Poor Overall Survival In Patients Research Articles

A Population of Tumor-Infiltrating CD4+ T Cells Co-Expressing CD38 and CD39 Is Associated with Checkpoint Inhibitor Resistance.

We previously showed that elevated frequencies of peripheral blood CD3+CD4+CD127-GARP-CD38+CD39+ T cells were associated with checkpoint immunotherapy resistance in patients with metastatic melanoma. In the present study, we sought to further investigate this population of ectoenzyme-expressing T cells (Teee). Teee derived from the peripheral blood of patients with metastatic melanoma were evaluated by bulk RNA-sequencing (RNA-seq) and flow cytometry. The presence of Teee in the tumor microenvironment was assessed using publically available single-cell RNA-seq datasets of melanoma, lung, and bladder cancers along with multispectral immunofluorescent imaging of melanoma patient formalin-fixed, paraffin-embedded specimens. Suppressive function of Teee was determined by an in vitro autologous suppression assay. Teee had phenotypes associated with proliferation, apoptosis, exhaustion, and high expression of inhibitory molecules. Cells with a Teee gene signature were present in tumors of patients with melanoma, lung, and bladder cancers. CD4+ T cells co-expressing CD38 and CD39 in the tumor microenvironment were preferentially associated with Ki67- CD8+ T cells. Co-culture of patient Teee with autologous T cells resulted in decreased proliferation of target T cells. High baseline intratumoral frequencies of Teee were associated with checkpoint immunotherapy resistance and poor overall survival in patients with metastatic melanoma. These results demonstrate that a novel population of CD4+ T cells co-expressing CD38 and CD39 is found both in the peripheral blood and tumor of patients with melanoma and is associated with checkpoint immunotherapy resistance.

JMJD6 functions as an oncogene and is associated with poor prognosis in esophageal squamous cell carcinoma

BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with a high prevalence and poor prognosis. It is an urgent problem to deeply understand the molecular mechanism of ESCC and develop effective diagnostic and prognostic methods.MethodsUsing tumor tissue and corresponding paracancerous samples from 141 resected ESCC patients, we assessed Jumonji domain-containing protein 6 (JMJD6) expression using Immunohistochemical (IHC) staining. Kaplan-Meier survival analysis and univariate or multivariate analysis were used to investigate the relationship between JMJD6 expression and clinicopathological features. The expression status and prognostic value of JMJD6 were analyzed by bioinformatics and enrichment analysis.ResultsThe expression of JMJD6 in ESCC samples was higher than that in the corresponding paracancerous samples, and high expression of JMJD6 was positively associated with poor prognosis of ESCC patients. In addition, bioinformatics analysis of the expression and prognosis of JMJD6 in a variety of tumors showed that high expression of JMJD6 was significantly associated with poor overall survival (OS) in ESCC patients. Enrichment analysis indicated that the high expression of genes similar to JMJD6, such as Conserved oligomeric Golgi 1(COG1), Major facilitator superfamily domain 11 (MFSD11) and Death Effector Domain Containing 2 (DEDD2), was associated with poor prognosis of ESCC, suggesting that JMJD6 might be involved in the occurrence and prognosis of ESCC.ConclusionOur study found that JMJD6 expression was significantly increased in ESCC patients and positively correlated with prognosis, indicating that targeting JMJD6 might be an attractive prognostic biomarker and provides a potential treatment strategy for ESCC.Trial registrationThe study was approved by Tangdu Hospital ethics committee (No. TDLL-202110-02).

