Poor Overall Survival In Patients Research Articles

Hepatocellular Carcinoma with Inferior Vena Cava Thrombus in a Child

Hepatocellular carcinoma (HCC) in children is the second common malignant liver tumor after hepatoblastoma. Chronic hepatitis B virus (HBV) infection causes most hepatocellular cancer worldwide. Metastases to the inferior vena cava (IVC) and right atrium (RA) tumor thrombi are even less common. We reported a case of a 13-year-8-month-old girl with HCC and IVC involvement. Vascular invasion predicts poor overall survival in HCC patients. Patients with HCC involving the IVC had a higher risk of sudden mortality and a poor treatment outcome. It is difficult to treat, and no standard therapy has been established. This case report aimed to describe HCC with IVC involvement. This is a rare disease with a poor prognosis, therefore it is important to detect and manage early.

Prognostic marker CXCL5 in glioblastoma polyformis and its mechanism of immune invasion

Glioblastoma multiforme (GBM) is the most aggressive brain cancer with a poor prognosis. Therefore, the correlative molecular markers and molecular mechanisms should be explored to assess the occurrence and treatment of glioma.WB and qPCR assays were used to detect the expression of CXCL5 in human GBM tissues. The relationship between CXCL5 expression and clinicopathological features was evaluated using logistic regression analysis, Wilcoxon symbolic rank test, and Kruskal–Wallis test. Univariate, multivariate Cox regression and Kaplan–Meier methods were used to assess CXCL5 and other prognostic factors of GBM. Gene set enrichment analysis (GSEA) was used to identify pathways associated with CXCL5. The correlation between CXCL5 and tumor immunoinfiltration was investigated using single sample gene set enrichment analysis (ssGSEA) of TCGA data. Cell experiments and mouse subcutaneous transplanted tumor models were used to evaluate the role of CXCL5 in GBM. WB, qPCR, immunofluorescence, and immunohistochemical assays showed that CXCL5 expression was increased in human GBM tissues. Furthermore, high CXCL5 expression was closely related to poor disease-specific survival and overall survival of GBM patients. The ssGSEA suggested that CXCL5 is closely related to the cell cycle and immune response through PPAR signaling pathway. GSEA also showed that CXCL5 expression was positively correlated with macrophage cell infiltration level and negatively correlated with cytotoxic cell infiltration level. CXCL5 may be associated with the prognosis and immunoinfiltration of GBM.

FLI-1 is expressed in a wide variety of hematolymphoid neoplasms: a special concern in the differential diagnosis

Friend Leukemia Virus Integration 1 (FLI-1) is a member of E26 transformation-specific family of transcription factors that participates in hematopoietic and vascular endothelial cell development. Immunohistochemical detection of FLI-1 has been widely used to diagnose vascular tumors or, more evidently, Ewing’s sarcoma. However, the expression pattern of FLI-1 in hematolymphoid neoplasms remains unclear. Therefore, in this study, we aimed to investigate the expression of FLI-1 in these tumors, focusing on high-grade lesions, which presents a diagnostic challenge by mimicking Ewing’s sarcoma. We evaluated the expression FLI-1 in various types of lymphoid and plasmacytic tumors, including 27 plasmablastic lymphomas, 229 diffuse large B-cell lymphomas, 22 precursor T- or B-lymphoblastic lymphomas, 24 angioimmunoblastic-type nodal T-follicular helper cell lymphomas, 52 peripheral T-cell lymphomas, NOS, 18 Burkitt lymphomas, 18 non-gastric lymphomas of mucosa-associated lymphoid tissue, 38 chronic lymphocytic leukemia/small lymphocytic lymphomas, 15 mantle cell lymphomas, 23 gastric MALT lymphomas, 50 plasma cell myelomas, and 38 follicular lymphomas. We calculated the H-scores of FLI-1 immunostaining, ranging from 0 to 200, and used the scores to analyze the clinicopathological significance of FLI-1 statistically. FLI-1 was expressed to varying degrees in all types of hematological tumors. FLI-1 expression was detected in 84.1% of patients (466/554). FLI-1 was highly expressed in precursor T- or B-lymphoblastic lymphomas. Follicular lymphomas exhibited low FLI-1 expression. In plasmablastic lymphoma, 85.2% of the patients were focally positive for FLI-1. FLI-1 expression did not correlate with clinicopathological variables, such as demographic data or disease stage, in patients with plasmablastic lymphoma and diffuse large B-cell lymphoma. However, FLI-1 overexpression was associated with poorer overall survival in patients with plasmablastic lymphoma. This study demonstrates that FLI-1 is expressed in various hematolymphoid neoplasms. FLI-1 expression can lead to diagnostic confusion, especially in small blue round cell tumors, such as lymphoblastic lymphoma, plasmablastic lymphoma, and plasma cell myeloma, when distinguishing tumors positive for CD99 and CD56 without CD3, CD20, or CD45. Our findings also suggested the possibility of FLI-1 as a potential prognostic biomarker for plasmablastic lymphoma.

