Comprehensive molecular interaction map of TGFß induced epithelial to mesenchymal transition in breast cancer.

Breast cancer is one of the prevailing cancers globally, with a high mortality rate. Metastatic breast cancer (MBC) is an advanced stage of cancer, characterised by a highly nonlinear, heterogeneous process involving numerous singling pathways and regulatory interactions. Epithelial-mesenchymal transition (EMT) emerges as a key mechanism exploited by cancer cells. Transforming Growth Factor-ß (TGFß)-dependent signalling is attributed to promote EMT in advanced stages of breast cancer. A comprehensive regulatory map of TGFß induced EMT was developed through an extensive literature survey. The network assembled comprises of 312 distinct species (proteins, genes, RNAs, complexes), and 426 reactions (state transitions, nuclear translocations, complex associations, and dissociations). The map was developed by following Systems Biology Graphical Notation (SBGN) using Cell Designer and made publicly available using MINERVA ( http://35.174.227.105:8080/minerva/?id=Metastatic_Breast_Cancer_1 ). While the complete molecular mechanism of MBC is still not known, the map captures the elaborate signalling interplay of TGFß induced EMT-promoting MBC. Subsequently, the disease map assembled was translated into a Boolean model utilising CaSQ and analysed using Cell Collective. Simulations of these have captured the known experimental outcomes of TGFß induced EMT in MBC. Hub regulators of the assembled map were identified, and their transcriptome-based analysis confirmed their role in cancer metastasis. Elaborate analysis of this map may help in gaining additional insights into the development and progression of metastatic breast cancer.

HER2 puzzle pieces: Non-Coding RNAs as keys to mechanisms, chemoresistance, and clinical outcomes in Ovarian cancer.

Ovarian cancer (OC) presents significant challenges, characterized by limited treatment options and therapy resistance often attributed to dysregulation of the HER2 signaling pathway. Non-coding RNAs (ncRNAs) have emerged as key players in regulating gene expression in OC. This comprehensive review underscores the pivotal role of ncRNAs in modulating HER2 signaling, with a specific focus on their mechanisms, impact on chemoresistance, and prognostic/diagnostic implications. MicroRNAs, long non-coding RNAs, and circular RNAs have been identified as essential regulators in the modulation of the HER2 pathway. By directly targeting key components of the HER2 axis, these ncRNAs influence its activation and downstream signaling cascades. Dysregulated ncRNAs have been closely associated with chemoresistance, leading to treatment failures and disease progression in OC. Furthermore, distinct expression profiles of ncRNAs hold promise as reliable prognostic and diagnostic markers, facilitating personalized treatment strategies and enhancing disease outcome assessments. A comprehensive understanding of how ncRNAs intricately modulate HER2 signaling is imperative for the development of targeted therapies and the improvement of patient outcomes. The integration of ncRNA profiles into clinical practice has the potential to enhance prognostic and diagnostic accuracy in the management of ovarian cancer. Further research efforts are essential to validate the clinical utility of ncRNAs and elucidate their precise roles in the regulation of HER2 signaling. In conclusion, ncRNAs play a crucial role in governing HER2 signaling in ovarian cancer, impacting chemoresistance and providing valuable prognostic and diagnostic insights. The exploration of ncRNA-mediated HER2 modulation offers promising avenues for the development of personalized treatment approaches, ultimately advancing patient care and outcomes in OC.

Pseudogene CSPG4P12 inhibits colorectal cancer progression by attenuating epithelial-mesenchymal transition.

Colorectal cancer is one of the most common malignant cancers. Pseudogenes have been identified as oncogenes or tumor suppressor genes in the development of various cancers. However, the function of pseudogene CSPG4P12 in colorectal cancer remains unclear. Therefore, the aim of this study was to investigate the potential role of CSPG4P12 in colorectal cancer and explore the possible underlying mechanism. The difference of CSPG4P12 expression between colorectal cancer tissues and adjacent normal tissues was analyzed using the online Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database. Cell viability and colony formation assays were conducted to evaluate cell viability. Transwell and wound healing assays were performed to assess cell migration and invasion capacities. Western blot was used to measure the expression levels of epithelial-mesenchymal transition-related proteins. Colorectal cancer tissues had lower CSPG4P12 expression than adjacent normal tissues. The overexpression of CSPG4P12 inhibited cell proliferation, invasion, and migration in colorectal cancer cells. Overexpressed CSPG4P12 promoted the expression of E-cadherin, whereas it inhibited the expression of vimentin, N-cadherin, and MMP9. These findings suggested that CSPG4P12 inhibits colorectal cancer development and may serve as a new potential target for colorectal cancer.

