Lower Survival Rate In Patients Research Articles

Antisense lncRNA CHROMR is linked to glioma patient survival.

Background: Natural non-coding antisense transcripts (ncNATs) are long non-coding RNAs (lncRNA) transcribed from the opposite strand of a separate protein coding or non-coding gene. As such, ncNATs can increase overlapping mRNA (and the coded protein) levels by stabilizing mRNA, absorbing inhibitory miRNAs and protecting the mRNA from degradation, or conversely decrease mRNA (or protein) levels by directing the mRNA towards degradation or inhibiting protein translation. Recently, growing numbers of ncNATs were shown to be dysregulated in cancerous cells, however, actual impact of ncNATs on cancer progression remains largely unknown. We therefore investigated gene expression levels of natural antisense lncRNA CHROMR (Cholesterol Induced Regulator of Metabolism RNA) and its sense protein coding gene PRKRA (Protein Activator of Interferon Induced Protein Kinase EIF2AK2) in gliomas. Next, we checked CHROMR effect on the survival of glioma patients. Methods: We performed RNA-seq on post-surgical tumor samples from 26 glioma patients, and normal brain tissue. Gene expression in TPM values were extracted for CHROMR and PRKRA genes. These data were validated using the TCGA and GTEx gene expression databases. Results: The gene expression level of ncNAT lncRNA CHROMR in glioma tissue was significantly higher compared to healthy brain tissue, while the expression of its sense counterpart protein coding PRKRA mRNA did not differ between glioma and healthy samples. Survival analysis showed lower survival rates in patients with low mRNA PRKRA/lncRNA CHROMR gene expression ratio compared to high ratio showing a link between lncRNA CHROMR and glioma patient survival prognosis. Conclusion: Here we show that elevated levels of lncRNA CHROMR (i.e., low ratio of mRNA PRKRA/lncRNA CHROMR) is associated with poor prognosis for glioma patients.

Identification of potential biomarkers for colorectal cancer by clinical database analysis and Kaplan-Meier curves analysis.

This study aimed to explore critical genes as potential biomarkers for the diagnosis and prognosis of colorectal cancer (CRC) for clinical utility. To identify and screen candidate genes involved in CRC carcinogenesis and disease progression, we downloaded microarray datasets GSE89076, GSE73360, and GSE32323 from the GEO database identified differentially expressed genes (DEGs), and performed a functional enrichment analysis. A protein-protein interaction network was constructed, and correlated module analysis was performed using STRING and Cytoscape. The Kaplan-Meier survival curve shows the survival of the hub genes. The expression of cyclin-dependent kinase (CDK1), cyclin B1 (CCNB1), and PCNA in tissues and changes in tumor grade were analyzed. A total of 329 DEGs were identified, including 264 upregulated and 65 downregulated genes. The functions and pathways of DEGs include the mitotic cell cycle, poly(A) RNA binding replication, ATP binding, DNA replication, ribosome biogenesis in eukaryotes, and RNA transport. Forty-seven Hub genes were identified, and biological process analysis showed that these genes were mainly enriched in cell cycle and DNA replication. Patients with mutations in CDK1, PCNA, and CCNB1 had poorer survival rates. CDK1, PCNA, and CCNB1 were significantly overexpressed in the tumor tissues. The expression of CDK1 and CCNB1 gradually decreased with increasing tumor grade. CDK1, CCNB1, and PCNA can be used as potential markers for the diagnosis and prognosis of CRC. These genes are overexpressed in colon cancer tissues and are associated with low survival rates in CRC patients.

Association of p53 protein expression with the presence of a 17p13 locus deletion of the TP53 gene and with the survival of patients with diffuse large B-cell lymphoma