ATG7 upregulation contributes to malignant transformation of human bronchial epithelial cells by B[a]PDE via DNMT3B protein degradation and miR-494 promoter methylation

Lung cancer primarily arises from exposure to various environmental factors, particularly airborne pollutants. Among the various lung carcinogens, benzo(a)pyrene and its metabolite B[a]PDE are the strongest ones that actively contribute to lung cancer development. ATG7 is an E1-like activating enzyme and contributes to activating autophagic responses in mammal cells. However, the potential alterations of ATG7 and its role in B[a]PDE-caused lung carcinogenesis remain unknown. Here, we found that B[a]PDE exposure promoted ATG7 expression in mouse lung tissues, while B[a]PDE exposure resulted in ATG7 induction in human normal bronchial epithelial cells. Our studies also demonstrated a significant correlation between high ATG7 expression levels and poor overall survival in lung cancer patients. ATG7 knockdown significantly repressed Beas-2B cell transformation upon B[a]PDE exposure, and such promotive effect of ATG7 on cell transformation mediated the p27 translation inhibition. Further studies revealed that miR-373 inhibition was required to stabilize ATG7 mRNA, therefore increasing ATG7 expression following B[a]PDE exposure, while ATG7 induction led to the autophagic degradation of the DNA methyltransferase 3 Beta (DNMT3B) protein, in turn promoted miR-494 transcription via its promoter region methylation status suppression. We also found that the miR-494 upregulation inhibited p27 protein translation and promoted bronchial epithelial cell transformation via its directly targeting p27 mRNA 3′-UTR region. Current studies, to the best of our knowledge, are for the first time to identify that ATG7 induction and its mediated autophagy is critical for B[a]PDE-induced transformation of human normal epithelial cells.

Preoperative C-Reactive Protein-to-Albumin Ratio and Its Ability to Predict Outcomes of Pancreatic Cancer Resection: A Systematic Review.

To evaluate the ability of the c-reactive protein-to-albumin ratio (CAR) in predicting outcomes in patients undergoing pancreatic cancer resection. A systematic search of electronic information sources and bibliographic reference lists was conducted. Survival outcomes and perioperative morbidity were the evaluated outcome parameters. Eight studies reporting a total of 1056 patients undergoing pancreatic cancer resection were identified. The median cut-off value for CAR was 0.05 (range 0.0003-0.54). Using multivariate analysis, all studies demonstrated that a higher CAR value was an independent and significant predictor of poor overall survival in patients undergoing pancreatic cancer resection. The estimated hazard ratio (HR) ranged from 1.4 to 3.6. Although there was a positive correlation between the reported cut-off values for CAR and HRs for overall survival, it was weak and non-significant (r = 0.36, n = 6, p = 0.480). There was significant between-study heterogeneity. Preoperative CAR value seems to be an important prognostic score in predicting survival outcomes in patients undergoing pancreatic cancer resection. However, the current evidence does not allow the determination of an optimal cut-off value for CAR, considering the heterogeneous reporting of cut-off values by the available studies and the lack of knowledge of their sensitivity and specificity. Future research is required.

C-JUN-induced upregulation of LINC00174 contributes to colorectal cancer proliferation and invasion through accelerating USP21 expression.

Colorectal cancer (CRC) is one of the most common human malignancies due to its invasiveness and metastasis. Recent studies revealed the pivotal roles of long noncoding RNAs (lncRNAs) in tumorigenesis and progressions of various tumors. However, the biological roles and molecular mechanisms of long intergenic noncoding RNA 00174 (LINC00174) in human CRC remain unclear. Here, we report that LINC00174 expression was higher in human CRC tissues and cell lines than in adjacent normal tissues and a colon epithelial cell line (FHC). High expression of LINC00174 was positively correlated with poor overall and disease-free survival in patients with CRC. Loss- and gain-of-function of LINC00174 demonstrated its critical roles in promoting cell proliferation, apoptosis resistance, migration, and invasion of CRC cells in vitro. Moreover, overexpression of LINC00174 enhanced tumor growth in vivo. Mechanistic experiments revealed that LINC00174 could bind to microRNA (miR)-2467-3p and augment the expression and function of ubiquitin-specific peptidase 21 (USP21). Rescue assays found that miR-2467-3p inhibition can offset the actions of LINC00174 or USP21 knockdown in CRC cells. Additionally, transcriptional factor c-JUN transcriptionally activated LINC00174 expression and mediated LINC00174-induced malignant phenotypes of CRC cell lines. Totally, our findings shed light on a new therapeutic strategy in modulating LINC00174/miR-2467-3p, which may interfere with the expression of USP21, and revealed that LINC00174 could be a new therapeutic target or prognostic marker in CRC.