Non-coding RNA mediated regulation of PI3K/Akt pathway in hepatocellular carcinoma: Therapeutic perspectives.

Hepatocellular carcinoma (HCC) is among the primary reasons for fatalities caused by cancer globally, highlighting the need for comprehensive knowledge of its molecular aetiology to develop successful treatment approaches. The PI3K/Akt system is essential in the course of HCC, rendering it an intriguing candidate for treatment. Non-coding RNAs (ncRNAs), such as long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are important mediators of the PI3K/Akt network in HCC. The article delves into the complex regulatory functions of ncRNAs in influencing the PI3K/Akt system in HCC. The study explores how lncRNAs, miRNAs, and circRNAs impact the expression as well as the function of the PI3K/Akt network, either supporting or preventing HCC growth. Additionally, treatment strategies focusing on ncRNAs in HCC are examined, such as antisense oligonucleotide-based methods, RNA interference, and small molecule inhibitor technologies. Emphasizing the necessity of ensuring safety and effectiveness in clinical settings, limitations, and future approaches in using ncRNAs as therapies for HCC are underlined. The present study offers useful insights into the complex regulation system of ncRNAs and the PI3K/Akt cascade in HCC, suggesting possible opportunities for developing innovative treatment approaches to address this lethal tumor.

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.

A multi-omics approach for biomarker discovery in neuroblastoma: a network-based framework.

Neuroblastoma (NB) is one of the leading causes of cancer-associated death in children. MYCN amplification is a prominent genetic marker for NB, and its targeting to halt NB progression is difficult to achieve. Therefore, an in-depth understanding of the molecular interactome of NB is needed to improve treatment outcomes. Analysis of NB multi-omics unravels valuable insight into the interplay between MYCN transcriptional and miRNA post-transcriptional modulation. Moreover, it aids in the identification of various miRNAs that participate in NB development and progression. This study proposes an integrated computational framework with three levels of high-throughput NB data (mRNA-seq, miRNA-seq, and methylation array). Similarity Network Fusion (SNF) and ranked SNF methods were utilized to identify essential genes and miRNAs. The specified genes included both miRNA-target genes and transcription factors (TFs). The interactions between TFs and miRNAs and between miRNAs and their target genes were retrieved where a regulatory network was developed. Finally, an interaction network-based analysis was performed to identify candidate biomarkers. The candidate biomarkers were further analyzed for their potential use in prognosis and diagnosis. The candidate biomarkers included three TFs and seven miRNAs. Four biomarkers have been previously studied and tested in NB, while the remaining identified biomarkers have known roles in other types of cancer. Although the specific molecular role is yet to be addressed, most identified biomarkers possess evidence of involvement in NB tumorigenesis. Analyzing cellular interactome to identify potential biomarkers is a promising approach that can contribute to optimizing efficient therapeutic regimens to target NB vulnerabilities.

IDH1 mutation produces R-2-hydroxyglutarate (R-2HG) and induces mir-182-5p expression to regulate cell cycle and tumor formation in glioma.

BACKGROUND: Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), are present in most gliomas. IDH1 mutation is an important prognostic marker in glioma. However, its regulatory mechanism in glioma remains incompletely understood. RESULTS: miR-182-5p expression was increased within IDH1-mutant glioma specimens according to TCGA, CGGA, and online dataset GSE119740, as well as collected clinical samples. (R)-2-hydroxyglutarate ((R)-2HG) treatment up-regulated the expression of miR-182-5p, enhanced glioma cell proliferation, and suppressed apoptosis; miR-182-5p inhibition partially eliminated the oncogenic effects of R-2HG upon glioma cells. By direct binding to Cyclin Dependent Kinase Inhibitor 2 C (CDKN2C) 3'UTR, miR-182-5p inhibited CDKN2C expression. Regarding cellular functions, CDKN2C knockdown promoted R-2HG-treated glioma cell viability, suppressed apoptosis, and relieved cell cycle arrest. Furthermore, CDKN2C knockdown partially attenuated the effects of miR-182-5p inhibition on cell phenotypes. Moreover, CDKN2C knockdown exerted opposite effects on cell cycle check point and apoptosis markers to those of miR-182-5p inhibition; also, CDKN2C knockdown partially attenuated the functions of miR-182-5p inhibition in cell cycle check point and apoptosis markers. The engineered CS-NPs (antagomir-182-5p) effectively encapsulated and delivered antagomir-182-5p, enhancing anti-tumor efficacy in vivo, indicating the therapeutic potential of CS-NPs(antagomir-182-5p) in targeting the miR-182-5p/CDKN2C axis against R-2HG-driven oncogenesis in mice models. CONCLUSIONS: These insights highlight the potential of CS-NPs(antagomir-182-5p) to target the miR-182-5p/CDKN2C axis, offering a promising therapeutic avenue against R-2HG's oncogenic influence to glioma.

