MKLN1-AS promotes pancreatic cancer progression as a crucial downstream mediator of HIF-1α through miR-185-5p/TEAD1 pathway.

In pancreatic ductal adenocarcinomas (PDAC), profound hypoxia plays key roles in regulating cancer cell behavior, including proliferation, migration, and resistance to therapies. The initial part of this research highlights the important role played by long noncoding RNA (lncRNA) MKLN1-AS, which is controlled by hypoxia-inducible factor-1 alpha (HIF-1α), in the progression of PDAC. Human samples of PDAC showed a notable increase in MKLN1-AS expression, which was linked to a worse outcome. Forced expression of MKLN1-AS greatly reduced the inhibitory impact on the growth and spread of PDAC cells caused by HIF-1α depletion. Experiments on mechanisms showed that HIF-1α influences the expression of MKLN1-AS by directly attaching to a hypoxia response element in the promoter region of MKLN1-AS.MKLN1-AS acts as a competitive endogenous RNA (ceRNA) by binding to miR-185-5p, resulting in the regulation of TEAD1 expression and promoting cell proliferation, migration, and tumor growth. TEAD1 subsequently enhances the development of PDAC. Our study results suggest that MKLN1-AS could serve as a promising target for treatment and a valuable indicator for predicting outcomes in PDAC. PDAC is associated with low oxygen levels, and the long non-coding RNA MKLN1-AS interacts with TEAD1 in this context.

Comprehensive analysis of the REST transcription factor regulatory networks in IDH mutant and IDH wild-type glioma cell lines and tumors.

The RE1-silencing transcription factor (REST) acts either as a repressor or activator of transcription depending on the genomic and cellular context. REST is a key player in brain cell differentiation by inducing chromatin modifications, including DNA methylation, in a proximity of its binding sites. Its dysfunction may contribute to oncogenesis. Mutations in IDH1/2 significantly change the epigenome contributing to blockade of cell differentiation and glioma development. We aimed at defining how REST modulates gene activation and repression in the context of the IDH mutation-related phenotype in gliomas. We studied the effects of REST knockdown, genome wide occurrence of REST binding sites, and DNA methylation of REST motifs in IDH wild type and IDH mutant gliomas. We found that REST target genes, REST binding patterns, and TF motif occurrence proximal to REST binding sites differed in IDH wild-type and mutant gliomas. Among differentially expressed REST targets were genes involved in glial cell differentiation and extracellular matrix organization, some of which were differentially methylated at promoters or gene bodies. REST knockdown differently impacted invasion of the parental or IDH1 mutant glioma cells. The canonical REST-repressed gene targets showed significant correlation with the GBM NPC-like cellular state. Interestingly, results of REST or KAISO silencing suggested the interplay between these TFs in regulation of REST-activated and repressed targets. The identified gene regulatory networks and putative REST cooperativity with other TFs, such as KAISO, show distinct REST target regulatory networks in IDH-WT and IDH-MUT gliomas, without concomitant DNA methylation changes. We conclude that REST could be an important therapeutic target in gliomas.

PESSA: A web tool for pathway enrichment score-based survival analysis in cancer.

The activation levels of biologically significant gene sets are emerging tumor molecular markers and play an irreplaceable role in the tumor research field; however, web-based tools for prognostic analyses using it as a tumor molecular marker remain scarce. We developed a web-based tool PESSA for survival analysis using gene set activation levels. All data analyses were implemented via R. Activation levels of The Molecular Signatures Database (MSigDB) gene sets were assessed using the single sample gene set enrichment analysis (ssGSEA) method based on data from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), The European Genome-phenome Archive (EGA) and supplementary tables of articles. PESSA was used to perform median and optimal cut-off dichotomous grouping of ssGSEA scores for each dataset, relying on the survival and survminer packages for survival analysis and visualisation. PESSA is an open-access web tool for visualizing the results of tumor prognostic analyses using gene set activation levels. A total of 238 datasets from the GEO, TCGA, EGA, and supplementary tables of articles; covering 51 cancer types and 13 survival outcome types; and 13,434 tumor-related gene sets are obtained from MSigDB for pre-grouping. Users can obtain the results, including Kaplan-Meier analyses based on the median and optimal cut-off values and accompanying visualization plots and the Cox regression analyses of dichotomous and continuous variables, by selecting the gene set markers of interest. PESSA (https://smuonco.shinyapps.io/PESSA/ OR http://robinl-lab.com/PESSA) is a large-scale web-based tumor survival analysis tool covering a large amount of data that creatively uses predefined gene set activation levels as molecular markers of tumors.