Dermokine mutations contribute to epithelial-mesenchymal transition and advanced melanoma through ERK/MAPK pathways.

To discover vulnerabilities associated with dermokine (DMKN) as a new trigger of the epithelial-mesenchymal transition (EMT) -driven melanoma, we undertook a genome-wide genetic screening using transgenic. Here, we showed that DMKN expression could be constitutively increased in human malignant melanoma (MM) and that this correlates with poor overall survival in melanoma patients, especially in BRAF-mutated MM samples. Furthermore, in vitro, knockdown of DMKN inhibited the cell proliferation, migration, invasion, and apoptosis of MM cancer cells by the activation of ERK/MAPK signaling pathways and regulator of STAT3 in downstream molecular. By interrogating the in vitro melanoma dataset and characterization of advanced melanoma samples, we found that DMKN downregulated the EMT-like transcriptional program by disrupting EMT cortical actin, increasing the expression of epithelial markers, and decreasing the expression of mesenchymal markers. In addition, whole exome sequencing was presented with p.E69D and p.V91A DMKN mutations as a novel somatic loss of function mutations in those patients. Moreover, our purposeful proof-of-principle modeled the interaction of ERK with p.E69D and p.V91A DMKN mutations in the ERK-MAPK kinas signaling that may be naturally associated with triggering the EMT during melanomagenesis. Altogether, these findings provide preclinical evidence for the role of DMKN in shaping the EMT-like melanoma phenotype and introduced DMKN as a new exceptional responder for personalized MM therapy.

Inhibition of phosphodiesterase 4D suppresses mTORC1 signaling and pancreatic cancer growth.

The mammalian target of rapamycin complex 1 (mTORC1) senses multiple upstream stimuli to orchestrate anabolic and catabolic events that regulate cell growth and metabolism. Hyperactivation of mTORC1 signaling is observed in multiple human diseases; thus, pathways that suppress mTORC1 signaling may help to identify new therapeutic targets. Here, we report that phosphodiesterase 4D (PDE4D) promotes pancreatic cancer tumor growth by increasing mTORC1 signaling. GPCRs paired to Gαs proteins activate adenylyl cyclase, which in turn elevates levels of 3',5'-cyclic adenosine monophosphate (cAMP), whereas PDEs catalyze the hydrolysis of cAMP to 5'-AMP. PDE4D forms a complex with mTORC1 and is required for mTORC1 lysosomal localization and activation. Inhibition of PDE4D and the elevation of cAMP levels block mTORC1 signaling via Raptor phosphorylation. Moreover, pancreatic cancer exhibits an upregulation of PDE4D expression, and high PDE4D levels predict the poor overall survival of patients with pancreatic cancer. Importantly, FDA-approved PDE4 inhibitors repress pancreatic cancer cell tumor growth in vivo by suppressing mTORC1 signaling. Our results identify PDE4D as an important activator of mTORC1 and suggest that targeting PDE4 with FDA-approved inhibitors may be beneficial for the treatment of human diseases with hyperactivated mTORC1 signaling.

High Intratumoral i-tRF-GlyGCC Expression Predicts Short-Term Relapse and Poor Overall Survival of Colorectal Cancer Patients, Independent of the TNM Stage.

Colorectal cancer (CRC), one of the most prevalent types of cancer, requires the discovery of new tumor biomarkers for accurate patient prognosis. In this work, the prognostic value of the tRNA fragment i-tRF-GlyGCC in CRC was examined. Total RNA extraction from 211 CRC patient cancer tissue specimens and 83 adjacent normal tissues was conducted. Each RNA extract was subjected to in vitro polyadenylation and reverse transcription. A real-time quantitative PCR assay was used to quantify i-tRF-GlyGCC in all samples. Extensive biostatics analysis showed that i-tRF-GlyGCC levels in CRC tissues were significantly lower than in matched normal colorectal tissues. Additionally, the disease-free survival (DFS) and overall survival (OS) time intervals were considerably shorter in CRC patients with high i-tRF-GlyGCC expression. i-tRF-GlyGCC expression maintained its prognostic value independently of other established prognostic factors, as shown by the multivariate Cox regression analysis. Additionally, survival analysis after TNM stage stratification revealed that higher i-tRF-GlyGCC levels were linked to shorter DFS time intervals in patients with TNM stage II tumors, as well as an increased probability of having a worse OS for patients in TNM stage II. In conclusion, i-tRF-GlyGCC has the potential to be a useful molecular tissue biomarker in CRC, independent of other clinicopathological variables.

