The feedback loop of EFTUD2/c-MYC impedes chemotherapeutic efficacy by enhancing EFTUD2 transcription and stabilizing c-MYC protein in colorectal cancer.

BACKGROUND: Chemoresistance presents a significant obstacle in the treatment of colorectal cancer (CRC), yet the molecular basis underlying CRC chemoresistance remains poorly understood, impeding the development of new therapeutic interventions. Elongation factor Tu GTP binding domain containing 2 (EFTUD2) has emerged as a potential oncogenic factor implicated in various cancer types, where it fosters tumor growth and survival. However, its specific role in modulating the sensitivity of CRC cells to chemotherapy is still unclear. METHODS: Public dataset analysis and in-house sample validation were conducted to assess the expression of EFTUD2 in 5-fluorouracil (5-FU) chemotherapy-resistant CRC cells and the potential of EFTUD2 as a prognostic indicator for CRC. Experiments both in vitro, including MTT assay, EdU cell proliferation assay, TUNEL assay, and clone formation assay and in vivo, using cell-derived xenograft models, were performed to elucidate the function of EFTUD2 in sensitivity of CRC cells to 5-FU treatment. The molecular mechanism on the reciprocal regulation between EFTUD2 and the oncogenic transcription factor c-MYC was investigated through molecular docking, ubiquitination assay, chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, and co-immunoprecipitation (Co-IP). RESULTS: We found that EFTUD2 expression was positively correlated with 5-FU resistance, higher pathological grade, and poor prognosis in CRC patients. We also demonstrated both in vitro and in vivo that knockdown of EFTUD2 sensitized CRC cells to 5-FU treatment, whereas overexpression of EFTUD2 impaired such sensitivity. Mechanistically, we uncovered that EFTUD2 physically interacted with and stabilized c-MYC protein by preventing its ubiquitin-mediated proteasomal degradation. Intriguingly, we found that c-MYC directly bound to the promoter region of EFTUD2 gene, activating its transcription. Leveraging rescue experiments, we further confirmed that the effect of EFTUD2 on 5-FU resistance was dependent on c-MYC stabilization. CONCLUSION: Our findings revealed a positive feedback loop involving an EFTUD2/c-MYC axis that hampers the efficacy of 5-FU chemotherapy in CRC cells by increasing EFTUD2 transcription and stabilizing c-MYC oncoprotein. This study highlights the potential of EFTUD2 as a promising therapeutic target to surmount chemotherapy resistance in CRC patients.

Machine-Learning-Assisted Procoagulant Extracellular Vesicle Barcode Assay toward High-Performance Evaluation of Thrombosis-Induced Death Risk in Cancer Patients.

Venous thromboembolism (VTE) is the most fatal complication in cancer patients. Unfortunately, the frequent misdiagnosis of VTE owing to the lack of accurate and efficient evaluation approaches may cause belated medical intervention and even sudden death. Herein, we present a rapid, easily operable, highly specific, and highly sensitive procoagulant extracellular vesicle barcode (PEVB) assay composed of TiO2 nanoflower (TiNFs) for visually evaluating VTE risk in cancer patients. TiNFs demonstrate rapid label-free EV capture capability by the synergetic effect of TiO2-phospholipids molecular interactions and topological interactions between TiNFs and EVs. From ordinary plasma samples, the PEVB assay can evaluate potential VTE risk by integrating TiNFs-based EV capture and in situ EV procoagulant ability test with machine-learning-assisted clinical data analysis. We demonstrate the feasibility of this PEVB assay in VTE risk evaluation by screening 167 cancer patients, as well as the high specificity (97.1%) and high sensitivity (96.8%), fully exceeding the nonspecific and posterior traditional VTE test. Together, we proposed a TiNFs platform allowing for highly accurate and timely diagnosis of VTE in cancer patients.

Interfacial Polymerization Produced Magnetic Particles with Nano-Filopodia for Highly Accurate Liquid Biopsy in the PSA Gray Zone.