Lung adenocarcinomas without driver genes converge to common adaptive strategies through diverse genetic, epigenetic, and niche construction evolutionary pathways.

Somatic evolution selects cancer cell phenotypes that maximize survival and proliferation in dynamic environments. Although cancer cells are molecularly heterogeneous, we hypothesized convergent adaptive strategies to common host selection forces can be inferred from patterns of epigenetic and genetic evolutionary selection in similar tumors. We systematically investigated gene mutations and expression changes in lung adenocarcinomas with no common driver genes (n = 313). Although 13,461 genes were mutated in at least one sample, only 376 non-synonymous mutations evidenced positive evolutionary selection with conservation of 224 genes, while 1736 and 2430 genes exhibited ≥ two-fold increased and ≥ 50% decreased expression, respectively. Mutations under positive selection are more frequent in genes with significantly altered expression suggesting they often "hardwire" pre-existing epigenetically driven adaptations. Conserved genes averaged 16-fold higher expression in normal lung tissue compared to those with selected mutations demonstrating pathways necessary for both normal cell function and optimal cancer cell fitness. The convergent LUAD phenotype exhibits loss of differentiated functions and cell-cell interactions governing tissue organization. Conservation with increased expression is found in genes associated with cell cycle, DNA repair, p53 pathway, epigenetic modifiers, and glucose metabolism. No canonical driver gene pathways exhibit strong positive selection, but extensive down-regulation of membrane ion channels suggests decreased transmembrane potential may generate persistent proliferative signals. NCD LUADs perform niche construction generating a stiff, immunosuppressive microenvironment through selection of specific collagens and proteases. NCD LUADs evolve to a convergent phenotype through a network of interconnected genetic, epigenetic, and ecological pathways.

Uncovering the relationship between YAP/ WWTR1 (TAZ) genes expression and LncRNAs of SNHG15, HCP5 and LINC01433 in breast cancer tissues.

In spite of the decrease in breast cancer (BC) death rates, it has remained a significant public health concern. Dysregulation of the Hippo pathway contributes to breast cancer development and progression by enhancing cancerous cell proliferation, survival, invasion, and migration. Investigating the connection between specific lncRNAs (SNHG15, HCP5, and LINC01433) and YAP and WWTR1, and the impact of these lncRNAs on the expression of YAP and WWTR1 proteins in the Hippo pathway, may offer valuable understanding for BC diagnosis and treatment. Forty BC tissue samples were acquired from the Tumor Bank and utilized for RNA and protein extraction. Real-time PCR and western blotting techniques were performed to assess the gene and protein expressions, respectively. Correlations between variables and their associations with clinicopathological features in BC were evaluated using Mann-Whitney U or Student's t-test. Additionally, the analysis of the GEO database was utilized to validate the findings. In cancerous tissue, the up-regulation of YAP, WWTR1, HCP5, SNHG15, and Linc01433 at both the mRNA and protein levels corresponds to the findings in GEO datasets. A significant association was found between YAP and histological grade, while WWTR1 showed a correlation with family history and HER-2. The distinct and notable expression of YAP, WWTR1, SNHG15, HCP5, and Linc01433 in BC tissues, together with the results of combined ROC curve analysis derived from our finding and GEO database suggest that a combined panel of these 5 RNAs may have great potential in predicting of BC and its management.

Targeting notch-related lncRNAs in cancer: Insights into molecular regulation and therapeutic potential.