Short- and Long-Term Outcomes of Patients with Postoperative Arrhythmia after Liver Surgery.

New-onset postoperative arrhythmia (PA) has previously been described as a pivotal risk factor for postoperative morbidity and mortality after visceral surgery. However, there is a lack of data concerning liver surgery. The incidence and impact of new-onset postoperative arrhythmia after liver surgery was, therefore, analyzed in a monocentric study. In total, n = 460 patients (221 female, 239 male) who underwent liver surgery between January 2012 and April 2020 without any prior arrhythmia in their medical history were included in this retrospective analysis. Clinical monitoring started with the induction of anesthesia and was terminated with discharge from the intensive care unit (ICU) or intermediate care unit (IMC). Follow-up included documentation of complications during the hospital stay, as well as long-term survival analysis. Postoperative arrhythmia after liver surgery was observed in 25 patients, corresponding to an incidence of 5.4%. The occurrence of arrhythmia was significantly associated with intraoperative complications (p < 0.05), liver fibrosis/cirrhosis (p < 0.05), bile fistula/bile leakage/bilioma (p < 0.05), and organ failure (p < 0.01). Survival analysis showed a significantly poorer overall survival of patients who developed postoperative arrhythmia after liver surgery (p < 0.001). New-onset postoperative arrhythmia after liver surgery has an incidence of only 5.4% but is significantly associated with higher postoperative morbidity and poorer overall survival.

Visualization of tumor-associated neutrophils in malignant ascites of ovarian cancer with aptamer-decorated AIE probes

Neoadjuvant chemotherapy followed by interval debulking surgery is a recommended treatment for advanced-stage ovarian cancer (OC) patients to avoid bowel and spleen resection. Pre-operative chemotherapy requires ascites from OC patients for cytopathological examinations based on hematoxylin & eosin staining to detect tumor cells, whose low ratio make them difficult to be detected in ascites. Sensitive detection of tumor-related immunocytes (TRI) in ascites is not only indicative of underlying malignant ascites, but also could predict chemoresistance and poor overall survival of OC patients. The antibodies can only recognize immunocytes but cannot distinguish TRI. Herein, we identified an aptamer99 (Apt-99) using a fluorescence-activated cell sorting-based aptamer selection strategy, which could target tumor-related neutrophils (TRNs) with high binding affinity. In contrast, FAM-labeled Apt-99 couldn’t distinguish the neutrophils in the smears of other patients’ derived ascites or peritoneal lavages, such as metastatic ovarian cancer from colon carcinoma and myomas of the uterus. LC-MS/MS analysis, and the molecular docking experiments demonstrated that the target molecule of Apt-99 were S100A8&A9 heterodimers. Moreover, Apt-99-labeled aggregation-induced emission dots were facilely prepared and used for specifically visualizing the TRNs in the ascites smears. The findings indicated the diagnostic potential of Apt-99 and the possibility of further clinical trials.

Leucine Zipper Downregulated in Cancer-1 Interacts with Clathrin Adaptors to Control Epidermal Growth Factor Receptor (EGFR) Internalization and Gefitinib Response in EGFR-Mutated Non-Small Cell Lung Cancer.