Magnetic particles are leading separation materials for biological purification and detection. Existing magnetic particles, which almost rely on molecule-level interactions, however, often encounter bottlenecks in highly efficient cell-level separation due to the underestimate of surface structure effects. Here, immune cell-inspired magnetic particles with nano-filopodia (NFMPs) produced by interfacial polymerization for highly efficient capture of circulating tumor cells (CTCs) and further accurate clinical diagnosis of prostate cancer are reported . The unprecedented construction of nano-filopodia on polymer-based magnetic particles is achieved by introducing electrostatic interactions in emulsion interfacial polymerization. Due to the unique nano-filopodia, the NFMPs allow remarkably enhanced CTCs capture efficiency (86.5% ± 2.8%) compared with smooth magnetic particles (SMPs, 35.7% ± 5.7%). Under the assistance of machine learning by combining with prostate-specific antigen (PSA) and free to total PSA (F/T-PSA), the NFMPs strategy demonstrates high sensitivity (100%), high specificity (93.3%), and a high area under the curve (AUC) value (98.1%) for clinical diagnosis of prostate cancer in the PSA gray zone. The NFMPs are anticipated as an efficient platform for CTCs-based liquid biopsy toward early cancer diagnosis and prognosis evaluation.

Pan-cancer patterns of cuproptosis markers reveal biologically and clinically relevant cancer subtypes.

Cuproptosis is a newly discovered type of cell death triggered by copper accumulation. Here we exhibited the genetic profiles of 10 cuproptosis-associated genes (CuAGs) across 21 cancer types. Only 8.0% (627/7839) of tumors possessed at least 1 mutation on CuAGs, while the copy number amplifications or deletions on the alleles of CuAGs were ubiquitous. Generally, the expression of CuAGs showed heterogeneity across cancer types and the expression of CuAGs showed different correlations with MSI, TMB, immune and stromal features in different cancer types. Therefore, CuAGs were ubiquitously and heterogeneously dysregulated in pan-cancer. With a Non-negative Matrix Factorization method, we divided patients of each cancer type into cuproptosis-based subtypes, which showed a close but heterogeneous correlation with different biological and clinical features. Accordingly, we summarized all cancer types into four categories. The cancers in which cuproptosis subtypes correlated with MSI and TMB were annotated as Genomic disturbed. Those correlated with stromal scores were categorized as Stromal remolded. The others only associated with immune infiltration were labeled as Immune inhibited. A minor fraction of cancers not correlated with any biological indicators were marked as Cuproptosis inert. Together, we provided a pan-cancer overview of cuproptosis markers which revealed biologically and clinically relevant cancer subtypes in different cancers.

Nano-drug delivery system for pancreatic cancer: A visualization and bibliometric analysis.

Background: Nano drug delivery system (NDDS) can significantly improve the delivery and efficacy of drugs against pancreatic cancer (PC) in many ways. The purpose of this study is to explore the related research fields of NDDS for PC from the perspective of bibliometrics. Methods: Articles and reviews on NDDS for PC published between 2003 and 2022 were obtained from the Web of Science Core Collection. CiteSpace, VOSviewer, R-bibliometrix, and Microsoft Excel were comprehensively used for bibliometric and visual analysis. Results: A total of 1329 papers on NDDS for PC were included. The number of papers showed an upward trend over the past 20 years. The United States contributed the most papers, followed by China, and India. Also, the United States had the highest number of total citations and H-index. The institution with the most papers was Chinese Acad Sci, which was also the most important in international institutional cooperation. Professors Couvreur P and Kazuoka K made great achievements in this field. JOURNAL OF CONTROLLED RELEASE published the most papers and was cited the most. The topics related to the tumor microenvironment such as "tumor microenvironment", "tumor penetration", "hypoxia", "exosome", and "autophagy", PC treatment-related topics such as "immunotherapy", "combination therapy", "alternating magnetic field/magnetic hyperthermia", and "ultrasound", and gene therapy dominated by "siRNA" and "miRNA" were the research hotspots in the field of NDDS for PC. Conclusion: This study systematically uncovered a holistic picture of the performance of NDDS for PC-related literature over the past 20 years. We provided scholars to understand key information in this field with the perspective of bibliometrics, which we believe may greatly facilitate future research in this field.