Critical role of MXRA7 in differentiation blockade in human acute promyelocytic leukemia cells

The biology of the matrix remodeling associated 7 (MXRA7) gene had been ill-defined. Inspired by public datasets and domestic findings concerning MXRA7, we hypothesized that MXRA7 might be involved in the pathogenesis of leukemia. This study aimed to investigate the role and effect of MXRA7 expression in acute promyelocytic leukemia (APL) cells differentiation and behavior. Bioinformatics of public datasets revealed MXRA7 mRNA was expressed highly in acute myeloid leukemia (AML), especially in APL. High expression of MXRA7 was associated with poor overall survival of AML patients. We confirmed MXRA7 expression was upregulated in APL patients and cell line. Knockdown or overexpression of MXRA7 did not affect the proliferation of NB4 cells directly. Knockdown of MXRA7 in NB4 cells promoted drug induced cell apoptosis, while overexpression of MXRA7 had no obvious influence on the drug induced cell apoptosis. Lowering MXRA7 protein levels in NB4 cells promoted ATRA-induced cell differentiation possibly through decreasing PML-RARα level and increasing PML and RARα levels. Correspondingly, overexpression of MXRA7 showed the consistent results. We also demonstrated that MXRA7 altered the expression of genes involved in leukemic cell differentiation and growth. Knockdown of MXRA7 upregulated the expression levels of C/EBPB, C/EBPD and UBE2L6, and downregulated the expression levels of KDM5A, CCND2 and SPARC. Moreover, knockdown of MXRA7 inhibited the malignancy of NB4 cells in NOD-SCID mice model. In conclusion, this study demonstrated that MXRA7 influences the pathogenesis of APL via regulation of the cell differentiation. The novel findings about the role of MXRA7 in leukemia not only shed lights on the biology of this gene, but also proposed this gene as a new target for APL treatment.

SOX9 and IL1A as the Potential Gene Biomarkers of the Oral Cancer.

Oral cancer is one of the most common malignant tumors in the head and neck. It is easy to relapse, and the prognosis is poor. However, the molecular mechanism in the development of oral cancer is still unclear. A total of 30 normal individuals and 30 patients with head and neck cancer who underwent surgery were recruited in the Fourth Hospital of Hebei Medical University between February 2019 and November 2021. Furthermore, Human Protein Atlas (HPA) analysis, RT-qPCR, and immunofluorescence were used to verify the expression of SOX9 and IL1A. The GSE69002 dataset was downloaded from the Gene Expression Omnibus (GEO) database. GEO2R was used to identify the differentially expressed genes (DEGs). The Protein-Protein Interaction (PPI) network was constructed by using the STRING, and Cytoscape software was performed for visualization. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for enrichment analysis were made via the DAVID, Metascape, Gene Set Enrichment Analysis (GSEA), and Bin Gene Ontology (BINGO) analysis. Gene Expression Profiling Interactive Analysis (GEPIA) analysis was used to analyze the expression level of hub genes and pathological stage. The cBioPortal can be used for mutation analysis and pathway prediction of hub genes. Kaplan Meier Plotter was used for survival analysis of hub genes. The relative expression level of SOX9 (P=0.021, t=4.332) and IL1A (P=0.011, t= -4.213) in oral cancer was significantly higher than that in the standard group (P<0.05). The DEGs are mainly enriched in cell division, inflammation, interleukin-12 beta-subunit binding, and interleukin- 10 receptor binding. All the differentially expressed gene pathways eventually converge in cell growth and apoptosis. No relationship between the pathologic stage and the expression of hub genes. The poor overall survival of patients with the high expression of SOX9 (Hazard Ratio (HR) = 1.46, P = 0.009) and IL1A (HR = 1.49, P = 0.008). There were strong correlations between the hub genes and the head and neck neoplasms via the Comparative Toxicogenomics Database (CTD). The immunofluorescence and PCR results showed that the level of SOX9 (P<0.001, t = -23.368) in the cancer group was significantly higher than that in the normal group; The level of IL1A in the cancer group was significantly higher than that in the normal group (P<0.001, t = -11.960). SOX9 and IL1A genes are highly expressed in oral cancer and might be potential therapeutic targets for oral cancer. The poor overall survival of patients with the high expression of SOX9 and IL1A.