Cancer is a group of diseases marked by unchecked cell proliferation and the ability for the disease to metastasize to different body areas. Enhancements in treatment and early detection are crucial for improved outcomes. LncRNAs are RNA molecules that encode proteins and have a length of more than 200 nucleotides. LncRNAs are crucial for chromatin architecture, gene regulation, and other cellular activities that impact both normal growth & pathological processes, even though they are unable to code for proteins. LncRNAs have emerged as significant regulators in the study of cancer biology, with a focus on their intricate function in the Notch signaling pathway. The imbalance of this pathway is often linked to a variety of malignancies. Notch signaling is essential for cellular functions like proliferation, differentiation, and death. The cellular response is shaped by these lncRNAs through their modulation of essential Notch pathway constituents such as receptors, ligands, and downstream effectors around it. Furthermore, a variety of cancer types exhibit irregular expression of Notch-related lncRNAs, underscoring their potential use as therapeutic targets and diagnostic markers. Gaining an understanding of the molecular processes behind the interaction between the Notch pathway and lncRNAs will help you better understand the intricate regulatory networks that control the development of cancer. This can open up new possibilities for individualized treatment plans and focused therapeutic interventions. The intricate relationships between lncRNAs & the Notch pathway in cancer are examined in this review.

FOXO3a deregulation in uterine smooth muscle tumors.

OBJECTIVE: The present study aimed to investigate FOXO3a deregulation in Uterine Smooth Muscle Tumors (USMT) and its potential association with cancer development and prognosis. METHODS: The authors analyzed gene and protein expression profiles of FOXO3a in 56 uterine Leiomyosarcomas (LMS), 119 leiomyomas (comprising conventional and unusual leiomyomas), and 20 Myometrium (MM) samples. The authors used techniques such as Immunohistochemistry (IHC), FISH/CISH, and qRT-PCR for the present analyses. Additionally, the authors conducted an in-silico analysis to understand the interaction network involving FOXO3a and its correlated genes. RESULTS: This investigation revealed distinct expression patterns of the FOXO3a gene and protein, including both normal and phosphorylated forms. Expression levels were notably elevated in LMS, and Unusual Leiomyomas (ULM) compared to conventional Leiomyomas (LM) and Myometrium (MM) samples. This upregulation was significantly associated with metastasis and Overall Survival (OS) in LMS patients. Intriguingly, FOXO3a deregulation did not seem to be influenced by EGF/HER-2 signaling, as there were minimal levels of EGF and VEGF expression detected, and HER-2 and EGFR were negative in the analyzed samples. In the examination of miRNAs, the authors observed upregulation of miR-96-5p and miR-155-5p, which are known negative regulators of FOXO3a, in LMS samples. Conversely, the tumor suppressor miR-let7c-5p was downregulated. CONCLUSIONS: In summary, the outcomes of the present study suggest that the imbalance in FOXO3a within Uterine Smooth Muscle Tumors might arise from both protein phosphorylation and miRNA activity. FOXO3a could emerge as a promising therapeutic target for individuals with Unusual Leiomyomas and Leiomyosarcomas (ULM and LMS), offering novel directions for treatment strategies.

The RAS oncogene in brain tumors and the involvement of let-7 microRNA.

RAS oncogenes are master regulator genes in many cancers. In general, RAS-driven cancers have an oncogenic RAS mutation that promotes disease progression (colon, lung, pancreas). In contrast, brain tumors are not necessarily RAS-driven cancers because RAS mutations are rarely observed. In particular, glioblastomas (the most lethal brain tumor) do not appear to have dominant genetic mutations that are suitable for targeted therapy. Standard treatment for most brain tumors continues to focus on maximal surgical resection, radiotherapy and chemotherapy. Yet the convergence of genomic aberrations such as EGFR, PDGFR and NF1 (some of which are clinically effective) with activation of the RAS/MAPK cascade is still considered a key point in gliomagenesis, and KRAS is undoubtedly a driving gene in gliomagenesis in mice. In cancer, microRNAs (miRNA) are small, non-coding RNAs that regulate carcinogenesis. However, the functional consequences of aberrant miRNA expression in cancer are still poorly understood. let-7 encodes an intergenic miRNA that is classified as a tumour suppressor, at least in lung cancer. Let-7 suppresses a plethora of oncogenes such as RAS, HMGA, c-Myc, cyclin-D and thus suppresses cancer development, differentiation and progression. let-7 family members are direct regulators of certain RAS family genes by binding to the sequences in their 3'untranslated region (3'UTR). let-7 miRNA is involved in the malignant behaviour in vitro-proliferation, migration and invasion-of gliomas and stem-like glioma cells as well as in vivo models of glioblastoma multiforme (GBM) via KRAS inhibition. It also increases resistance to certain chemotherapeutic agents and radiotherapy in GBM. Although let-7 therapy is not yet established, this review updates the current state of knowledge on the contribution of miRNA let-7 in interaction with KRAS to the oncogenesis of brain tumours.