Distinct tumor microenvironment landscapes of rectal cancer for prognosis and prediction of immunotherapy response.

PURPOSE: Tumor microenvironment (TME) affects the progression of rectal cancer (RC), and the clinical relevance of its immune elements was widely reported. Here we aim to delineate the complete TME landscape, including non-immune features, to improve our understanding of RC heterogeneity and provide a better strategy for precision medicine. METHODS: Single-cell analysis of GSE161277 using Seurat and Cellcall was performed to identify cell-cell interactions. The ssGSEA was employed to quantify the TME elements in TCGA patients, which were further clustered into subtypes by hclust. WGCNA and LASSO were combined to construct a degenerated signature for prognosis, and its performance was validated in two GEO datasets. RESULTS: We proposed a subtyping strategy based on the abundance of both immune and non-immune components, which divided all RC patients into 4 subtypes (Immune-, Canonical-, Dormant- and Stem-like). Different subtypes exhibited distinct mutation landscapes, biological features, immune characteristics, immunotherapy responses and prognoses. Next, WGCNA and LASSO regression were combined to construct a 10-gene signature based on differentially expressed genes among different subtypes. Subgroups divided by this signature also exhibited different clinical parameters and responses to immune checkpoint blockades. Diverse machine learning algorithms were applied to achieve higher accuracy for survival prediction and a nomogram was further established in combination with M stage and age to provide an accurate and visual prediction of prognosis. CONCLUSIONS: We identified four TME-based RC subtypes with distinct biological and clinical features. Based on those subtypes, we also proposed a degenerated 10-gene signature to predict the prognosis and immunotherapy response.

The Janus-faced role of TRPM2-S in retroperitoneal liposarcoma via increasing ROS levels.

BACKGROUND: Retroperitoneal liposarcoma (RPLS) is a specific soft tissue sarcoma with a high recurrence rate. The short isoform of transient receptor potential cation channel subfamily M member 2 (TRPM2-S) plays an important role in the regulation of reactive oxygen species (ROS). However, the association between TRPM2-S and RPLS and its underlying mechanisms remains unclear. METHODS: The expression of both TRPM2-S and TRPM2-L in RPLS tissues was verified by kimmunohistochemistry (IHC). The regulation on Ca2+ influx by TRPM2-S was evaluated by Fluo-4 AM staining. The effect of TRPM2-S on cell proliferation and apoptosis was tested by 5-Ethynyl-2'-deoxyuridine (EdU) staining and Flow cytometry respectively. The level of cellular ROS was assessed by the DCFH-DA probe. Different concentrations of H2O2 were used to provide oxidative stress on RPLS cells. The underlying mechanisms were further explored by Western blotting. RESULTS: The IHC assays showed that TRPM2-S, but not TRPM2-L, was prognostic in RPLS. Low TRPM2-S level was associated with poor disease-free survival (DFS). Calcium influx signal intensity was significantly decreased under TRPM2-S overexpression, which resulted in a decrease in the levels of FOXO3a and PTEN. Correspondingly, the levels of pERK, pAKT, pP65, pGSK-3ß, Bcl-2, and ß-catenin were upregulated, and cellular ROS was gently increased under TRPM2-S overexpression. Moreover, TRPM2-S slightly promoted cell proliferation and inhibited apoptosis of RPLS cell lines under normoxia, but largely increased apoptosis rates under oxidative stress. The cleaved caspase3 was significantly upregulated by TRPM2-S overexpression under oxidative stress. N-Acetyl-L-cysteine (NAC), a small molecule antioxidant, could largely rescue RPLS cells from the apoptosis induced by H2O2. CONCLUSION: TRPM2-S exerts Janus-faced effects in RPLS by increasing the ROS levels via inhibition on FOXO3a, which promotes cell proliferation under normoxia but induces apoptosis under oxidative stress. Video abstract.

FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression.

Pancreatic cancer (PC) is one of the deadliest malignant tumors, and its resistance to gemcitabine chemotherapy is the primary reason for poor prognosis in patients. Ubiquitin-like protein FAT10 has recently been reported to promote tumor chemotherapy resistance. In this study, the expression of FAT10 in PC was significantly higher than that in adjacent noncancerous tissues. Increased expression of FAT10 in PC was related to a late TNM stage and decreased overall survival. Functional experiments revealed that downregulating the expression of FAT10 inhibits the proliferation and epithelial-mesenchymal transition (EMT) of PC cells, promotes the apoptosis of PC cells, and enhances sensitivity to gemcitabine chemotherapy. In addition, upregulation of FAT10 increased the expression of FOXM1 protein. The effect of downregulating FAT10 was reversed by FOXM1 overexpression, and FOXM1 knockdown inhibited EMT driven by FAT10 overexpression. Mechanistically, FAT10 stabilized the expression of FOXM1 by competing with ubiquitin to bind FOXM1 and inhibiting the ubiquitination-mediated degradation of FOXM1. In conclusion, the FAT10-FOXM1 axis is a pivotal driver of PC proliferation and gemcitabine resistance, and the results provide novel insights into chemotherapy resistance in PC.

Construction of a new immune-related lncRNA model and prediction of treatment and survival prognosis of human colon cancer.

BACKGROUND: An increasing number of studies have shown that immune-related long noncoding RNAs (lncRNAs) do not require a unique expression level. This finding may help predict the survival and drug sensitivity of patients with colon cancer. METHODS: We retrieved original transcriptome and clinical data from The Cancer Genome Atlas (TCGA), sorted the data, differentiated mRNAs and lncRNAs, and then downloaded immune-related genes. Coexpression analysis predicted immune-related lncRNAs (irlncRNAs) and univariate analysis identified differentially expressed irlncRNAs (DEirlncRNAs). We have also amended the lasso pending region. Next, we compared the areas under the curve (AUCs), counted the Akaike information standard (AIC) value of the 3-year receiver operating characteristic (ROC) curve, and determined the cutoff point to establish the best model to differentiate the high or low disease risk group of colon cancer patients. RESULTS: We reevaluated the patients regarding the survival rate, clinicopathological features, tumor-infiltrating immune cells, immunosuppressive biomarkers, and chemosensitivity. A total of 155 irlncRNA pairs were confirmed, 31 of which were involved in the Cox regression model. After the colon cancer patients were regrouped according to the cutoff point, we could better distinguish the patients based on adverse survival outcomes, invasive clinicopathological features, the specific tumor immune cell infiltration status, high expression of immunosuppressive biomarkers, and low chemosensitivity. CONCLUSIONS: In this study, we established a characteristic model by pairing irlncRNAs to better predict the survival rate, chemotherapy efficacy, and prognostic value of patients with colon cancer.

Expression of LOX Suggests Poor Prognosis in Gastric Cancer.