Pan-Cancer Analysis Reveals CENPI as a Potential Biomarker and Therapeutic Target in Adrenocortical Carcinoma.

Centromere protein I (CENPI) has been shown to affect the tumorigenesis of breast and colorectal cancers. However, its biological role and prognostic value in other kinds of cancer, especially adrenocortical carcinoma (ACC), remained to be further investigated. Various bioinformatics tools were adopted for exploring the significance of differential expression of CENPI in several malignant tumors from databases such as Depmap portal, GTEx, and TCGA. ACC was selected for further analyzed, and information such as clinicopathological features, the prognostic outcome of diverse subgroups, differentially expressed genes (DEGs), co-expression genes, as well as levels of tumor-infiltrating immune cells (TIIC), was extracted from multiple databases. To verify the possibility of CENPI as a therapeutic target in ACC, drug sensitivity assay and si-RNA mediate knockdown of CENPI were carried out. The pan-cancer analyses showed that the CENPI mRNA expression levels differed significantly among most cancer types. Additionally, a high precision in cancer prediction and close relation with cancer survival indicated that CENPI could be a potential candidate biomarker to diagnose and predict cancer prognosis. In ACC, CENPI was closely related to multiple clinical characteristics, such as pathological stage and primary therapy outcome. High CENPI levels predicted poor overall survival (OS), progression-free interval (PFI), and disease-specific survival (DSS) of ACC patients, particularly for different clinical subgroups. Moreover, the expression of CENPI showed positive relationship to Th2 cells but negatively related to most of the TIICs. Furthermore, drug sensitivity assay showed that vorinostat inhibit CENPI expression and ACC cell growth. Additionally, si-RNA mediated knockdown of CENPI inhibited ACC cell growth and invasion and showed synergistic anti-proliferation effect with AURKB inhibitor barasertib. Pan-cancer analysis demonstrated that CENPI is a potential diagnostic and prognostic biomarker in various cancers as well as an anti-ACC therapeutic target.

Identification of Moesin (MSN) as a Potential Therapeutic Target for Colorectal Cancer via the β-Catenin-RUNX2 Axis.

CRC is the second leading cause of cancer-related death. The complex mechanisms of metastatic CRC limit available therapeutic choice. Thus, identifying new CRC therapeutic targets is essential. Moesin (MSN), a member of the ezrin-radixin-moesin family, connects the cell membrane to the actin-based cytoskeleton and regulates cell morphology. We investigated the role of MSN in the progression of CRC. GENT2 and oncomine were used to study MSN expression and CRC patient outcomes. MSN-specific shRNAs or MSN-overexpressed plasmid were used to establish MSN-KD and MSN overexpressed cell lines, respectively. SRB, migration, wound healing, and flow cytometry were used to test cell survival and migration. Propidium iodide and annexin V stain were used to analyze the cell cycle and apoptosis. MSN expression was found to be higher in CRC tissues than in normal tissues. Higher MSN expression is associated with poor overall survival, disease-free survival, and relapse-free survival rates in CRC patients. MSN silencing inhibits cell proliferation, adhesion, migration, and invasion in vitro, whereas MSN overexpression accelerates cell proliferation, adhesion, migration, and invasion. RNA sequencing was used to investigate differentially expressed genes, and RUNX2 was discovered as a possible downstream target for MSN. In CRC patients, RUNX2 expression was significantly correlated with MSN expression. We also found that MSN silencing decreased cytoplasmic and nuclear β-catenin levels. Additionally, pharmacological inhibition of β-catenin in MSN-overexpressed cells led to a reduction of RUNX2, and activating β-catenin signaling by inhibiting GSK3β rescued the RUNX2 downregulation in MSN-KD cells. This confirms that MSN regulates RUNX2 expression via activation of β-catenin signaling. Finally, our result further determined that RUNX2 silencing reduced the ability of MSN overexpression cells to proliferate and migrate. MSN accelerated CRC progression via the β-catenin-RUNX2 axis. As a result, MSN holds the potential to become a new target for CRC treatment.