Background. A significant role in the pathogenesis, resistance to treatment and progression of many types of lymphomas, including diffuse large B-cell lymphoma, is assigned to the TP53 gene. Literature data on the prognostic significance of the expression of its product, the p53 protein, and its association with aberrations at the 17p13 locus are ambiguous.
 Aim. To assess the relationship of p53 protein expression with the presence of a 17p13 locus deletion of the TP53 gene and the survival of patients with diffuse large B-cell lymphoma.
 Material and methods. The study included 75 patients with newly diagnosed diffuse large B-cell lymphoma who received R-CHOP therapy. The calculation of the relative content of tumor cells expressing p53 was carried out using immunohistochemical and morphometric methods on biopsy samples of lymph nodes. The 17p13/TP53 deletion was determined by fluorescent in situ hybridization. The threshold level of p53-positive tumor cells, corresponding to 43%, was calculated by ROC analysis. The association between p53 protein expression and the presence of a 17p13 deletion was assessed using Fisher's (F) and Pearson's 2 tests. The correlation dependence was evaluated by the Cramer method (V). Five-year overall and progression-free survival was calculated using the KaplanMeier method. Differences between the indicators were considered statistically significant at p 0.05.
 Results. The frequency of 17p13/TP53 deletion was higher in patients with high expression of p53 (43%) compared to the group of patients with low expression: 87.5 and 12.5%, respectively (p=0.018). A direct correlation between a high level of p53 expression (43%) and the presence of a 17p13/TP53 deletion was found (p=0.018). Five-year overall and progression-free survival in patients with a proportion of p53-positive cells 43% was significantly lower than in patients with its subthreshold value: 54.5 versus 81.0% (p=0.014) and 45.5 versus 66.7% (p=0.022), respectively.
 Conclusion. High expression of the p53 protein is associated with the presence of a 17p13 locus deletion and a low five-year survival rate in patients with diffuse large B-cell lymphoma.

Molecular genetic testing in ovarian cancer

Ovarian cancer (OC) remains to be a leading cause of mortality among oncogynaecological patients. The low five-year survival rate of OC patients is associated with a lack of highly sensitive screening, early diagnostics and preventive methods, as well as high metastasis, recurrence and chemoresistance rates. Molecular genetic techniques for OC diagnosis based on standardized genetic panels can be used to detect a limited range of mutations in the BRCA1 and BRCA2 genes. However, the spectrum of genes potentially responsible for OC development is much wider. Recent data emphasize the importance of personalized approaches to account for ethno-population specifics in molecular genetic testing. This paper reviews recent data on the pathogenesis, molecular genetic diagnostic methods, and preventive strategies for OC.

Predicting chemoresponsiveness in epithelial ovarian cancer patients using circulating small extracellular vesicle-derived plasma gelsolin

BackgroundResistance to chemotherapy continues to be a challenge when treating epithelial ovarian cancer (EOC), contributing to low patient survival rates. While CA125, the conventional EOC biomarker, has been useful in monitoring patients’ response to therapy, there are no biomarkers used to predict treatment response prior to chemotherapy. Previous work in vitro showed that plasma gelsolin (pGSN) is highly expressed in chemoresistant EOC cell lines, where it is secreted in small extracellular vesicles (sEVs). Whether sEVs from tumour cells are secreted into the circulation of EOC patients and could be used to predict patient chemoresponsiveness is yet to be determined. This study aims to identify if sEV-pGSN in the circulation could be a predictive biomarker for chemoresistance in EOC.MethodsSandwich ELISA was used to measure pGSN concentrations from plasma samples of 96 EOC patients (primarily high grade serous EOC). sEVs were isolated using ExoQuick ULTRA and characterized using western blot, nanoparticle tracking analysis, and electron microscopy after which pGSN was measured from the sEVs. Patients were stratified as platinum sensitive or resistant groups based on first progression free interval (PFI) of 6 or 12 months.ResultsTotal circulating pGSN was significantly decreased and sEV-pGSN increased in patients with a PFI ≤ 12 months (chemoresistant) compared to those with a PFI > 12 months (chemosensitive). The ratio of total pGSN to sEV-pGSN further differentiated these groups and was a strong predictive marker for chemoresistance (sensitivity: 73.91%, specificity: 72.46%). Predetermined CA125 was not different between chemosensitive and chemoresistant groups and was not predictive of chemoresponsiveness prior to treatment. When CA125 was combined with the ratio of total pGSN/sEV-pGSN, it was a significant predictor of chemoresponsiveness, but the test performance was not as robust as the total pGSN/sEV-pGSN alone.ConclusionsTotal pGSN/sEV-pGSN was the best predictor of chemoresponsiveness prior to treatment, outperforming the individual biomarkers (CA125, total pGSN, and sEV-pGSN). This multianalyte predictor of chemoresponsiveness could help to inform physicians’ treatment and follow up plan at the time of EOC diagnosis, thus improving patients’ outcomes.