Potential roles of PIWI-interacting RNAs in breast cancer, a new therapeutic strategy.

Breast cancer (BC) has been the focus of numerous studies aimed at identifying novel biological markers for its early detection. PIWI-interacting RNAs (piRNAs), a subset of small non-coding RNAs, have emerged as potential markers due to their aberrant expression in various cancers. PiRNAs have recently gained attention due to their aberrant expression in various cancers, including BC. PiRNAs, exhibit diverse biological activities, such as epigenetic regulation of gene and protein expression and their association with cell proliferation and metastasis has been well-established. As the field of non-coding RNAs rapidly evolves, there is great anticipation that therapies targeting piRNAs will advance swiftly. This review will delve into the various biological functions of piRNAs, such as gene suppression, transposon silencing, and epigenetic regulation of genes. The review will also highlight the role of piRNAs as either progenitors or suppressors in cancers, with a particular focus on BC. Lastly, it will touch upon the potential of piRNAs as biomarkers and therapeutic targets for BC.

Identification of genes related to ribosomal proteins in colorectal cancer: exploring their potential as biomarkers, prognostic indicators, and therapeutic targets.

BACKGROUND: Colorectal cancer (CRC) ranks as the third most commonly diagnosed cancer in both females and males, underscoring the need for the identification of effective biomarkers. METHODS AND RESULTS: We assessed the expression levels of ribosomal proteins (RPs) at both mRNA and protein levels. Subsequently, leveraging the STRING database, we constructed a protein-protein interaction network and identified hub genes. The co-expression network of differentially expressed genes associated with CRC and their target hub RPs was constructed using the weighted gene co-expression network analysis algorithm. Gene ontology and molecular signatures database were conducted to gain insights into the biological roles of genes associated with the identified module. To confirm the results, the expression level of the candidate genes in the CRC samples compared to the adjacent healthy was evaluated by the RT-qPCR method. Our findings indicated that the genes related to RPs were predominantly enriched in biological processes associated with Myc Targets, Oxidative Phosphorylation, and cell proliferation. Also, results demonstrated that elevated levels of GRWD1, MCM5, IMP4, and RABEPK that related to RPs were associated with poor prognostic outcomes for CRC patients. Notably, IMP4 and RABEPK exhibited higher diagnostic value. Moreover, the expression of IMP4 and RABEPK showed a significant association with drug resistance using cancer cell line encyclopedia and genomics of drug sensitivity in cancer databases. Also, the results showed that the expression level of IMP4 and RABEPK in cancerous samples was significantly higher compared to the adjacent healthy ones. CONCLUSION: The general results of this study have shown that many genes related to RPs are increased in cancer and could be associated with the death rate of patients. We also highlighted the therapeutic and prognostic potentials of RPs genes in CRC.

Upregulation of circ_0076684 in osteosarcoma facilitates malignant processes by mediating miRNAs/CUX1.