TMEM200A is a potential prognostic biomarker and correlated with immune infiltrates in gastric cancer.

Gastric cancer (GC) is one of the most common malignant tumors in the digestive system. Several transmembrane (TMEM) proteins are defined as tumor suppressors or oncogenes. However, the role and underlying mechanism of TMEM200A in GC remain unclear. We analyzed the expression of TMEM200A in GC. Furthermore, the influence of TMEM200A on survival of GC patients was evaluated. The correlations between the clinical information and TMEM200A expression were analyzed using chi-square test and logistic regression. Relevant prognostic factors were identified performing univariate and multivariate analysis. Gene set enrichment analysis (GSEA) was performed based on the TCGA dataset. Finally, we explore the relationship between TMEM200A expression and cancer immune infiltrates using CIBERSORT. TMEM200A was up-regulated in GC tissues than that in adjacent non-tumor tissues based on TCGA database. Meta-analysis and RT-qPCR validated the difference in TMEM200A expression. Kaplan-Meier curves suggested the increased TMEM200A had a poor prognosis in GC patients. The chi-square test and logistic regression analyses showed that the TMEM200A expression correlates significantly with T stage. Multivariate analysis showed that TMEM200A expression might be an important independent predictor of poor overall survival in GC patients. GSEA identified five immune-related signaling pathways and five tumor-related signaling pathways significantly enriched in the high TMEM200A expression phenotype pathway. Finally, we found CD8+ T cells is apparently decreased in high TMEM200A expression group. Conversely, eosinophils is increased in high expression group compared with low expression group. TMEM200A is a potential prognostic biomarker and correlated with immune infiltrates in GC.

FBXO5 acts as a novel prognostic biomarker for patients with cervical cancer.

Background: Cervical cancer (CC) remains one of the most common and deadly malignancies in women worldwide. FBXO5, a protein-coding gene, is highly expressed in a variety of primary tumors and promotes tumor progression, however, its role and prognostic value in CC remain largely unknown. Methods: A key differential gene, FBXO5, was screened according to WGCNA based on immunohistochemical assays of clinical samples, multiple analyses of the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, including survival analysis, tumor mutational burden, GO, KEGG, tumor immune infiltration, and chemotherapeutic drug sensitivity, to explore the expression and prognostic value of FBXO5 in CC. The migration and invasiveness of cervical cancer cells following FBXO5 knockdown and overexpression were examined using wound healing and transwell assays, and the viability of cancer cells was assessed using CCK8 and EdU assays. Results: FBXO5 was discovered to be substantially expressed in CC tissues using data from our CC cohort and the TCGA database, and a survival analysis indicated FBXO5 as a predictive factor for poor overall survival in CC patients. In vitro, CC cells were more inclined to proliferate, migrate, and invade when FBXO5 was upregulated as opposed to when it was knocked down.

THSD7A Positivity Predicts Poor Survival and Is Linked to High FAK Expression and FGFR1-Wildtype in Female Patients with Squamous Cell Carcinoma of the Lung.