Abstract A045: Examining the role of RNA:DNA hybrids (r loops) in glioblastoma multiforme cell motility and invasion

Abstract Glioblastoma multiforme (GBM) is a highly aggressive brain cancer. The standard course of treatment is a combination of radiation and chemotherapy. Even with the dual treatment, the 5-year survival rate of patients with GBM is between 4-10%. A possible cause of the low survival rate for GBM patients is the presence of motile neoplastic cells with efficient DNA repair abilities. Thus, the two major obstacles to treating GBMs is 1) the tumors inherent invasive nature and 2) the recurrent tumors ability to acquire treatment resistance. As such, gaining a better understanding of the mechanisms mediating GBM recurrence would allow us to design better treatment strategies for patients. We have found that the 5’-3’ exoribonuclease XRN2 is upregulated in GBMs as compared to normal and other brain cancer types. While XRN2 is traditionally associated with the process of transcription termination, our published work has defined a role for XRN2 in the DNA damage response. Our group has shown that loss of XRN2 sensitizes to a variety of DNA damaging agents but in particular ionizing radiation. Previously, we have shown that XRN2 is required for DNA repair, specifically double stranded break (DSB) repair. Loss of XRN2 impairs both the non-homologous end-joining and homologous recombination DSB repair pathways. Loss of XRN2 also results in increased spontaneous DSB formation, chromosomal aberrations and RNA:DNA hybrid (R-loop) formation. In addition to a role in the DNA damage response, we found that loss of XRN2 is required for GBM cell motility, invasion through a matrix and decreased tumor volume in mouse models. Interestingly, R-loop formation can affect gene expression by modulating the access of genes to transcription factors, miRNA transcription, and methylation status of genes. To gain a better understanding of how XRN2 modulates gene expression, we conducted RNA-Seq analyses of GBM cell lines with and without XRN2 expression and found that XRN2 can regulate genes involved in cell movement, cell development and cellular organization programs. Consistent with our findings that XRN2 impairs DNA damage and tumor invasion; XRN2 loss results in R-loop formation in promoters of genes important for tumor invasiveness and DNA repair such as FOXM1 and Cyclin B1. These data suggest that the regulation of R-loop formation is an important determinant in tumor progression. Citation Format: Julio C. Morales, Tuyen T. Dang. Examining the role of RNA:DNA hybrids (r loops) in glioblastoma multiforme cell motility and invasion [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A045.

CASP4 can be a diagnostic biomarker and correlated with immune infiltrates in gliomas.

Gliomas are the most common and invasive malignant tumors that originate in the central nervous system. Currently, the primary treatment modality for gliomas is maximum surgical resection, supplemented by radiotherapy and chemotherapy. However, the long-term survival rate has not signifificantly increased. Pyroptosis is a new form of programmed lytic death that has been recently discovered. Caspase 4 (CASP4) plays a key role in pyroptosis. Many studies have shown that pyroptosis is not only related to inflflammation but is also closely related to the occurrence and development of most tumors. This study aimed to prove that CASP4 has a key role in the mechanism of gliomas. We used expression data from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas to explore the relationship between CASP4 expression and glioma prognosis. The differential expression of CASP4 in gliomas and normal tissues was fifirst tested, and then the connection between CASP4 and tumor prognosis was explored. The relationship between CASP4 expression and immune cell infifiltration was also investigated. Finally, the possible pathways were analyzed using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis. CASP4 was highly expressed and associated with a signifificantly lower survival rate in patients with glioma. It could also inflfluence immune cell infifiltration by releasing cytokines. CASP4 can be a diagnostic biomarker and is a promising therapeutic target for gliomas.

Integrated proteome and phosphoproteome analysis of gastric adenocarcinoma reveals molecular signatures capable of stratifying patient outcome.