Background: Lysyl oxidase (LOX) is a key enzyme for the cross-linking of collagen and elastin in the extracellular matrix. This study evaluated the prognostic role of LOX in gastric cancer (GC) by analyzing the data of The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) dataset. Methods: The Wilcoxon rank-sum test was used to calculate the expression difference of LOX gene in gastric cancer and normal tissues. Western blot and immunohistochemical staining were used to evaluate the expression level of LOX protein in gastric cancer. Kaplan-Meier analysis was used to calculate the survival difference between the high expression group and the low expression group in gastric cancer. The relationship between statistical clinicopathological characteristics and LOX gene expression was analyzed by Wilcoxon or Kruskal-Wallis test and logistic regression. Univariate and multivariate Cox regression analysis was used to find independent risk factors affecting the prognosis of GC patients. Gene set enrichment analysis (GSEA) was used to screen the possible mechanisms of LOX and GC. The CIBERSORT calculation method was used to evaluate the distribution of tumor-infiltrating immune cell (TIC) abundance. Results: LOX is highly expressed in gastric cancer tissues and is significantly related to poor overall survival. Wilcoxon or Kruskal-Wallis test and Logistic regression analysis showed, LOX overexpression is significantly correlated with T-stage progression in gastric cancer. Multivariate Cox regression analysis on TCGA and GEO data found that LOX (all p < 0.05) is an independent factor for poor GC prognosis. GSEA showed that high LOX expression is related to ECM receptor interaction, cancer, Hedgehog, TGF-beta, JAK-STAT, MAPK, Wnt, and mTOR signaling pathways. The expression level of LOX affects the immune activity of the tumor microenvironment in gastric cancer. Conclusion: High expression of LOX is a potential molecular indicator for poor prognosis of gastric cancer.

Comprehensive analysis of Syk gene methylation in colorectal cancer.

BACKGROUND: Metastasis of colorectal cancer (CRC) extremely affects the prognosis of CRC patients. Recently, the genetic methylation has been shown to associate with tumor metastasis. This research aimed to explore the Syk gene, which is frequently hypermethylated in different cancers, and its impact on the metastasis of CRC cells. METHODS: We employed the UALCAN database for the detection of the methylation levels of Syk in different cancers. CIBERSORT, TIMER and TISIDB tools were employed to analyze the association of Syk expression with immune features of CRC. Treatment with decitabine has been noted to restore the expression of Syk in CRC cells. The invasion and migration abilities of CRC cell lines were determined using transwell and wound healing assays. The correlation between Syk and c-Myc was established using the GEPIA2 database and Western blot assays. ​Results: Our results, based on UALCAN, revealed that the methylation level of Syk was altered in diverse cancers including colon adenocarcinoma. We found that expression profile and methylation level of Syk was correlated with immune features of colon adenocarcinoma. Decitabine can restore the expression of Syk in HCT116 and SW480 cells, hence affecting their migration and invasion. Results from GEPIA2 showed that Syk expression was correlated with c-Myc, while Western blotting analysis revealed a negative association between the expression level of Syk and c-Myc. ​Conclusions:​ ​This study demonstrates that the expression of Syk could be restored by decitabine in colorectal cancer, thus affecting the migration and invasion abilities of CRC cells.

RP11-51O6.1 sponges miR-206 to accelerate colorectal cancer carcinogenesis and metastasis through upregulating YAP1.

Long non-coding RNAs (lncRNAs) have been characterized by playing a crucial role in tumorigenesis. However, the detail biological function and clinical importance of lncRNAs in colorectal cancer (CRC) are unclear and have attracted different levels of in-depth research. In this context, we explored the differentially expressed profiles of lncRNAs in six CRC tissues and three adjacent non-tumor tissues from RNA-sequencing (RNA-seq) study and noted a lncRNA, RP11-51O6.1, which is markedly overexpressed in CRC tissues, particularly in aggressive cases. Impressively, an elevated RP11-51O6.1 level was highly correlated with poor prognosis in clinical patients. Functional analyses revealed that RP11-51O6.1 could promote cell proliferation in vitro and in vivo. Furthermore, we reported that RP11-51O6.1 enhances cell migration and invasion in vitro. Mechanistic studies (Bioinformatics binding site analyses, the Luciferase reporter, Ago2 immunoprecipitation, the RNA pull-down, immunofluorescence colocalization, rescued assays and western blotting) implicated that RP11-51O6.1 could regulate YAP1 expression by competitively sponging miR-206 and blocking its activity in promoting CRC progression. Conclusively, our findings identify a novel RP11-51O6.1/miR-206/YAP1 regulatory axis that participates in CRC progression and development, suggesting RP11-51O6.1 is an exploitable biomarker and appealing therapeutic target in treating CRC.