Lung cancer is the leading cause of cancer-related deaths in the western world, with squamous cell carcinoma being one of the most common histological subtypes. Prognostic and predictive markers are still largely missing for squamous cell carcinoma of the lung (LSCC). Several studies indicate that THSD7A might at least play a role in the prognosis of different tumors. FAK seems to play an important role in lung cancer and is discussed as a potential therapeutic target. In addition, there is evidence that FAK-dependent signaling pathways might be affected by THSD7A. For that reason, we investigated the role of THSD7A as a potential tumor marker in LSCC and whether THSD7A expression has an impact on the expression level of FAK. A total of 101 LSCCs were analyzed by immunohistochemistry using tissue microarrays. THSD7A positivity was associated with poor overall survival in female patients and showed a relation to high FAK expression in this subgroup. To our knowledge, we are the first to report these correlations in lung cancer. The results might be proof of the assumed activation of FAK-dependent signaling pathways by THSD7A and that as a membrane-associated protein, THSD7A might serve as a putative therapeutic target in LSCC.

E2F2 modulates cell adhesion through the transcriptional regulation of PECAM1 in multiple myeloma.

Multiple myeloma (MM) is the second most common haematological malignancy. Despite the development of new drugs and treatments in recent years, the therapeutic outcomes of patients are not satisfactory. It is necessary to further investigate the molecular mechanism underlying MM progression. Herein, we found that high E2F2 expression was correlated with poor overall survival and advanced clinical stages in MM patients. Gain- and loss-of-function studies showed that E2F2 inhibited cell adhesion and consequently activated cell epithelial-to-mesenchymal transition (EMT) and migration. Further experiments revealed that E2F2 interacted with the PECAM1 promoter to suppress its transcriptional activity. The E2F2-knockdown-mediated promotion of cell adhesion was significantly reversed by the repression of PECAM1 expression. Finally, we observed that silencing E2F2 significantly inhibited viability and tumour progression in MM cell models and xenograft mouse models respectively. This study demonstrates that E2F2 plays a vital role as a tumour accelerator by inhibiting PECAM1-dependent cell adhesion and accelerating MM cell proliferation. Therefore, E2F2 may serve as a potential independent prognostic marker and therapeutic target for MM.

LINC01480 as a Prognostic Biomarker Associated With Proliferation, Migration, and Invasion of Clear Cell Renal Cell Carcinoma.

The present study aimed to identify key long noncoding RNAs (lncRNAs) involved in survival and metastasis of clear cell renal cell carcinoma (ccRCC). A systemic screening for genes with differential expression in ccRCC was performed using publicly available databases. Cox regression analysis was used to identify lncRNAs associated with survival. A competing endogenous RNAs (ceRNA) regulation network of metastasis-related lncRNAs was constructed and hub lncRNAs were identified. Functional and pathway enrichment analyses were performed to investigate the role of lncRNA in ccRCC. Cell Counting Kit-8 and Transwell assays were used to determine the levels of cell proliferation, migration, and invasion. A total of 732 lncRNAs were found to be differentially expressed between ccRCC tumors and healthy samples. Among them, 139 lncRNAs were differentially expressed between metastasis and non-metastasis ccRCC samples and 75 lncRNAs were associated with overall survival and curated metastasis-related genes. Notably, LINC01480 was identified as the hub lncRNA involved in regulation of ccRCC metastasis. Clinically, LINC01480 may act as an independent factor for poor overall survival of ccRCC patients (log-rank p<0.05). Reverse transcription-quantitative PCR analysis validated that LINC01480 was significantly up-regulated in ccRCC compared to paired normal samples (n=20). Moreover, LINC01480 silencing inhibited the proliferation, migration, and invasion of ccRCC cells in vitro. Gene set enrichment analysis showed that high LINC01480 expression may promote ccRCC metastasis through enhancing immunodeficiency and amino acid metabolism. LINC01480 may act as a novel biomarker for overall prognosis in ccRCC and exhibit potential as a therapeutic target for the treatment of metastatic ccRCC.

Low expression of acyl-CoA thioesterase 13 is associated with poor prognosis in ovarian serous cystadenocarcinoma.