Metastasis is one of the main causes of low survival rate of gastric cancer patients. Exploring key proteins in the progression of gastric adenocarcinoma (GAC) may provide new candidates for prognostic biomarker development and therapeutic intervention. We applied quantitative mass spectrometry to compare the proteome and phosphoproteome of primary tumor tissues between GAC patients with and without lymph node metastasis (LNM). We then performed an integrated analysis of the proteomic and transcriptomic data to reveal the molecular features. We quantified a total of 5536 proteins, and we found 218 upregulated and 49 downregulated proteins in tumor samples from patients with LNM compared to those without LNM. Clustering analysis identified a number of hub proteins that have been previously shown to play important roles in gastric cancer progression. We also found that two extracellular proteins, TNXB and SPON1, are overexpressed in patients with LNM, which correlates with poor survival of GAC patients. Overexpression of TNXB and SPON1 was validated by western blotting and immunohistochemistry. Furthermore, treating gastric cancer cells with anti-TNXB antibody significantly reduced cell migration. Finally, quantitative phosphoproteomic analysis combined with activity-based kinase capture revealed a number of activated kinases in primary tumor tissues from patients with LNM, among which GSK3 might be a new target that warrants further study. Our study provides a snapshot of the proteome and phosphoproteome of GAC tumor tissues that have metastatic potential, and identifies potential biomarkers for GAC progression.

Voltage-Gated Sodium Channel NaV1.5 Controls NHE−1−Dependent Invasive Properties in Colon Cancer Cells

Colorectal cancer (CRC) is the second leading cause of death worldwide, with 0.9 million deaths per year. The metastatic stage of the disease is identified in about 20% of cases at the first diagnosis and is associated with low patient-survival rates. Voltage-gated sodium channels (NaV) are abnormally overexpressed in several carcinomas including CRC and are strongly associated with the metastatic behavior of cancer cells. Acidification of the extracellular space by Na+/H+ exchangers (NHE) contributes to extracellular matrix degradation and cell invasiveness. In this study, we assessed the expression levels of pore-forming α-subunits of NaV channels and NHE exchangers in tumor and adjacent non-malignant tissues from colorectal cancer patients, CRC cell lines and primary tumor cells. In all cases, SCN5A (gene encoding for NaV1.5) was overexpressed and positively correlated with cancer stage and poor survival prognosis for patients. In addition, we identified an anatomical differential expression of SCN5A and SLC9A1 (gene encoding for NHE-1) being particularly relevant for tumors that originated on the sigmoid colon epithelium. The functional activity of NaV1.5 channels was characterized in CRC cell lines and the primary cells of colon tumors obtained using tumor explant methodologies. Furthermore, we assessed the performance of two new small-molecule NaV1.5 inhibitors on the reduction of sodium currents, as well as showed that silencing SCN5A and SLC9A1 substantially reduced the 2D invasive capabilities of cancer cells. Thus, our findings show that both NaV1.5 and NHE-1 represent two promising targetable membrane proteins against the metastatic progression of CRC.

Celiac Artery Coverage During TEVAR for Dissection and Acute Aortic Injury is Not Associated with Worse Outcomes