The epidermal growth factor receptor (EGFR) is a common driver of non-small cell lung cancer (NSCLC). Clathrin-mediated internalization (CMI) sustains EGFR signaling. AXL is associated with resistance to EGFR-tyrosine kinase inhibitors (TKIs) in EGFR-mutated (EGFRM) NSCLC. We investigated the effects of Leucine zipper downregulated in cancer-1 (LDOC1) on EGFR CMI and NSCLC treatment. Coimmunoprecipitation, double immunofluorescence staining, confocal microscopy analysis, cell surface labelling assays, and immunohistochemistry studies were conducted. We revealed that LDOC1 interacts with clathrin adaptors through binding motifs. LDOC1 depletion promotes internalization and plasma membrane recycling of EGFR in EGFRM NSCLC PC9 and HCC827 cells. Membranous and cytoplasmic EGFR decreased and increased, respectively, in LDOC1 (-) NSCLC tumors. LDOC1 depletion enhanced and sustained activation of EGFR, AXL, and HER2 and enhanced activation of HER3 in PC9 and HCC827 cells. Sensitivity to first-generation EGFR-TKIs (gefitinib and erlotinib) was significantly reduced in LDOC1-depleted PC9 and HCC827 cells. Moreover, LDOC1 downregulation was significantly associated (p < 0.001) with poor overall survival in patients with EGFRM NSCLC receiving gefitinib (n = 100). In conclusion, LDOC1 may regulate the efficacy of first-generation EGFR-TKIs by participating in the CMI of EGFR. Accordingly, LDOC1 may function as a prognostic biomarker for EGFRM NSCLC.

Lysine methyltransferase SMYD2 enhances androgen receptor signaling to modulate CRPC cell resistance to enzalutamide.

Androgen receptors (ARs) play key roles in prostate cancer (PCa) progression and castration-resistant prostate cancer (CRPC) resistance to drug therapy. SET and MYND domain containing protein 2 (SMYD2), a lysine methyltransferase, has been reported to promote tumors by transcriptionally methylating important oncogenes or tumor repressor genes. However, the role of SMYD2 in CRPC drug resistance remains unclear. In this study, we found that SMYD2 expression was significantly upregulated in PCa tissues and cell lines. High SMYD2 expression indicated poor CRPC-free survival and overall survival in patients. SMYD2 knockdown dramatically inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) potential of 22Rv1 and C4-2 cells. Conversely, ectopic overexpression of SMYD2 promoted these effects in 22Rv1 and C4-2 cells. Mechanistically, SMYD2 methylated and phosphorylated ARs to affect AR ubiquitination and proteasome degradation, which further alters the AR transcriptome in CRPC cells. Importantly, the SMYD2 inhibitor AZ505 had a synergistic therapeutic effect with enzalutamide in CRPC cells and mouse models; however, it could also re-sensitize resistant CRPC cells to enzalutamide. Our findings demonstrated that SMYD2 enhances the methylation and phosphorylation of ARs and affects AR ubiquitination and proteasome degradation to modulate CRPC cell resistance to enzalutamide, indicating that SMYD2 serves as a crucial oncogene in PCa and is an ideal therapeutic target for CRPC.

Fludarabine Enhances Radiosensitivity by Promoting Ferroptosis in B-Cell Lymphoma.

The objective of this study is to investigate the impact of fludarabine, a signal transducer and activator of transcription-1 (STAT1) inhibitor, on the radiosensitivity of B-cell lymphoma (BCL) and to explore the underlying mechanisms. Radiotherapy is one of the primary treatments for BCL, and STAT1 plays a critical role in the transcription of cell proliferation-related genes, which are associated with radiotherapy and ferroptosis. This study aims to determine whether fludarabine can enhance the radiosensitivity of BCL and to elucidate the molecular pathways involved. Various in vitro methodologies, including CCK-8 assays, clonogenic formation assays, immunohistochemistry, immunofluorescence, flow cytometry, qRT-PCR, and Western blot analyses, were employed in B-cell lymphoma cell models to thoroughly investigate the effects of fludarabine on radiosensitivity. Subsequently, the obtained results were further validated through invivo animal models and by examining human diffuse large B-cell lymphoma (DLBCL) cancer samples. Our findings demonstrate that the combination of fludarabine and irradiation synergistically inhibits cell viability and colony formation, while inducing apoptosis and ferroptosis in B-cell lymphoma cell lines Raji and Su-DHL-10. Moreover, fludarabine was found to enhance the ferroptosis induced by radiation, thereby synergistically impeding the growth of BCL. In vivo experiments confirmed these findings, revealing that the intraperitoneal injection of fludarabine significantly enhanced the inhibitory effects of radiation on Raji cell xenograft models, leading to an increased percentage of ferroptosis compared to models without fludarabine. Additionally, the administration of liproxstatin-1, a ferroptosis inhibitor, attenuated the inhibition of xenograft growth caused by the combination of fludarabine and irradiation. Furthermore, our analysis of clinical data revealed that increased co-expression of STAT1 and GPX4 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. These results highlight the potential of fludarabine to enhance radiosensitivity and ferroptosis induction as a promising therapeutic strategy for BCL. Our results demonstrated that fludarabine promoted radiation-induced BCL death through the ferroptosis pathway. We have identified a previously unrecognized mechanism in the fludarabine and radiation combination, indicating that it is necessary to conduct prospective clinical trials to verify this new treatment regimen in BCL.

