to therapies because patients are often diagnosed at an advanced stage. The advanced stage of PDAC is characterized by metastasis, which typically renders it unresectable by surgery or untreatable by chemotherapy. The tumor microenvironment (TME) of PDAC comprises highly proliferative myofibroblast-like cells and hosts the intense deposition of a extracellular matrix component that forms dense fibrous connective tissue, a process called the desmoplastic reaction. In desmoplastic TMEs, the incessant aberration of signaling pathways contributes to immunosuppression by suppressing antitumor immunity. This feature offers a protective barrier that impedes the targeted delivery of drugs. In addition, the efficacy of immunotherapy is compromised because of the immune cold TME of PDAC. Targeted therapy approaches towards stromal and immunosuppressive TMEs are challenging. In this review, we discuss cellular and non-cellular TME components that contain actionable targets for drug development. We also highlight findings from preclinical studies and provide updates about the efficacies of new investigational drugs in clinical trials.

Gemcitabine (GEM) resistance affects chemotherapy efficacy of pancreatic cancer (PC). Cancer-associated fibroblasts (CAFs) possess the ability of regulating chemoresistance. This study probed the mechanism of hypoxia-treated CAFs regulating cell stemness and GEM resistance in PC. Miapaca-2/SW1990 were co-cultured with PC-derived CAFs under normoxic/hypoxic conditions. Cell viability/self-renewal ability was determined by MTT/sphere formation assays, respectively. Protein levels of CD44, CD133, Oct4, and Sox2 were determined by western blot. GEM tumoricidal assay was performed. PC cell GEM resistance was evaluated by MTT assay. CAFs were cultured at normoxia/hypoxia. HIF-1α and miR-21 expression levels were assessed by RT-qPCR and western blot, with their binding sites and binding relationship predicted and verified. CAF-extracellular vesicles (EVs) were incubated with Miapaca-2 cells. The RAS/AKT/ERK pathway activation was detected by western blot. PC xenograft models were established and treated with hypoxic CAF-EVs and GEM. CAFs and PC cell co-culture increased cell stemness maintenance, GEM resistance, cell viability, stem cell sphere number, and protein levels of CD44, CD133, Oct4, and Sox2, and weakened GEM tumoricidal ability to PC cells, with the effects further enhanced by hypoxia. Hypoxia induced HIF-1α and miR-21 overexpression in CAFs. Hypoxia promoted CAFs to secrete high-level miR-21 EVs via the HIF-1α/miR-21 axis, and activated the miR-21/RAS/AKT/ERK pathway. CAF-EVs promoted GEM resistance in PC via the miR-21/RAS/ATK/ERK pathway in vivo. Hypoxia promoted CAFs to secrete high-level miR-21 EVs through the HIF-1α/miR-21 axis, and activated the miR-21/RAS/AKT/ERK pathway via EVs to trigger stemness maintenance and GEM resistance in PC.

Imatinib is the current gold standard for patients with chronic myeloid leukemia (CML). However, the primary and acquired drug resistance seriously limits the efficacy. To identify novel therapeutic target in Imatinib-resistant CML is of crucial clinical significance. CircRNAs have been demonstrated the essential regulatory roles in the progression and drug resistance of cancers. In this study, we identified a novel circRNA (circ_SIRT1), derived from the SIRT1, which is up-regulated in CML. The high expression of circ_SIRT1 is correlated with drug resistance in CML. Knockdown of circ_SIRT1 regulated K562/R cells viability, invasion and apoptosis. Besides, the inhibition of circ_SIRT1 attenuated autophagy level and reduced IC50 to Imatinib of K562/R cells. Mechanistically, circ_SIRT1 directly binds to the transcription factor Eukaryotic Translation Initiation Factor 4A3(EIF4A3) and regulated EIF4A3-mediated transcription of Autophagy Related 12 (ATG12), thereby affecting Imatinib resistance and autophagy level. Overexpression of ATG12 reversed the regulative effects induced by knockdown of circ_SIRT1. Taken together, our findings revealed circ_SIRT1 acted as a potential tumor regulator in CML and unveiled the underlying mechanism on regulating Imatinib resistance. circ_SIRT1 may serve as a novel therapeutic target and provide crucial clinical implications for Imatinib-resistant CML treatment.