Studies have previously identified increased morbidity and mortality with celiac artery coverage during thoracic endovascular aortic repair (TEVAR) for aneurysmal disease. This study aimed to delineate the risks associated with celiac artery coverage in all patients undergoing TEVAR for dissection, trauma, or aneurysmal disease. Using the Vascular Quality Initiative database, we identified all patients undergoing TEVAR from 2012 to 2020 and categorized them based on the underlying pathology (aneurysm, dissection, or acute/trauma). Patients were excluded if their endograft was deployed distal to aortic zone 6 or if they had any preoperative/operative celiac revascularization procedure. Univariate, regression, and Kaplan-Meier analysis were performed for all 3 groups, focusing on postoperative complications and survival. There were 8,265 patients who underwent TEVAR over the 8-year study period with 142 (1.7%) having celiac artery coverage during their index procedure. Of those patients, theceliac artery was covered during TEVAR in 1.2% of patients with dissection, 1.3% with aneurysm, and 0.7% with trauma. On unadjusted analysis, celiac artery coverage in TEVAR for aneurysmal disease was associated with increased in-hospital mortality (16% vs. 5%, P<0.001), 30-day mortality (33% vs. 23%, P=0.029), any postoperative complication (excluding death) (42% vs. 25%, P<0.001), and postoperative bowel complication (3% vs. 0.7%, P = 0.003). There were no differences in outcomes for patients treated with celiac coverage versus those without celiac coverage during TEVAR for dissection or trauma on univariate analysis. After risk adjustment, celiac artery coverage remained predictive of worse postoperative outcomes in patients with aneurysmal disease: in-hospital mortality (odds ratio [OR]=3.6, confidence interval [CI] 1.8-6.9), 30-day death (OR=1.6, CI 1.0-2.4), any postoperative complication (OR 2.2, CI 1.4-3.5), and bowel-specific postoperative complication (3.3, CI 1.0-10.8). There were no differences in patient outcomes for those treated with celiac coverage versus those without celiac coverage during TEVAR for dissection or trauma on multivariate analysis. Kaplan-Meier curves show a significant difference in overall survival based on pathology, specifically lower survival rates for patients with celiac coverage treated for aneurysmal disease. Cox regression analysis showed that celiac artery coverage for aneurysmal disease was associated with significantly increased hazard ratio affecting overall survival (hazard ratio=2.6, P<0.001), but there was no impact on survival in patients who underwent TEVAR with celiac coverage for dissection or trauma. Celiac artery coverage for patients with aneurysmal disease was correlated with a significant increase in postoperative morbidity, mortality, and lowers overall survival. However, for patients with dissection or acute/traumatic aortic pathology, celiac artery coverage does not portend worse outcomes.

Computational Prediction of Resistance Induced Alanine-Mutation in ATP Site of Epidermal Growth Factor Receptor.

Epidermal growth factor receptor (EGFR) resistance to tyrosine kinase inhibitors can cause low survival rates in mutation-positive non-small cell lung cancer patients. It is necessary to predict new mutations in the development of more potent EGFR inhibitors since classical and rare mutations observed were known to affect the effectiveness of the therapy. Therefore, this research aimed to perform alanine mutagenesis scanning on ATP binding site residues without COSMIC data, followed by molecular dynamic simulations to determine their molecular interactions with ATP and erlotinib compared to wild-type complexes. Based on the result, eight mutations were found to cause changes in the binding energy of the ATP analogue to become more negative. These included G779A, Q791A, L792A, R841A, N842A, V843A, I853A, and D855A, which were predicted to enhance the affinity of ATP and reduce the binding ability of inhibitors with the same interaction site. Erlotinib showed more positive energy among G779A, Q791A, I853A, and D855A, due to their weaker binding energy than ATP. These four mutations could be anticipated in the development of the next inhibitor to overcome the incidence of resistance in lung cancer patients.

CSIG-31. T-TYPE CALCIUM CHANNEL BLOCKERS INDUCE METABOLIC ALTERATIONS AND APOPTOSIS IN MEDULLOBLASTOMA CELLS

Abstract Medulloblastoma (MB) is the most common malignant paediatric brain tumour. In our previous studies, in a screen of a panel of calcium channel modulators in our novel high-throughput 3D assay, we identified T-type (CaV3) channel inhibitors, mibefradil and NNC-55-0396 (NNC) as selective inhibitors of MB cell growth. Mibefradil was originally approved for the treatment of hypertension and angina pectoris, and recently successfully completed a Phase-I trial for recurrent high-grade glioma. NNC is an analogue of mibefradil with multiple advantages compared to mibefradil that makes it attractive for potential future clinical trials. T-type channels have a unique low voltage-dependent activation/inactivation, and many studies suggest that they have a direct regulatory role in controlling Ca2+ signalling in non-excitable tissues, including cancers. In this study, we characterized the effect of mibefradil and NNC on MB cells and elucidated their mechanism of action. This study demonstrates that the induction of toxicity in MB cells is selective to T-type but not to L-type Ca2+ channel inhibitors. Addition of CaV3 inhibitors to vincristine sensitised MB cells to this MB chemotherapeutic agent, suggesting an additive effect. Furthermore, CaV3 inhibitors induced cell death in MB cells via apoptosis. Supported by proteomics data and cellular assays, apoptotic cell death was associated with reduced mitochondrial membrane potential and reduced ATP levels, which suggests that both compounds alter the metabolism of MB cells. We also identified that CACNA1H (encoding the CaV3.2 protein) is significantly upregulated in aggressive Groups 3 and 4 MB patient samples, and its higher expression is associated with higher metastasis and lower patient survival rates. This study offers new insights into the action of mibefradil and NNC and will pave the way to test these molecules or their analogues in pre-clinical MB models alone and in combination with vincristine to assess their suitability as a potential MB therapy.