TrkA promotes MDM2-mediated AGPS ubiquitination and degradation to trigger prostate cancer progression

BackgroundAs a novel necrosis manner, ferroptosis has been increasingly reported to play a role in tumor progression and treatment, however, the specific mechanisms underlying its development in prostate cancer remain unclear. Growing evidence showed that peroxisome plays a key role in ferroptosis. Herein, we identified a novel mechanism for the involvement of ferroptosis in prostate cancer progression, which may provide a new strategy for clinical treatment of prostate cancer.MethodsLabel-Free Mass spectrometry was used to screen and identify candidate proteins after ferroptosis inducer-ML210 treatment. Immunohistochemistry was undertaken to explore the protein expression of AGPS in prostate cancer tissues compared with normal tissues. Co-immunoprecipitation and GST pull-down were used to identify the directly binding of AGPS to MDM2 in vivo and in vitro. CCK8 assay and colony formation assay were used to illustrate the key role of AGPS in the progression of prostate cancer in vitro. The xenograft model was established to verify the key role of AGPS in the progression of prostate cancer in vivo.ResultsAGPS protein expression was downregulated in prostate cancer tissues compared with normal tissues from the first affiliated hospital of Zhengzhou University dataset. Lower expression was correlated with poorer overall survival of patients compared to those with high expression of AGPS. In addition, AGPS can promote ferroptosis by modulating the function of peroxisome-resulting in the lower survival of prostate cancer cells. Furthermore, it was shown that AGPS can be ubiquitinated and degraded by the E3 ligase-MDM2 through the proteasomal pathway. Meanwhile, kinase TrkA can promote the combination of AGPS and MDM2 by phosphorylating AGPS at Y451 site. It was verified that kinase TrkA inhibitor—Larotrectinib can increase the susceptibility of prostate cancer cells to ferroptosis, which leads to the inhibition of prostate cancer proliferation to a great extent in vitro and in vivo.ConclusionBased on these findings, we proposed the combination of ferroptosis inducer and TrkA inhibitor to synergistically exert anti-tumor effects, which may provide a new strategy for the clinical treatment of prostate cancer.

KNSTRN Is a Prognostic Biomarker That Is Correlated with Immune Infiltration in Breast Cancer and Promotes Cell Cycle and Proliferation

Kinetochore-localized astrin/SPAG5-binding protein (KNSTRN) promotes the progression of bladder cancer and lung adenocarcinoma. However, its expression and biological function in breast cancer remain largely unknown. Therefore, this study aimed to analyze KNSTRN expression, prognoses, correlation with immune infiltration, expression-associated genes, and regulated signaling pathways to characterize its role in regulating the cell cycle using both bioinformatics and in vitro functional experiments. Analyses of The Cancer Genome Atlas, Gene Expression Omnibus, TIMER, and The Human Protein Atlas databases revealed a significant upregulation of KNSTRN transcript and protein levels in breast cancer. Kaplan–Meier survival analyses demonstrated a significant association between high expression of KNSTRN and poor overall survival, relapse-free survival, post-progression survival, and distant metastases-free survival in patients with breast cancer. Furthermore, multivariate Cox regression analyses confirmed that KNSTRN is an independent prognostic factor for breast cancer. Immune infiltration analysis indicated a positive correlation between KNSTRN expression and T regulatory cell infiltration while showing a negative correlation with Tgd and natural killer cell infiltration. Gene set enrichment analysis along with single-cell transcriptome data analysis suggested that KNSTRN promoted cell cycle progression by regulating the expression of key cell cycle proteins. The overexpression and silencing of KNSTRN in vitro, respectively, promoted and inhibited the proliferation of breast cancer cells. The overexpression of KNSTRN enhanced the expression of key cell cycle regulators, including CDK4, CDK6, and cyclin D3, thereby accelerating the G1/S phase transition and leading to aberrant proliferation of breast cancer cells. In conclusion, our study demonstrates that KNSTRN functions as an oncogene in breast cancer by regulating immune response, promoting G1/S transition, and facilitating breast cancer cell proliferation. Moreover, KNSTRN has potential as a molecular biomarker for diagnostic and prognostic prediction in breast cancer.