Objective: Acyl-CoA thioesterase 13 (ACOT13) encodes a member of the thioesterase superfamily. It has not been reported in ovarian cancer. This research aimed at evaluating the expression and prognostic value of ACOT13 in ovarian serous cystadenocarcinoma (OSC). Methods: We extracted and analyzed TCGA, GEPIA, THPA, GTEx, miRWalk, and GDSC databases to investigate the potential carcinogenic mechanism of ACOT13 in OSC, including the correlation of ACOT13 with prognosis, immune checkpoint, tumor mutational burden (TMB), and 50% inhibition concentration (IC50) score. The incidence of endpoint events was compared with Kaplan-Meier survival analysis. Independent prognostic factors for OSC were evaluated with univariate and multivariate Cox regression analyses, and a nomogram was established. Results: The expression of ACOT13 was increased in OSC and correlated with tumor stage, with higher expression in stages I and II than in stages III and IV. Besides, it was observed that low expression of ACOT13 is correlated with poor overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS) in patients with OSC. There was a positive correlation between ACOT13 expression and immune checkpoint sialic acid-binding Ig-like lectin (SIGLEC) 15 and TMB. Patients with low ACOT13 expression had higher cisplatin IC50 scores. Conclusion: ACOT13 is an independent prognostic factor and a promising clinical target for OSC. In the future, the carcinogenic mechanism and clinical application value of ACOT13 in ovarian cancer need to be further studied.

TACC3 is an independent prognostic marker, and knockdown of TACC3 enhances the efficacy of CDK1 inhibitor RO3306 in liver cancer cells.

The drug resistance of single-target therapy has gradually become an intractable clinical problem. Combination therapy may be an effective treatment to overcome or postpone drug resistance in cancer. Herein, we discussed the synergistic effect of transforming acidic coiled-coil containing protein 3 (TACC3) suppression and cyclin-dependent kinase 1 (CDK1) in hepatocellular carcinoma (HCC). The Cancer Genome Atlas database and bioinformatics methods were implemented to analyze the expression of CDK1 and TACC3, and predict the biological function of TACC3-related genes in HCC. In addition, in vitro experiments, including cell counting kit 8, transwell and flow cytometry were utilized to evaluate cell proliferation, migration, invasion, cell cycle arrest and apoptosis of HCC cells. Our results demonstrated that TACC3 is an unfavorable and independent prognostic factor to predict poor overall survival (OS) in HCC patients. Genetic inhibition of TACC3 exhibited a remarkable antineoplastic activity of HCC cell lines. Bioinformatic prediction proposed that CDK1 may be the main regulator of TACC3-related genes in HCC. In vitro experimental measurements suggested that a combination of si-TACC3 and CDK1 inhibitor synergistically inhibited cell proliferation and migration, and induced G2 cell cycle arrest and apoptosis of HepG2 or MHCC97H cells. In conclusion, our results revealed a prospective dual-target, TACC3 and CDK1, therapeutic strategy to improve the treatment of HCC.

MGST1 Expression Is Associated with Poor Prognosis, Enhancing the Wnt/β-Catenin Pathway via Regulating AKT and Inhibiting Ferroptosis in Gastric Cancer.

The role of microsomal glutathione S-transferase 1 (MGST1) underlying gastric cancer (GC) is unclear. The purpose of this research was to study the expression level and biological functions of MGST1 in GC cells. Expression of MGST1 was detected by RT-qPCR, Western blot (WB), and immunohistochemical staining. MGST1 was knockdown and overexpression by short hairpin RNA lentivirus in GC cells. Cell proliferation was evaluated by the CCK-8 assay and EDU assay. The cell cycle was detected by flow cytometry. The TOP-Flash reporter assay was used to examine the activity of T-cell factor/lymphoid enhancer factor transcription based on β-catenin. WB was performed to assess the protein levels involved in the cell signaling pathway and ferroptosis. The MAD assay and C11 BODIPY 581/591 lipid peroxidation probe assay were performed to determine the reactive oxygen species lipid level in GC cells. MGST1 expression was upregulated in GC and it was correlated with poor overall survival of GC patients. MGST1 knockdown significantly inhibited GC cell proliferation and cell cycle by regulating the AKT/GSK-3β/β-catenin axis. In addition, we found that MGST1 inhibits ferroptosis in GC cells. These findings suggested that MGST1 played a confirmed role in promoting GC development and serving as a possible independent prognostic factor for GC.