Mitochondrial Factor C20orf7 Facilitates the EMT-Mediated Cancer Cell Migration and the Proliferation of Colon Cancer In Vitro and In Vivo.

Colon cancer is a major malignant neoplasm with a low survival rate for late-stage patients. Therefore, the investigation of molecules regulating colon cancer progression and the discovery of novel therapeutic targets is critical. Mitochondria play a vital role in maintaining the homeostasis of cells. Abnormal mitochondrial metabolism alterations and the induction of glycolysis can facilitate tumor growth; therefore, targeting mitochondrial molecules is suggested to be a promising strategy for cancer treatment. In this study, we investigated the role of this largely unknown mitochondrial factor, chromosome 20 open reading frame 7 (C20orf7), in colon cancer progression. Clustered regularly interspaced short palindromic repeats (CRISPR) technology was utilized for C20orf7 depletion, and functional assays were performed to examine the regulation of C20orf7 in colon cancer cells. We demonstrated that C20orf7 facilitates epithelial-mesenchymal transition (EMT)-mediated cell migration and promotes the proliferation of colon cancer. The anti-cancer drug 5-fluorouracil (5FU) was also applied, and C20orf7 was targeted with a combination of 5FU treatment, which could further enhance the anti-cancer effect in the colon cancer cell line and the xenograft mice model. In summary, this study demonstrated, for the first time, that C20orf7 plays a promotional role in cancer tumorigenesis and could be a promising therapeutic target in colon cancer treatment.

Prognostic value of right ventricular strain and peak oxygen consumption in heart failure with reduced ejection fraction.

Our purpose is to evaluate the combined predictive value of cardiopulmonary exercise testing (CPET) and echocardiographic evidence of left ventricular (LV) and right ventricular (RV) strain in predicting mortality and heart transplant (HTx) in a series of outpatients with heart failure with reduced ejection fraction (HFrEF). A retrospective cohort study of 66 patients with HFrEF (median age, 57years; 51% women) who underwent CPET and echocardiography (up to 90days apart) to assess prognosis. The primary outcome was a composite of death and need for HTx. At a median follow-up of 27 [20-39] months, 19 patients (29%) experienced the primary outcome. In unadjusted analysis, most echocardiographic and CPET parameters were associated with the primary outcome, including percentage of predicted peak oxygen consumption (ppVO2), VE/VCO2 slope, LV ejection fraction, and LV and RV longitudinal strain. After adjusting for other clinical, echocardiographic and CPET variables, RV free wall longitudinal strain and ppVO2 remained significantly associated with the primary outcome. Kaplan-Meier survival curves for death and HTx, based on the best cutoff values, showed lower survival rates in patients with impairment in both ppVO2 and RV FW-LS than in those with one or neither parameter impaired (p < 0.001). RV dysfunction and low cardiorespiratory fitness were independent markers of death and need for HTx. Impairment of both ppVO2 and RV FW-LS had a strong additive impact on prognostic assessment in this cohort of patients with HFrEF.

PPP1R14D promotes the proliferation, migration and invasion of lung adenocarcinoma via the PKCα/BRAF/MEK/ERK signaling pathway.