GSDMB: A novel, independent prognostic marker and potential new therapeutic target in clear cell renal cell carcinoma.

Gasdermin (GSDM) family members are involved in numerous biological processes, including pyroptosis, as well as in the initiation and progression of various types of cancer. However, the specific role of GSDM genes in clear cell renal cell carcinoma (ccRCC) has yet to be fully clarified. The present study investigated the differential expression and genetic alterations GSDM genes, their effects on prognosis and immune modulation, and their functional enrichment in ccRCC. Several bioinformatics databases were used, including UALCAN, The Cancer Genome Atlas, Gene Expression Profiling Interactive Analysis, Metascape, Tumor Immune Estimation Resource, GSCALite and cBioPortal. The results revealed that the expression levels of GSDMA, GSDMB, GSDMC and GSDMD were significantly upregulated in cancer tissues compared with those in paracancerous tissues in patients with ccRCC, whereas the expression of DFNB59 exhibited the opposite trend. The results were experimentally validated in patients with ccRCC, and it was confirmed that the expression levels of GSDMA, GSDMB, GSDMC, GSDMD and GSDME (DFNA5) were significantly enhanced, whereas (PJVK, DFNB59) expression was reduced. In addition, elevated GSDMB, GSDMD and DFNA5 expression levels were clearly associated with worse pathological characteristics of ccRCC, including a high pathological stage and high tumor grade. Furthermore, the high expression levels of GSDMB, GSDMC, GSDMD, DFNA5 and PJVK were shown to be associated with worse overall survival (OS) and progression-free interval in patients with ccRCC. Both univariate and multivariate analyses indicated that the expression of GSDMB was independently associated with the OS of patients with ccRCC. Additionally, a high mutation rate of GSDM genes (33%) was observed in patients with ccRCC, and GSDM gene mutations were also significantly associated with a poor OS in patients with ccRCC. Significant associations between GSDM genes and ccRCC immunoprofiling and drug sensitivity were also determined. In conclusion, the findings of the present study indicated that GSDMB, GSDMD and DFNA5 may be considered promising therapeutic agents and potential biomarkers for patients with ccRCC. Furthermore, GSDMB could act as an independent predictor for the OS of patients with ccRCC.

Suppressing MTERF3 inhibits proliferation of human hepatocellular carcinoma via ROS-mediated p38 MAPK activation

Mitochondrial transcription termination factor 3 (MTERF3) negatively regulates mitochondrial DNA transcription. However, its role in hepatocellular carcinoma (HCC) progression remains elusive. Here, we investigate the expression and function of MTERF3 in HCC. MTERF3 is overexpressed in HCC tumor tissues and higher expression of MTERF3 positively correlates with poor overall survival of HCC patients. Knockdown of MTERF3 induces mitochondrial dysfunction, S-G2/M cell cycle arrest and apoptosis, resulting in cell proliferation inhibition. In contrast, overexpression of MTERF3 promotes cell cycle progression and cell proliferation. Mechanistically, mitochondrial dysfunction induced by MTERF3 knockdown promotes ROS accumulation, activating p38 MAPK signaling pathway to suppress HCC cell proliferation. In conclusion, ROS accumulation induced by MTERF3 knockdown inhibits HCC cell proliferation via p38 MAPK signaling pathway suggesting a promising target in HCC patients.

RACGAP1 promotes the progression and poor prognosis of lung adenocarcinoma through its effects on the cell cycle and tumor stemness.