Data mining combined with experiments to validate CEP55 as a prognostic biomarker in colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) is a common tumor with high morbidity and mortality. Current specific diagnosis regarding CRC remains complicated and costly, and specific diagnostic biomarkers are lacking. METHODS: To find potential diagnostic and prognostic biomarkers for CRC, we screened and analyzed many CRC sequencing data by The Cancer Genome Atlas Program and Gene Expression Omnibus, and validated that CEP55 may be a potential diagnostic biomarker for CRC by molecular cytological experiments and immunohistochemistry, among others. RESULTS: We found that CEP55 is upregulated in CRC tissues and tumor cells and can promote CRC proliferation and metastasis by activating the p53/p21 axis and that CEP55 mutations in tumor patients result in worse overall survival and disease-free survival time. Besides, we also found that genes, such as CDK1, CCNB1, NEK2, KIF14, CDCA5, and RFC3 were upregulated in tumors, and their mutations would affect the prognosis of CRC patients, but these results await for more experimental evidence. CONCLUSION: Our study validates CEP55 as a potential diagnostic and prognostic biomarker for CRC, and we also provide multiple genes and potential molecular mechanisms that may serve as diagnostic and prognostic markers for CRC.

Comprehensive analysis of the prognosis for chromobox family in gastric cancer.

BACKGROUND: Chromobox (CBX) family proteins are a class of transcriptional repressors involved in epigenetic regulation and developmental processes of various tumors, including gastric cancer. However, the function and prognosis of different CBXs in gastric cancer remain unknown. METHODS: This study addresses this issue by synthesizing several mainstream databases (Oncomine, GEPIA2, cBioportal, and Kaplan-Meier plotter, among others) that currently contain many tumor samples and provide very reliable analysis results, investigating the role of CBXs in the prognosis of gastric cancer. RESULTS: The mRNA of CBX1/2/3/4/5/8 was highly expressed in gastric cancer, the mRNA of CBX7 was lowly expressed in gastric cancer, and the mRNA expression of CBX6 was not significantly different in CRC. Besides, high and low CBXs mRNA expression correlated with cancer stage, node metastasis status, H. pylori infection status, and tumor grade in CRC patients. We found that high mRNA expression of CBX4/5/6/7/8 was significantly associated with worse overall survival (OS), progression-free survival (FP), and post-progression survival (PPS) in a large number of CRC patients. High mRNA expression of CBX3 was significantly associated with better OS and FP. We also found that none of the eight CBXs family genes had a mutation rate of less than 5% in gastric cancer, and the highest mutation rate was in CBX3 (14%). CONCLUSIONS: These results suggest that CBX3/4/5/6/7/8 could be a prognostic biomarker in gastric cancer patients.

Bioinformatics Analysis Identifies a Novel Role of GINS1 Gene in Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most lethal malignancies and the incidence of CRC has been on the rise. Herein, we aimed to identify effective biomarkers for early diagnosis and treatment of colorectal cancer via bioinformatic tools. METHODS: To identify differentially expressed genes (DEGs) in CRC, we downloaded CRC gene expression data from GSE24514 and GSE110223 datasets in Gene Expression Omnibus (GEO) and employed R to analyze the data. We further performed functional enrichment analysis of the DEGs on the DAVID gene ontology analysis tool. STRING database and Cytoscape visualization tool were employed to construct a PPI (protein-protein interaction) network and establish intensive intervals in the network. Immunohistochemistry, qRT-PCR and Western blotting were performed to identify the expression level of GINS1 in CRC. In vitro and in vivo experiments were performed to assess the impact of GINS1 in the pathogenesis of CRC in terms of proliferation, migration and metastasis. RESULTS: Among the two datasets, 389 DEGs were identified and used to construct a PPI network. These genes were mainly involved in cell proliferation and cell cycle. Among them, 15 genes including GINS1 were found to be strongly associated with the PPI network. We further performed immunohistochemistry, qRT-PCR and Western blotting to identify that GINS1 expression was higher in CRC than in paired normal tissues. Moreover, in vitro and in vivo experiments demonstrated GINS1 could promote the proliferation, invasion and migration of colorectal cancer cells. CONCLUSIONS: GINS1 could be considered as a potential biomarker for CRC patients.