Protein phosphatase 1 (PP1) inhibitors play a role in tumor progression through different mechanisms. Protein phosphatase 1 regulatory subunit 14D (PPP1R14D) is an inhibitor of PP1. However, the role of PPP1R14D in tumors and its mechanism of action are largely unknown. The purpose of the present study was to investigate the expression, function and mechanism of PPP1R14D in lung adenocarcinoma (LUAD). In the present study, GEPIA database analysis and immunohistochemistry demonstrated that PPP1R14D was highly expressed in LUAD tissues and that the expression of PPP1R14D in LUAD was negatively correlated with the age of patients and positively correlated with the 8th American Joint Committee on Cancer staging among patients. In addition, Kaplan‑Meier Plotter database analysis showed that PPP1R14D expression was associated with lower survival rates in patients with LUAD. PPP1R14D knockdown significantly inhibited LUAD cell proliferation, migration and invasion and induced LUAD cell arrest at the G1 phase of the cell cycle. Mechanistic analyses revealed that PPP1R14D knockdown may inhibit cell proliferation, migration and invasion by inactivating PKCα/BRAF/MEK/ERK pathway signaling and its downstream key proteins c‑Myc/Cyclin E1‑CDK2 and MMP2/MMP9/Vimentin. Moreover, knockdown of PPP1R14D suppressed tumor growth invivo. All these results showed that PPP1R14D plays an important role in LUAD tumorigenesis and may serve as a potential prognostic factor and therapeutic target in LUAD.

Recent advances in the diagnostic and therapeutic roles of microRNAs in colorectal cancer progression and metastasis.

Colorectal cancer (CRC) is the third most common malignancy in the world and one of the leading causes of cancer death; its incidence is still increasing in most countries. The early diagnostic accuracy of CRC is low, and the metastasis rate is high, resulting in a low survival rate of advanced patients. MicroRNAs (miRNAs) are a small class of noncoding RNAs that can inhibit mRNA translation and trigger mRNA degradation, and can affect a variety of cellular and molecular targets. Numerous studies have shown that miRNAs are related to tumour progression, immune system activity, anticancer drug resistance, and the tumour microenvironment. Dysregulation of miRNAs occurs in a variety of malignancies, including CRC. In this review, we summarize the recent research progress of miRNAs, their roles in tumour progression and metastasis, and their clinical value as potential biomarkers or therapeutic targets for CRC. Furthermore, we combined the roles of miRNAs in tumorigenesis and development with the therapeutic strategies of CRC patients, which will provide new ideas for the diagnosis and treatment of CRC.

Overexpression of TCERG1 as a prognostic marker in hepatocellular carcinoma: A TCGA data-based analysis.

Objective: Transcription elongation factor 1 (TCERG1) is a nuclear protein consisted of multiple protein structural domains that plays an important role in regulating the transcription, extension, and splicing regulation of RNA polymerase II. However, the prognostic and immunological role of TCERG1 in human cancer remains unknown. In this study, we analyzed the expression of TCERG1 gene in hepatocellular carcinoma (HCC) patients, its clinical significance, and its possible prognostic value by bioinformatics. Methods: RNA sequencing data and clinicopathological characteristics of patients with HCC were collected from TCGA and CCLE databases. The Wilcoxon rank-sum test was used to analyze the expression of TCERG1 in HCC tissues and normal tissues. The protein levels of TCERG1 between normal and liver cancer tissues were analyzed by the Human Protein Atlas Database (HPA) (www.proteinatlas.org). Validation was performed using the Gene Expression Omnibus (GEO) dataset of 167 samples. The expression of TCERG1 in HCC cells were verified by qRT-PCR, and CCK-8, scratch assay and Transwell assay were performed to detect cell proliferation, migration and invasion ability. According to the median value of TCERG1 expression, patients were divided into high and low subgroups. Logistic regression, GSEA enrichment, TME, and single-sample set gene enrichment analysis (ssGSEA) were performed to explore the effects of TCERG1 on liver cancer biological function and immune infiltrates. TCERG1 co-expression networks were studied through the CCLE database and the LinkedOmics database to analyze genes that interact with TCERG1. Results: The expression levels of TCERG1 in HCC patient tissues were significantly higher than in normal tissues. Survival analysis showed that high levels of TCERG1 expression were significantly associated with low survival rates in HCC patients. Multifactorial analysis showed that high TCERG1 expression was an independent risk factor affecting tumor prognosis. This result was also verified in the GEO database. Cellular experiments demonstrated that cell proliferation, migration and invasion were inhibited after silencing of TCERG1 gene expression. Co-expression analysis revealed that CPSF6 and MAML1 expression were positively correlated with TCERG1. GSEA showed that in samples with high TCERG1 expression, relevant signaling pathways associated with cell cycle, apoptosis, pathways in cancer and enriched in known tumors included Wnt signaling pathway, Vegf signaling pathway, Notch signaling pathway, MAPK signaling pathway and MTOR pathways. The expression of TCERG1 was positively correlated with tumor immune infiltrating cells (T helper two cells, T helper cells). Conclusion: TCERG1 gene is highly expressed in hepatocellular carcinoma tissues, which is associated with the poor prognosis of liver cancer, and may be one of the markers for the diagnosis and screening of liver cancer and the prediction of prognosis effect. At the same time, TCERG1 may also become a new target for tumor immunotherapy.