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.

Comprehensive analysis of recently discovered lncRNA-associated competing endogenous RNA network in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) arises from the epithelium of the nasopharynx and is characterized by geography-dependent incidence. Despite the high mortality rate, specifically in some ethnic groups, the mechanisms underlying NPC pathogenesis are not thoroughly understood and there is an urgent need to detect the potential and clinically applicable biomarkers to ameliorate the overall survival rate and improve the prognosis of patients. In recent years, research has increasingly focused on the importance of long non-coding RNAs (LncRNAs) in cancer progression. LncRNAs play critical roles in regulating gene expression through mechanisms such as competitively binding to microRNAs (CeRNA). While numerous LncRNAs have been studied in nasopharyngeal carcinoma (NPC), their potential as diagnostic and prognostic biomarkers have not been systematically examined. In the present study, we delve into elucidating the biological functions, molecular mechanisms, and clinical significance of newly identified LncRNAs that serve as sponges for different microRNAs in NPC. We highlight their regulatory mechanisms in promoting cell proliferation, invasion, and metastasis, and discuss their implications in diverse cancer-related signaling pathways. Our overall goal is to emboss the fundamental roles of LncRNA-mediated CeRNA networks in NPC progression, which may open up new avenues for determining the pathogenesis of NPC and developing effective prevention and treatment strategies.

Expression analysis of necroptosis related genes and lncRNAs in patients with pituitary neuroendocrine tumors.

Necroptosis can either be the cause of tumorigenesis or it can impede its process. Recently, it has been proved that long non-coding RNAs (lncRNAs) have different crucial roles at cellular level, especially on cell death. Regarding the important role of necroptosis and lncRNAs in the pathogenesis of different cancers, especially pituitary adenomas (PAs), we assessed expression levels of two necroptosis related genes, namely TRADD and BIRC2, in addition to three related lncRNAs, namely FLVCR1-DT, MAGI2-AS3, and NEAT1 in PAs compared with adjacent normal tissues (ANTs). TRADD had no significant difference between two groups; however, BIRC2, FLVCR1-DT, MAGI2-AS3, and NEAT1 were upregulated in PAs compared to ANTs (Expression ratios [95% CI] = 2.3 [1.47-3.6], 2.13 [1.02-4.44], 3.01 [1.76-5.16] and 2.47 [1.37-4.45], respectively). When taking into account different types of PAs, significant upregulation of BIRC2, MAGI2-AS3 and NEAT1 was recorded in non-functioning PAs compared with corresponding ANTs (Expression ratios [95% CI] =1.9 [1.04-3.43], 2.69 [1.26-5.72] and 2.22 [0.98-5.01], respectively). Additionally, higher levels of BIRC2 were associated with higher flow of CSF (P value=0.048). Moreover, higher Knosp classified tumors had lower levels of BIRC2 (P value=0.001). Finally, lower levels of MAGI2-AS3 were associated with larger tumor size (P value=0.006). NEAT1 expression was correlated with FLVCR1-DT and TRADD. TRADD expression was correlated with FLVCR1-DT. Additional correlation was observed between expression of BIRC2 and MAGI2-AS3. In sum, this study provides evidence that dysregulated levels of studied genes could contribute to the pathogenesis of pituitary tumors.

Effects of miR-330 restoration on pancreatic cancer cells oncogenesis.