Investigating the key genes and mechanisms that influence stemness in lung adenocarcinoma. First, consistent clustering analysis was performed on lung adenocarcinoma patients using stemness scoring to classify them. Subsequently, WGCNA was utilized to identify key modules and hub genes. Then, machine learning methods were employed to screen and identify the key genes within these modules. Lastly, functional analysis of the key genes was conducted through cell scratch assays, colony formation assays, transwell migration assays, flow cytometry cell cycle analysis, and xenograft tumor models. First, two groups of patients with different stemness scores were obtained, where the high stemness score group exhibited poor prognosis and immunotherapy efficacy. Next, LASSO regression analysis and random forest regression were employed to identify genes (PBK, RACGAP1) associated with high stemness scores. RACGAP1 was significantly upregulated in the high stemness score group of lung adenocarcinoma and closely correlated with clinical pathological features, poor overall survival (OS), recurrence-free survival (RFS), and unfavorable prognosis in lung adenocarcinoma patients. Knockdown of RACGAP1 suppressed the migration, proliferation, and tumor growth of cancer cells. RACGAP1 not only indicates poor prognosis and limited immunotherapy benefits but also serves as a potential targeted biomarker influencing tumor stemness.

Understanding the autophagic functions in cancer stem cell maintenance and therapy resistance.

Complex tumour ecosystem comprising tumour cells and its associated tumour microenvironment (TME) constantly influence the tumoural behaviour and ultimately impact therapy failure, disease progression, recurrence and poor overall survival of patients. Crosstalk between tumour cells and TME amplifies the complexity by creating metabolic changes such as hypoxic environment and nutrient fluctuations. These changes in TME initiate stem cell-like programmes in cancer cells, contribute to tumoural heterogeneity and increase tumour robustness. Recent studies demonstrate the multifaceted role of autophagy in promoting fibroblast production, stemness, cancer cell survival during longer periods of dormancy, eventual growth of metastatic disease and disease resistance. Recent ongoing studies examine autophagy/mitophagy as a powerful survival strategy in response to environmental stress including nutrient deprivation, hypoxia and environmental stress in TME. It prevents irreversible senescence, promotes dormant stem-like state, induces epithelial-mesenchymal transition and increases migratory and invasive potential of tumour cells. The present review discusses various theories and mechanisms behind the autophagy-dependent induction of cancer stem cell (CSC) phenotype. Given the role of autophagic functions in CSC aggressiveness and therapeutic resistance, various mechanisms and studies based on suppressing cellular plasticity by blocking autophagy as a powerful therapeutic strategy to kill tumour cells are discussed.

Prognostic value and immunomodulatory role of DNM1L in gastric adenocarcinoma.

Mitochondrial fusion and fission are critical for the morphology and function of cells. DNM1L encodes dynamin-related protein 1 (DRP1), a key protein mediating mitochondrial fission, which is upregulated in a variety of cancers and is strongly associated with tumorigenesis. We aim to investigate the relationship between DNM1L and the prognosis of gastric cancer, as well as to explore the function and mechanism of DNM1L in gastric cancer (GC). In this study, we analyzed the expression differences of DNM1L in gastric cancer tissues and paracancerous tissues using The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. This was followed by validation through tissue microarrays. We then utilized the cohort information from these microarrays to explore the relationship between DNM1L expression and gastric cancer prognosis. Furthermore, we conducted enrichment analysis to investigate the function and mechanisms of DNM1L in gastric cancer, and lastly, we performed immune cell infiltration analysis using the CIBERSORT algorithm. We discovered that the expression of DNM1L is elevated in GC tissues. TCGA data showed that the overexpression of DNM1L was positively correlated with the T-stage of GC but not with lymph node metastasis, which was also corroborated by our immunohistochemistry experiments. Based on the Kaplan-Meier curves, the high DNM1L expression was remarkably correlated with poor overall survival in patients with GC. In addition, results of COX regression analysis indicated that high DNM1L expression was an independent prognostic factor in patients with GC. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene set enrichment analysis (GSEA) showed that DNM1L was closely associated with multiple signaling pathways and immune responses. CIBERSORT analysis indicated that increased DNM1L expression may affect the infiltration of immune cells in the tumor microenvironment. The results of this study indicate that DNM1L is upregulated in gastric cancer (GC) and positively correlates with the T-stage and poor prognosis of GC patients, and it plays an important role in tumor immune infiltration.

MicroRNA-190b Targets RFWD3 in Estrogen Receptor-Positive Breast Cancer.