DHRS7 is an immune-related prognostic biomarker of KIRC and pan-cancer.

Renal clear cell carcinoma (KIRC) is one malignancy whose development and prognosis have been associated with aberrant DHRS7 expression. However, the catalytic activity and pathophysiology of KIRC are poorly understood, and no sensitive tumor biomarkers have yet been discovered. In our study, we examined the significant influence of DHRS7 on the tumor microenvironment (TME) and tumor progression using an overall predictable and prognostic evaluation approach. We found novel cancer staging, particularly in KIRC, as well as potential therapeutic drugs out of 27 drug sensitivity tests. Using Perl scripts, it was possible to determine the number of somatic mutations present in 33 tumors, as well as the relative scores of 22 immune cells using CIBERSORT, the relationship between immune infiltration and differential expression using TCGA data, and the immune microenvironment score using the estimate technique. Our results show that DHRS7 is abnormally expressed in pan-cancer patients, which influences their survival. Low DHRS7 expression was associated with late clinical stages and a low survival rate in KIRC patients, suggesting a poor prognosis and course of treatment, in HNSG, MESO, and KIRC patients. We also found that DHRS7 was associated with TMB and MSI in certain tumors. Using KIRC as an example, we discovered a negative correlation between DHRS7 expression and immunological assessments, suggesting that this substance might be used as a tumor biomarker.

Multiple approaches to repurposing drugs for neuroblastoma

Neuroblastoma (NB) is the second leading extracranial solid tumor of early childhood with about two-thirds of cases presenting before the age of 5, and accounts for roughly 15 percent of all pediatric cancer fatalities in the United States. Treatments against NB are lacking, resulting in a low survival rate in high-risk patients. A repurposing approach using already approved or clinical stage compounds can be used for diseases for which the patient population is small, and the commercial market limited. We have used Bayesian machine learning, in vitro cell assays, and combination analysis to identify molecules with potential use for NB. We demonstrated that pyronaridine (SH-SY5Y IC50 1.70 µM, SK-N-AS IC50 3.45 µM), BAY 11–7082 (SH-SY5Y IC50 0.85 µM, SK-N-AS IC50 1.23 µM), niclosamide (SH-SY5Y IC50 0.87 µM, SK-N-AS IC50 2.33 µM) and fingolimod (SH-SY5Y IC50 4.71 µM, SK-N-AS IC50 6.11 µM) showed cytotoxicity against NB. As several of the molecules are approved drugs in the US or elsewhere, they may be repurposed more readily for NB treatment. Pyronaridine was also tested in combinations in SH-SY5Y cells and demonstrated an antagonistic effect with either etoposide or crizotinib. Whereas when crizotinib and etoposide were combined with each other they had a synergistic effect in these cells. We have also described several analogs of pyronaridine to explore the structure–activity relationship against cell lines. We describe multiple molecules demonstrating cytotoxicity against NB and the further evaluation of these molecules and combinations using other NB cells lines and in vivo models will be important in the future to assess translational potential.

130P Endothelin-1 promotes epithelial-mesenchymal transition in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is one of the most common and deadliest malignancies in the head and neck region with the survival rate ranging between 25%-55%. Epithelial-mesenchymal transition (EMT) plays a major role in cancer progression and tissue invasion and is considered to be the key process associated with recurrence, lymph node metastasis and low survival rate in patients with OSCC. Studies have shown that Endothelin-1 (ET-1), a potent vasoconstrictor, promotes EMT in various human cancers.