Expression Profile of GINS Complex Predicts the Prognosis of Pancreatic Cancer Patients.

BACKGROUND: The GINS complex has been implicated in the prognosis of various cancers. It comprises four subunits, encoded by GINS1, GINS2, GINS3, and GINS4 genes. Based on the current understanding, no report exists on the role of the GINS complex in pancreatic cancer. METHODS: We employed various bioinformatics databases including GEPIA, UALCAN, GEPIA2, and Kaplan Meier Plotter to identify the expression profile of the four genes (GINS1, GINS2, GINS3, and GINS4), their correlation with pancreatic cancer grade as well as their prognostic value of in pancreatic cancer. Western blotting and qRT-PCR analyses were conducted to verify the expression profiles of the four genes in pancreatic cancer. CCK8 and EdU cell experiments were conducted to reveal the role played by the four genes in pancreatic cancer cell proliferation. RESULTS: Based on GEPIA, Western blotting, and qRT-PCR analyses, all the four genes in the GINS complex were overexpressed in pancreatic cancer. Notably, the expression of each member was significantly associated with pancreatic cancer grade. The prognostic analysis revealed that not only the whole GINS complex but also each individual were prognostic biomarkers for pancreatic cancer. CCK8 and EdU experiments demonstrated that inhibition of the expression of each GINS member lowered pancreatic cancer cell proliferation. CONCLUSION: This work implicated GINS1, GINS2, GINS3, and GINS4 genes as critical prognostic markers for pancreatic cancer.

A signature of 18 immune-related gene pairs to predict the prognosis of pancreatic cancer patients.

Pancreatic cancer is one of the most lethal malignancies. With the promising prospects conveyed by immunotherapy in cancers, we aimed to construct an immune-related gene pairs (IRGPs) signature to predict the prognosis of pancreatic cancer patients. We downloaded clinical and transcriptional data of pancreatic cancer patients from The Cancer Genome Atlas data set as the training group and GSE57495 data set as the verification group. We filtered immune-related transcriptional data by IMMPORT. With the assistance of lasso penalized Cox regression, we constructed our prognostic IRGPs signature and divided all samples into high-/low-risk groups by receiver operating characteristic curve for further comparisons. The comparisons between high- and low-risk groups including survival rate, multivariate, and univariate Cox proportional-hazards analysis, infiltration of immune cells, and Gene Set Enrichment Analysis (GSEA). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) are facilitated to analyze the proceedings in which our IRGPs signature may involve in. The results revealed that 18 IRGPs were defined as our prognostic signature. The prognostic value of this IRGPs signature was verified from the GSE57495 data set. We further demonstrated the independent prognostic value of this IRGPs signature. The contents of six immune cells between high-/low-risk groups were different, which was associated with the progression of diverse cancers. Results from GO, KEGG, and GSEA revealed that this IRGPs signature was involved in extracellular space, immune response, cancer pathways, cation channel, and gated channel activities. Evidently, this IRGPs signature will provide remarkable value for the therapy of pancreatic cancer patients.

Long noncoding RNA RP11-757G1.5 sponges miR-139-5p and upregulates YAP1 thereby promoting the proliferation and liver, spleen metastasis of colorectal cancer.