In the year 2020, breast cancer was the most common form of cancer worldwide. Roughly 70% of breast cancers are estrogen receptor-positive (ER+). MicroRNA-190b (miR-190b) has previously been reported to be upregulated in ER+ breast cancers. Previously, we have demonstrated that miR-190b is hypomethylated in ER+ breast cancers, potentially leading to its upregulation. To further study the role of miR-190b in ER+ breast cancer and to identify its clinically relevant targets in breast cancer. Patient cohort and cell line-based RNA-sequencing analysis. The Cancer Genome Atlas was used to obtain gene expression data and clinical information on patients with breast cancer. To identify messenger RNA (mRNA) targets for miR-190b, the ER+ breast cancer cell line T-47D was used to immunoprecipitate biotin-labeled miR-190b followed by RNA sequencing. Western blot was used to confirm miR-190b target. Patient survival based on miR-190b and selected target was studied using the Cancer Genome Atlas. In this study, we confirm that miR-190b is overexpressed in breast cancer via differential expression analysis and show that high expression of miR-190b results in more favorable outcomes in Luminal A patients, hazard ratio (HR) = 0.29, 95% confidence interval [CI] = 0.12-0.71, P = .0063. MicroRNA-190b target analysis identified RING finger and WD repeat domain 3 (RFWD3) as one of miR-190b regulatory targets in ER+ breast cancer. Survival analysis of RFWD3 showed that elevated levels result in poorer overall survival in patients with Luminal A breast cancer (HR = 2.22, 95% CI = 1.33-3.71, P = .002). Gene ontology analysis of our sequencing results indicates that miR-190b may have a role in breast cancer development and/or tumorigenesis and that it may be a suitable tool in characterization between the ER+ subtypes, Luminal A, and Luminal B. We show that miR-190b targets RFWD3 in ER+ breast cancers leading to lower RFWD3 protein expression. Low levels of RFWD3 are associated with better outcomes in patients with Luminal A breast cancer but not in patients with Luminal B breast cancer. These findings provide novel insights into miR-190b role in breast cancer and that its clinical relevance is subtype specific.

CENPF Upregulation is Associated with Immunosuppressive Status and Poor Clinical Outcomes in Lung Adenocarcinoma Validated by qRT-PCR.

CENPF-differentially expressed in various types of cancers-is a marker of poor prognosis. However, studies on the impact of CENPF on patient prognosis in lung adenocarcinoma regarding immune infiltration are lacking. CENPF expression profiles were analyzed in the GEO and TCGA databases. qRT-PCR was used to verify CENPF mRNA expression in lung adenocarcinoma cell lines. The prognostic value of CENPF was evaluated by combining data from clinical samples in the GEPIA2 and TCGA databases. Metascape and WebGestalt were used for enrichment analysis of gene sets most positively associated with CENPF. Immune cell infiltration score data were retrieved from TCGA and the correlation between CENPF expression and immune cell infiltration was analyzed. CENPF expression was elevated in 29 types of cancer. CENPF was highly expressed and increased with tumor grade in lung adenocarcinoma. Immunohistochemical and qRT-PCR analyses revealed that CENPF expression was upregulated in lung adenocarcinoma tissues and cells. High expression of CENPF significantly worsened prognoses in patients with multiple malignancies, including lung adenocarcinoma. Results from gene set enrichment analysis indicated significant enrichment of the progesterone-mediated oocyte maturation pathway. Immune infiltration analysis revealed that CD4+ Th2 cell infiltration was significantly higher in the high CENPF expression group. Upregulation of CENPF expression was related to poor progression-free survival, disease- free survival, and overall survival in patients with lung adenocarcinoma. High expression of CENPF was markedly related to genes associated with the immune checkpoint. Lung adenocarcinoma samples with high CENPF expression had increased CD4+ Th2 cell infiltration. Our findings indicate that CENPF promotes CD4+ Th2 cell infiltration through oncogenic activity and may be used as a biomarker for predicting patient outcomes in lung adenocarcinoma.

Ectopic Expression of TIGIT in Lung Adenocarcinoma and Its Clinical Significance.