Circular RNAs (circRNAs) are a newly appreciated type of endogenous noncoding RNAs that play vital roles in the development of various human cancers, including osteosarcoma (OS). In this study, we investigated three circRNAs (circ_0076684, circ_0003563, circ_0076691) from the RUNX Family Transcription Factor 2 (RUNX2) gene locus in OS. We found that the expression of circ_0076684, circ_0003563, circ_0076691, and RUNX2 mRNA is upregulated in OS, which is a consequence of CBX4-mediated transcriptional activation. Among these three RUNX2-circRNAs, only circ_0076684 is significantly associated with the clinical features and prognosis of OS patients. Functional experiments indicate that circ_0076684 promotes OS progression in vitro and in vivo. Circ_0076684 acts as a sponge for miR-370-3p, miR-140-3p, and miR-193a-5p, raising Cut Like Homeobox 1 (CUX1) expression by sponging these three miRNAs. Furthermore, we presented that circ_0076684 facilitates OS progression via CUX1. In conclusion, this study found that the expression of three circRNAs and RUNX2 mRNA from the RUNX2 gene locus is significantly upregulated in OS, as a result of CBX4-mediated transcriptional activation. Circ_0076684 raises CUX1 expression by sponging miR-370-3p, miR-140-3p, and miR-193a-5p, and facilitates OS progression via CUX1.

Expression of lncRNA LINC00943 in lung squamous cell carcinoma and its relationship with tumor progression.

BACKGROUND: Molecular biology has been applied to the diagnosis, prognosis and treatment of various diseases, and long noncoding RNA LINC00943 (lncRNA LINC00943; LINC00943) plays an important role in a variety of cancers. Therefore, this study explored the prognostic role of LINC00943 in lung squamous cell carcinoma (LUSC) and understood its impact on the development of LUSC. METHODS: There are 89 LUSC patients were involved in current assay. By detecting the expression of LINC00943 and miR-196b-5p in tissues and cells, LINC00943 and its correlation with the characteristics of clinical data were analyzed. The biological function of LINC00943 was studied by Transwell migration and invasion assays. In addition, Pearson correlation coefficient and luciferase activity experiments were chosen to characterize the relationship between LINC00943 and miR-196b-5p and explore the mechanism of LINC00943. RESULTS: Compared with normal controls, LINC00943 expression in LUSC tissues and cells was significantly reduced, miR-196b-5p was markedly increased, there was a negative correlation between LINC00943 and miR-196b-5p. According to the in vitro cell experiments, migration and invasion of LUSC cells were suppressed by overexpression of LINC00943. Besides, LINC00943 was demonstrated to have prognostic power and targeting miR-196b-5p was involved in the progression of LUSC. CONCLUSIONS: Overexpression of LINC00943 was molecular sponge for miR-196b-5p that controlled the deterioration of LUSC, which had great potential as a prognostic biomarker for LUSC.

ERN1 knockdown modifies the hypoxic regulation of homeobox gene expression in U87MG glioblastoma cells.

OBJECTIVE.: Homeobox genes play an important role in health and disease including oncogenesis. The present investigation aimed to study ERN1-dependent hypoxic regulation of the expression of genes encoding homeobox proteins MEIS (zinc finger E-box binding homeobox 2) and LIM homeobox 1 family, SPAG4 (sperm associated antigen 4) and NKX3-1 (NK3 homeobox 1) in U87MG glioblastoma cells in response to inhibition of ERN1 (endoplasmic reticulum to nucleus signaling 1) for evaluation of their possible significance in the control of glioblastoma growth. METHODS.: The expression level of homeobox genes was studied in control (transfected by vector) and ERN1 knockdown U87MG glioblastoma cells under hypoxia induced by dimethyloxalylglycine (0.5 mM for 4 h) by quantitative polymerase chain reaction and normalized to ACTB. RESULTS.: It was found that hypoxia down-regulated the expression level of LHX2, LHX6, MEIS2, and NKX3-1 genes but up-regulated the expression level of MEIS1, LHX1, MEIS3, and SPAG4 genes in control glioblastoma cells. At the same time, ERN1 knockdown of glioblastoma cells significantly modified the sensitivity of all studied genes to a hypoxic condition. Thus, ERN1 knockdown of glioblastoma cells removed the effect of hypoxia on the expression of MEIS1 and LHX1 genes, but increased the sensitivity of MEIS2, LHX2, and LHX6 genes to hypoxia. However, the expression of MEIS3, NKX3-1, and SPAG4 genes had decreased sensitivity to hypoxia in ERN1 knockdown glioblastoma cells. Moreover, more pronounced changes under the conditions of ERN1 inhibition were detected for the pro-oncogenic gene SPAG4. CONCLUSION.: The results of the present study demonstrate that hypoxia affected the expression of homeobox genes MEIS1, MEIS2, MEIS3, LHX1, LHX2, LHX6, SPAG4, and NKX3-1 in U87MG glioblastoma cells in gene-specific manner and that the sensitivity of all studied genes to hypoxia condition is mediated by ERN1, the major pathway of the endoplasmic reticulum stress signaling, and possibly contributed to the control of glioblastoma growth. A fundamentally new results of this work is the establishment of the fact regarding the dependence of hypoxic regulation of SPAG4 gene expression on ER stress, in particular ERN1, which is associated with suppression of cell proliferation and tumor growth.