BACKGROUND: Accumulating evidence indicates that long non-coding RNAs (lncRNAs) acting as crucial regulators in tumorigenesis. However, its biological functions of lncRNAs in colorectal cancer (CRC) have not been systematically clarified. METHODS: An unbiased screening was performed to identify disregulated lncRNAs revealed to be implicated in CRC carcinogenesis according to an online-available data dataset. In situ hybridization (ISH), RT-qPCR and RNA fluorescence in situ hybridization (RNA-FISH) were applied to detect RP11-757G1.5 expression in CRC tissues and cell lines. The associations of RP11-757G1.5 with clinicopathological characteristics were analyzed. Their effects on prognosis were analyzed by the Kaplan-Meier analysis, Log-rank test, Univariate and Multivariate Cox regression analysis. The potential biological function of RP11-757G1.5 in CRC was investigated by Colony formation, Edu cell proliferation, Flow cytometry, Wound healing and Transwell assays. Bioinformatics binding site analysis, Luciferase reporter assay, Ago2 immunoprecipitation assays, RNA pull-down assay, RT-qPCR and Western blotting were utilized to demonstrate the mechanism of RP11-757G1.5 acts as a molecular sponge of miR-139-5p to regulate the expression of YAP1. Finally, we further explore the potential role of RP11-757G1.5 in CRC orthotopic xenografts in vivo. RESULTS: We discovered a novel oncogenic lncRNA RP11-757G1.5, that was overexpressed in CRC tissues, especially in aggressive cases. Moreover, up-regulation of RP11-757G1.5 strongly correlated with poor clinical outcomes of patients with CRC. Functional analyses revealed that RP11-757G1.5 promoted cell proliferation in vitro and in vivo. Furthermore, RP11-757G1.5 stimulated cell migration and invasion in vitro and in vivo. Mechanistic studies illustrated that RP11-757G1.5 regulated the expression of YAP1 through sponging miR-139-5p and inhibiting its activity thereby promoting CRC progression and development. CONCLUSIONS: Altogether, these results reveal a novel RP11-757G1.5/miR-139-5p/YAP1 regulatory axis that participates in CRC carcinogenesis and progression.

RBFOX3 Promotes Gastric Cancer Growth and Progression by Activating HTERT Signaling.

Tumor invasion, metastasis, and recrudescence remain a considerable challenge in the treatment of gastric cancer (GC). Herein we first identified that RNA binding protein fox-1 homolog 3 (RBFOX3) was markedly overexpressed in GC tissues and negatively linked to the survival rate of GC patients. RBFOX3 promoted cell division and cell cycle progression in vitro and in vivo. Furthermore, RBFOX3 increased the cell invasion and migration ability. The suppression of GC cell multiplication and invasion, caused by silencing of RBFOX3, was rescued by HTERT overexpression. Additionally, RBFOX3 augmented the resistance of GC cells to 5-fluorouracil by repressing RBFOX3. Mechanistically, the exogenous up-regulation of RBFOX3 triggered promoter activity and HTERT expression, thereby enhancing the division and the development of GC cells. Further co-immunoprecipitation tests revealed that RBFOX3 bound to AP-2ß to modulate HTERT expression. In conclusion, our study indicates that a high expression of RBFOX3 promotes GC progression and development and predicts worse prognosis. Collectively, these results indicate that the RBFOX3/AP-2ß/HTERT signaling pathway can be therapeutically targeted to prevent and treat GC recurrence and metastasis.

29 immune-related genes pairs signature predict the prognosis of cervical cancer patients.

To screen the key immune genes in the development of cervical cancer, construct immune related gene pairs (IRGPs), and evaluate their influence on the prognosis of cervical cancer. Tumor Genome Atlas (TCGA) database and geo database were downloaded as training set and validation set respectively, and immune related gene data were downloaded from immport. IRGPs model is established by machine learning, and the model is analyzed and evaluated. Using the Uclcan to analyze the immune genes expression in cervical cancer, and to further explore the association with the expression level and the clinical stage and prognosis of cervical cancer. According to the analysis of training set, we identified 29 IRGPs as key gene pairs and constructed the model. The AUC value of the model was greater than 0.9, and the model group survival rate was conspicuous different (P < 0.001). The reliability of the model was confirmed in the validation group. Our IRGPs play an important role in the occurrence and development of cervical cancer, and can be used as a prognostic marker and potential new target of cervical cancer.