BACKGROUND: Inappropriate expressions of various miRNAs have reported in different human malignancies. Evidence suggested that miR-330 may play as both onco-miR and/or tumor suppressor-miR in different cancers. In the present study, we evaluated effects of miR-330 on proliferation and migration of pancreatic cancer (PC) cells as well as underlying molecular mechanisms. DESIGN: The expression of miR-330 was evaluated in clinical tissue samples of patients with PC. Transfection of the PC cells (PANC-1) by miR-330 was conducted by pCMV vector. The cancer-related genes expression was investigated in mRNA and protein level following transfection of the PC cells. Furthermore, the PC cells viability, invasion, migration, mitochondrial membrane potential, apoptosis, autophagy, and cell cycle profile were investigated after transfection by miR-330. RESULTS: The results indicated that expression of miR-330 downregulated in patients with PC. Stable increase of miR-330 expression after transfection in PC cells reduces viability, mitochondrial membrane potential, invasion, and migration. Further assessments demonstrated that upregulation of miR-330 increases apoptosis and autophagy percentage in the PC cells. Moreover, a cell cycle arrest was observed in G1, Sub-G1, and S phases following transfection of the PC cells. These findings can be explained by modified mRNA and protein expression of apoptosis- and metastasis-related genes. CONCLUSION: Our study suggested that miR-330 acts as a tumor suppressor in PC cells, and revealed that upregulation of miR-330 may provide an effective therapeutic approach for overcoming progression and metastasis in patients with PC.

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.

CDK1 and CCNA2 play important roles in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a malignant tumor that occurs in oral cavity and is dominated by squamous cells. The relationship between CDK1, CCNA2, and OSCC is still unclear. The OSCC datasets GSE74530 and GSE85195 configuration files were downloaded from the Gene Expression Omnibus (GEO) database and were derived from platforms GPL570 and GPL6480. Differentially expressed genes (DEGs) were screened. The weighted gene co-expression network analysis, functional enrichment analysis, gene set enrichment analysis, construction and analysis of protein-protein interaction (PPI) network, Comparative Toxicogenomics Database analysis were performed. Gene expression heatmap was drawn. TargetScan was used to screen miRNAs that regulate central DEGs. A total of 1756 DEGs were identified. According to Gene Ontology (GO) analysis, they were predominantly enriched in processes related to organic acid catabolic metabolism, centromeric, and chromosomal region condensation, and oxidoreductase activity. In Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the DEGs were mainly concentrated in metabolic pathways, P53 signaling pathway, and PPAR signaling pathway. Weighted gene co-expression network analysis was performed with a soft-thresholding power set at 9, leading to the identification of 6 core genes (BUB1B, CCNB1, KIF20A, CCNA2, CDCA8, CDK1). The gene expression heatmap revealed that core genes (CDK1, CCNA2) were highly expressed in OSCC samples. Comparative Toxicogenomics Database analysis demonstrated associations between the 6 genes (BUB1B, CCNB1, KIF20A, CCNA2, CDCA8, CDK1) and oral tumors, precancerous lesions, inflammation, immune system disorders, and tongue tumors. The associated miRNAs for CDK1 gene were hsa-miR-203a-3p.2, while for CCNA2 gene, they were hsa-miR-6766-3p, hsa-miR-4782-3p, and hsa-miR-219a-5p. CDK1 and CCNA2 are highly expressed in OSCC. The higher the expression of CDK1 and CCNA2, the worse the prognosis.

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.

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.

A novel hypergraph model for identifying and prioritizing personalized drivers in cancer.

Cancer development is driven by an accumulation of a small number of driver genetic mutations that confer the selective growth advantage to the cell, while most passenger mutations do not contribute to tumor progression. The identification of these driver genes responsible for tumorigenesis is a crucial step in designing effective cancer treatments. Although many computational methods have been developed with this purpose, the majority of existing methods solely provided a single driver gene list for the entire cohort of patients, ignoring the high heterogeneity of driver events across patients. It remains challenging to identify the personalized driver genes. Here, we propose a novel method (PDRWH), which aims to prioritize the mutated genes of a single patient based on their impact on the abnormal expression of downstream genes across a group of patients who share the co-mutation genes and similar gene expression profiles. The wide experimental results on 16 cancer datasets from TCGA showed that PDRWH excels in identifying known general driver genes and tumor-specific drivers. In the comparative testing across five cancer types, PDRWH outperformed existing individual-level methods as well as cohort-level methods. Our results also demonstrated that PDRWH could identify both common and rare drivers. The personalized driver profiles could improve tumor stratification, providing new insights into understanding tumor heterogeneity and taking a further step toward personalized treatment. We also validated one of our predicted novel personalized driver genes on tumor cell proliferation by vitro cell-based assays, the promoting effect of the high expression of Low-density lipoprotein receptor-related protein 1 (LRP1) on tumor cell proliferation.

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.

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.