This study aimed to investigate the T cell immunoreceptor with ITIM and Ig domains (TIGIT) expression in lung adenocarcinoma (LUAD). TIGIT expression was measured by western blot, reverse transcription quantitative polymerase chain reaction. Seventy-two paired surgical specimens were collected from patients with stage I-IV LUAD. The expression of TIGIT in surgical specimens was determined using immunohistochemistry. TIGIT was overexpressed in LUAD tissues. Moreover, overexpressed TIGIT was significantly associated with advanced clinical staging, lymph node metastasis, distant metastasis, and TP53 mutations in LUAD. Moreover, high expression of TIGIT was negatively correlated with purity of CD4+ T cells. High rations of TIGIT+CD4+ T cells predicted poor overall survival of LUAD patients. Additionally, high ratios of TIGIT+CD4+ T cells is closely related to CD4+ T cell depletion. Taken together, TIGIT was overexpressed in LUAD patients. High levels of TIGIT induced the alteration of CD4+ T cell based immunomodulation and predicted poor prognosis of LUAD patients. Therefore, TIGIT can be potential biomarker for LUAD.

Pan-cancer analysis of HS6ST2: associations with prognosis, tumor immunity, and drug resistance.

In this comprehensive study spanning 33 malignancies, we explored the differential expression and prognostic significance of Heparan sulfate 6-O-sulfotransferase 2 (HS6ST2). TIMER2, UALCAN, and GEPIA2 were used for the expression analysis. cBioPortal was used for mutational analysis. CancerSEA, STRING, and DAVID, were employed for the single cell sequencing data analysis, protein-protein interaction network development, and gene enrichment analyses, respectively. GSCAlite and RT-qPCR were used for drug sensitivity and expression validation analysis. HS6ST2 exhibited significant (P < 0.05) overexpression in multiple cancers. Prognostically, elevated HS6ST2 expression was significantly associated with poor overall survival (OS) in patients with cervical squamous cell carcinoma (CESC), kidney chromophobe (KICH), lung adenocarcinoma (LUAD), and stomach adenocarcinoma (STAD), emphasizing its potential as a prognostic indicator in these cancers. Moreover, HS6ST2 expression correlated with pathological stages in CESC, KICH, LUAD, and STAD patients. Exploration of genetic alterations using cBioPortal unveiled distinct mutational landscapes, with low mutation frequencies in CESC, KICH, LUAD, and STAD. Additionally, reduced DNA methylation in CESC, KICH, LUAD, and STAD suggested a potential link between hypomethylation and heightened HS6ST2 expression. Analysis of immune cell infiltration revealed a positive correlation between HS6ST2 expression and the infiltration of CD8+ T and CD4+ T cells in CESC, KICH, LUAD, and STAD, highlighting its involvement in the tumor immunology processes. Single-cell functional states analysis demonstrated associations between HS6ST2 and diverse cellular processes. Moreover, gene enrichment analysis revealed the involvement HS6ST2 in crucial cellular activities. GSCAlite analysis underscored the potential of HS6ST2 as a therapeutic target, showing associations with drug sensitivity. Finally, experimental validation through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry in LUAD tissues confirmed elevated HS6ST2 expression. Overall, this study provides a comprehensive understanding of HS6ST2 in CESC, KICH, LUAD, and STAD, emphasizing its potential as a prognostic biomarker and therapeutic target.

Integrative bioinformatics and in vitro exploration of EVI2A expression: unraveling its immunological and prognostic implications in kidney renal clear cell carcinoma.

EVI2A has emerged as a significant biomarker in various diseases; however, its biological role and mechanism in kidney renal clear cell carcinoma (KIRC) remains unexplored. We used TCGA and GEO databases to analyze EVI2A gene expression comprehensively and performed pan-cancer assessments. Clinical relevance was evaluated through Kaplan-Meier analysis and ROC curves. The gene's immune relevance was explored through analyses of the tumor microenvironment (TME), Tumor Immune Single-cell Hub (TISCH), immune checkpoints, and immunotherapy sensitivity. Our results indicate that EVI2A expression is upregulated in KIRC, showing correlations with tumor grade and T/N/M stage. EVI2A demonstrates high diagnostic accuracy (AUC=0.906) and predicts poor overall and progression-free survival in KIRC patients. Furthermore, EVI2A expression exhibits significant associations with immunity, including TME scores and specific immune cell types such as Tfh cells, CD4 memory T cells, and CD8+ T cells. Elevated EVI2A expression suggests increased sensitivity to PD-1/CTLA-4 and tyrosine kinase inhibitors. In vitro assays confirmed the impact of EVI2A on KIRC behavior, with its knockdown resulting in reduced cell proliferation and migration. In conclusion, our comprehensive analysis identifies EVI2A as a promising biomarker and a novel therapeutic target for intervening in KIRC. These findings hold significant implications for further research and potential clinical applications.