The evaluation of miR-1181 and miR-4314 as serum microRNA biomarkers for epithelial ovarian cancer diagnosis and prognosis.

AIM: Epithelial ovarian cancer (EOC) is the most ominous tumor of gynecological cancers due to its poor early detection rate and unfavorable prognosis. To date, there is no reliable screening method for the diagnosis of ovarian cancer at an early stage. MiRNAs are small non-coding RNA molecules, and their main function is to regulate gene expression. The present study compared the serum miR-1181 and miR-4314 levels in patients with EOC and healthy controls to measure the diagnostic and prognostic value as candidate biomarkers. MATERIALS AND METHODS: We collected serum samples from a total of 135 participants (69 patients with EOC and 66 healthy controls). Relative expressions of miR-1181 and miR-4314 were measured by quantitative real-time polymerase chain reaction assay (qPCR). RESULTS: The present study revealed that both serum miR-1181 and miR-4314 levels in patients with EOC were significantly increased compared to healthy controls for each marker. In addition, there was a significant relationship between miR-1181 and miR-4314 overexpressions and the stage and prognosis of the disease. Finally, patients with high expression levels of miR-1181 and miR-4314 had significantly shorter survival rates than those with low expression levels. CONCLUSION: The current study proposed that serum miR-1181 and miR-4314 could discriminate the EOC patients from healthy controls. In addition, both miR-1181 and miR-4314 may be predictive biomarkers for ovarian cancer prognosis. Further studies are needed to confirm the findings of the present study.

Identification of miR-125a and miR-106b signature as a potential diagnostic biomarker in breast cancer tissues.

MicroRNAs (miRNAs) have essential roles in the etiology of breast cancer and are regarded as possible markers in this malignancy. In order to find new markers for breast cancer, the current study has measured expression level of four miRNAs, namely miR-125a, miR-106b, miR-96 and miR-92a-3p in the paired breast samples. Expression levels of miR-125a and miR-106b were higher in tumoral tissues compared with control tissues (Expression ratios (95% CI) = 4.01 (1.96-8.19) and 3.9 (1.95-7.81); P values = 0.0005 and 0.0003, respectively). miR-106b and miR-125a differentiated between malignant and non-malignant tissues with AUC values of 0.7 and 0.67, respectively. We detected association between expression of miR-106b and clinical stage (P = 0.03), in a way that its expression was the lowest in the advanced stages. Finally, significant relationships were found between miR-96 and miR-125a in both tumoral and non-tumoral specimens (ρ = 0.76 and 0.69, respectively). This nonparametric measure of rank correlation also showed relationship between miR-106b and miR-96 in both sets of samples (ρ = 0.63 and 0.61, respectively). Cumulatively, the assessed miRNAs, particularly miR-125a and miR-106b are putative targets for further expression and functional assays in breast cancer.

Personalized identification and characterization of genome-wide gene expression differences between patient-matched intracranial and extracranial melanoma metastasis pairs.

Melanoma is the most serious type of skin cancer that frequently spreads to other organs of the human body. Especially melanoma metastases to the brain (intracranial metastases) are hard to treat and a major cause of death of melanoma patients. Little is known about molecular alterations and altered mechanisms that distinguish intra- from extracranial melanoma metastases. So far, almost all existing studies compared intracranial metastases from one set of patients to extracranial metastases of an another set of melanoma patients. This neglects the important facts that each melanoma is highly individual and that intra- and extracranial melanoma metastases from the same patient are more similar to each other than to melanoma metastases from other patients in the same organ. To overcome this, we compared the gene expression profiles of 16 intracranial metastases to their corresponding 21 patient-matched extracranial metastases in a personalized way using a three-state Hidden Markov Model (HMM) to identify altered genes for each individual metastasis pair. This enabled three major findings by considering the predicted gene expression alterations across all patients: (i) most frequently altered pathways include cytokine-receptor interaction, calcium signaling, ECM-receptor interaction, cAMP signaling, Jak-STAT and PI3K/Akt signaling, (ii) immune-relevant signaling pathway genes were downregulated in intracranial metastases, and (iii) intracranial metastases were associated with a brain-like phenotype gene expression program. Further, the integration of all differentially expressed genes across the patient-matched melanoma metastasis pairs led to a set of 103 genes that were consistently down- or up-regulated in at least 11 of the 16 of the patients. This set of genes contained many genes involved in the regulation of immune responses, cell growth, cellular signaling and transport processes. An analysis of these genes in the TCGA melanoma cohort showed that the expression behavior of 11 genes was significantly associated with survival. Moreover, a comparison of the 103 genes to three closely related melanoma metastasis studies revealed a core set of eight genes that were consistently down- or upregulated in intra- compared to extracranial metastases in at least two of the three related studies (down: CILP, DPT, FGF7, LAMP3, MEOX2, TMEM119; up: GLDN, PMP2) including FGF7 that was also significantly associated with survival. Our findings contribute to a better characterization of genes and pathways that distinguish intra- from extracranial melanoma metastasis and provide important hints for future experimental studies to identify potential targets for new therapeutic approaches.

Exosome secretion related gene signature predicts chemoresistance in patients with colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a highly heterogeneous malignancy, and patients often have different responses to treatment. In this study, the genetic characteristics related to exosome formation and secretion procedure were used to predict chemoresistance and guide the individualized treatment of patients. METHODS: Firstly, seven microarray datasets in Gene Expression Omnibus (GEO) and RNA-Seq dataset from the Cancer Genome Atlas (TCGA) were used to analysis the transcriptome profiles and associated characteristics of CRC patients. Then, a predictive model based on gene features linked to exosome formation and secretion was created and validated using Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) machine learning. Finally, we evaluated the model using chemoresistant/chemosensitive cells and tissues by immunofluorescence (IF), western blot (WB), quantitative real-time PCR (qRT-PCR) and immunocytochemistry (IHC) experiments, and the predictive value of integrated model in the clinical validation cohort were performed by Receiver Operating Characteristic (ROC) and Kaplan-Meier (K-M) curves analyses. RESULTS: We established a risk score signature based on three genes related to exosome secretion in CRC. Better Overall Survival (OS) and greater chemosensitivity were seen in the low-risk group, whereas the high-risk group exhibited chemoresistance and a subpar response to immune checkpoint blockade (ICB) therapy. Higher expression of the model genes EXOC2, EXOC3 and STX4 were observed in chemoresistant cells and specimens. The AUC of 5-year disease-free survival (DFS) was 0.804. Compared with that in the low-risk group, patients' DFS was found to be significantly worse in the high-risk group. CONCLUSIONS: In summary, the gene signature related to exosome formation and secretion could reliably predict patients' chemosensitivity and ICB treatment response, which providing new independent biomarkers for the treatment of CRC.

Riddle of the Sphinx: Emerging role of circular RNAs in cervical cancer.

Cervical cancer is a prominent cause of cancer-related mortality among women, with recent attention directed toward exploring the involvement of circular RNAs (circRNAs) in this particular cancer. CircRNAs, characterized by a covalently closed loop structure, belong to a class of single-stranded non-coding RNA (ncRNA) molecules that play crucial roles in cancer development and progression through diverse mechanisms. The abnormal expression of circRNAs in vivo is significantly associated with the development of cervical cancer. Notably, circRNAs actively interact with miRNAs in cervical cancer, leading to the regulation of diverse signaling pathways, and they can contribute to cancer hallmarks such as self-sufficiency in growth signals, insensitivity to antigrowth signals, limitless proliferation, evading apoptosis, tissue invasion and metastasis, and sustained angiogenesis. Moreover, the distinctive biomedical attributes exhibited by circRNAs, including their abundance, conservation, and stability in body fluids, position them as promising biomarkers for various cancers. In this review, we elucidate the tremendous potential of circRNAs as diagnostic markers or therapeutic targets in cervical cancer by expounding upon their biogenesis, characteristics, functions, and databases, highlighting the novel advances in the signaling pathways associated with circRNAs in cervical cancer.

Hsa_circ_0087862 contributes to the progression of colorectal cancer through regulating miR-512-3p/HK2 axis.

BACKGROUND: Colorectal cancer (CRC) theratened thousands of people every year. Emerging evidences suggested that circular RNAs (circRNAs) were involved in CRC malignancies. However, the underlying mechanisms have yet not been revealed. METHODS: Quantitative real-time PCR (qRT-PCR) was used to determine the expression of circ_0087862 and microRNA-512-3p (miR-512-3p). Western blot was performed to measure the protein expression of hexokinase 2 (HK2), B-cell lymphoma-2 (Bcl-2), BCL2-associated X (Bax) and BCL2 antagonist/killer 1 (Bak). Moreover, 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay, colony formation and 5-ethynyl-2'-deoxyuridine (EdU) assay were employed to assess CRC cell proliferation. Also, migration/invasion abilities and apoptosis rates were investigated by transwell assay and flow cytometry. Glucose consumption, lactate production and ATP production were detected using the corresponding kits. Dual-luciferase reporter analysis and RNA immunoprecipitation (RIP) experiments were utilized to analyze the target association of miR-512-3p and circ_0087862 or HK2. Finally, xenograft assay was carried out to analyze the function of circ_0087862 in tumor growth in vivo. RESULTS: Circ_0087862 expression was elevated in CRC tissues and cells. Circ_0087862 silencing repressed cell viabilities, proliferation, migration/invasion and glycolysis, and reinforced cell apoptosis. However, HK2 could weaken these impacts. Additionally, miR-512-3p targeted HK2, and circ_0087862 could regulate HK2 expression by miR-512-3p. Furthermore, circ_0087862 silencing decreased CRC cell xenograft tumor growth. CONCLUSION: Collectively, our data suggested that circ_0087862 knockdown impeded cell viabilities, proliferation, and glycolysis, and contributed to cell apoptosis in CRC, indicating circ_0087862 as a promising tumor promoter.

Circular RNA hsa_circ_0094976 modulates GPR155 to inhibit gastric adenocarcinoma malignant characteristics by targeting miR-223-3p.

BACKGROUND: The abnormal expression of circular RNA (circRNA) has been confirmed to be closely related to the development of many human diseases including gastric adenocarcinoma (GA). This study aimed to elucidate the molecular mechanism and biological function of hsa_circ_0094976 (circ_0094976) in GA. METHODS: The expression of circ_0094976, miR-223-3p, and G protein-coupled receptor 155 (GPR155) mRNA was measured by quantitative real-time polymerase chain reaction. Cell viability, cell proliferation, colony formation, migration, and invasion were estimated by cell counting kit-8 assay, 5-Ethynyl-2'-deoxyuridine assay, colony formation assay, and transwell assay, respectively. The bioinformatics analysis, dual-luciferase reporter assay, and RNA pull-down assay were used for predicting and verifying the interaction of the circ_0094976/miR-223-3p/GPR155 axis. A xenograft mouse model was performed in nude mice to reveal the role of circ_0094976 in vivo. RESULTS: Circ_0094976 was down-regulated in GA tissues and GA cell lines compared to normal controls. Overexpression of circ_0094976 inhibited the GA cell growth, migration, and invasion in vitro, and tumor growth in vivo. Circ_0094976 directly targeted miR-223-3p, and GPR155 was a direct target of miR-223-3p. Moreover, circ_0094976 sponging miR-223-3p to increase the expression of GPR155. CONCLUSION: We disclosed that circ_0094976 could act as a sponge of miR-223-3p to regulate the expression of GPR155, and further restrain the development of GA, which may provide new insight into the therapy of GA.