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Acyl-CoA synthetases (ACSs) are responsible for acyl-CoA synthesis from nonpolar hydrophilic fatty acids and play a vital role in many metabolic processes. As a category of ACS isozymes, members of ACS family (AACS, ACSF2-3, AASDH) participate in lipid metabolism; however, their expression patterns, regulatory mechanisms and effects in hepatocellular carcinoma (HCC) are poorly understood. Here, through evaluating the expression profiles of ACSF gene family, we found that upregulated AACS might be more significant and valuable in development and progression of HCC. Consequently, the mRNA expression levels of AACS and ACSF2 was accordantly increased in HCC. Kaplan-Meier plotter revealed that HCC patients with high level of AACS were highly related to a shorter overall survival time and relapse-free survival. Genetic alterations using cBioPortal revealed that the alteration rate of AACS were 5%. We also found that the functions of ACSF gene family were linked to several cancer-associated pathways, including long-term potentiation, phospholipase D signaling pathway and purine metabolism. TIMER database indicated that the AACS and ACSF2 had a strong relationship with the infiltration of six types of immune cells (macrophages, neutrophils, CD8+ T-cells, B-cells, CD4+ T-cells and dendritic cells). Next, Diseasemeth database revealed that the global methylation levels of ACSF2 was higher in HCC patients. In conclusion, this study firstly demonstrated that Acyl-CoA synthesis gene family, in particular, AACS, could be associated with immune microenvironment, thereby influencing the development and prognosis of patients with HCC.

Hepatocellular carcinoma (HCC) is the most common high malignancy with insidious onset, invasive fast-growing, high recurrence rate and fatality. YTH domain family plays essential roles in development of HCC. However, the biological function of YTH domain family in HCC have not been clarified. Here, through evaluating the expression profiles of YTH domain family, we found that upregulated YTHDF1 might be more significant and valuable in development and progression of HCC. There was a strong correlation between YTHDC1, YTHDF1 and YTHDF2 and pathological stage of HCC patients. Kaplan-Meier plotter revealed that HCC patients with high level of YTHDF1 and YTHDF2 were highly related to a shorter overall survival time, and low level of YTHDF1 (p = 0.0017) has an important association with a longer progression-free survival time. Genetic alterations using cBioPortal revealed that the alteration rates of YTHDF3 were the highest. We also found that the functions of YTH domain family were linked to several cancer-associated pathways, including peptidyl-serine modification, peptidyl-tyrosine modification and negative regulation of cellular component movement. TIMER database indicated that the YTH domain family had a strong relationship with the infiltration of six types of immune cells (macrophages, neutrophils, CD8+ T-cells, B-cells, CD4+ T-cells and dendritic cells). Next, Ualcan databases revealed that the global methylation levels of YTHDC1 was higher in HCC patients, while YTHDF2 was lower in HCC patients. In conclusion, our findings will enhance the understanding of YTH domain family in HCC pathology, and provide novel insights into YTH-targeted therapy for HCC patients.

Background. All YTH domain family members are m6A reader proteins accounting for the methylation modulation involved in the process of tumorgenesis and tumor progression. However, the expression profiles and roles of the YTH domain family in lung adenocarcinoma (LUAD) remain to be further illustrated. Methods. GEPIA2 and TNMplot databases were used to generate the expression profiles of the YTH family. Kaplan-Meier plotter database was employed to analysis the prognostic value of the YTH family. Coexpression profiles and genetic alterations analysis of the YTH family were undertaken using the cBioPortal database. YTH family protein-associated protein-protein interaction (PPI) network was identified by using STRING. Functional enrichment analysis was performed with the help of the WebGestalt database. The correlation analysis between the YTH family and immune cell infiltration in LUAD was administrated by using the TIMER2.0 database. Results. mRNA expression of YTHDC1 and YTHDC2 was significantly lower in LUAD, whereas YTHDF1, YTHDF2, and YTHDF3 with apparently higher expression. YTHDF2 expression was observed to be the highest in the nonsmoker subgroup, and its expression gradually decreased with the increased severity of smoking habit. LUAD patients with low expression of YTHDC2, YTHDF1, and YTHDF2 were correlated with a better overall survival (OS) time. The YTHDF1 genetic alteration rate was 26%, which was the highest in the YTH family. The major cancer-associated functions of YTH family pointed in the direction of immunomodulation, especially antigen processing and presentation. Most of the YTH family members were significantly correlated with the infiltration of CD4+ T cells, CD8+ T cells, macrophages, and neutrophils, indicating the deep involvement of the YTH domain family in the immune cell infiltration in LUAD. Conclusion. The molecular and expression profiles of the YTH family were dysregulated in LUAD. YTH family members (especially YTHDC2) were promising biomarkers and potential therapeutic targets that may bring benefit for the patients with LUAD.

Fibroblast growth factor receptor 3 (FGFR3) alters frequently across various cancer types and is a common therapeutic target in bladder urothelial carcinoma (BLCA) with FGFR3 variants. Although emerging evidence supports the role of FGFR3 in individual cancer types, no pan-cancer analysis is available. In this work, we used the open comprehensive datasets, covering a total of 10,953 patients with 10,967 samples across 32 TCGA cancer types, to identify the full alteration spectrum of FGFR3. FGFR3 abnormal expression, methylation patterns, alteration frequency, mutation location distribution, functional impact, and prognostic implications differed greatly from cancer to cancer. The overall alteration frequency of FGFR3 was relatively low in all cancers. Targetable mutations were mainly detected in BLCA, and S249C, Y373C, G370C, and R248C were hotspot mutations that could be targeted by an FDA approved erdafitinib. Genetic fusions were mainly observed in glioma, followed by BLCA. FGFR3-TACC3 was the most common fusion type which was proposed as novel therapeutic targets in glioma and was targetable with erdafitinib in BLCA. Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were two lung cancer subtypes, FGFR3 fusion and hotspot mutation like S249C were observed more commonly in LUSC but not in LUAD. DNA methylation was correlated with the expression of FGFR3 and its downstream genes in some tumors. FGFG3 abnormal expression and alterations exhibited clinical correlations with patient prognosis in several tumors. This work exhibited the full alteration spectrum of FGFR3 and indicated several new clues for their application as potential therapeutic targets and prognostic indicators.

AlkB family of Fe (II) and α-ketoglutarate-dependent dioxygenases plays essential roles in development of ovarian serous carcinoma (OV). However, the molecular profiles of AlkB family in OV have not been clarified. The results indicated that the expression of ALKBH1/3/5/8 and FTO was lower in OV patients while ALKBH2/4/6/7 expression was higher. There was a strong correlation between ALKBH5/7 and pathological stage of OV patients. Kaplan-Meier plotter revealed that OV patients with high ALKBH4 level showed longer overall survival (OS). However, patients with high levels of ALKBH5/6 and FTO showed shorter OS and progression-free survival (PFS). Genetic alterations using cBioPortal revealed that the alteration rates of FTO were the highest. We also found that the functions of AlkB family were linked to several cancer-associated signaling pathways, including chemokine receptor signaling. TIMER database indicated that the AlkB family had a strong relationship with the infiltration of six types of immune cells (macrophages, neutrophils, CD8+ T-cells, B-cells, CD4+ T-cells and dendritic cells). Next, DiseaseMeth databases revealed that the global methylation levels of ALKBH1/2/3/4/5/6/7/8 and FTO were all lower in OV patients. Thus, our findings will enhance the understanding of AlkB family in OV pathology, and provide novel insights into AlkB-targeted therapy for OV patients.

Receptor interacting protein kinases (RIPKs) are a family of serine/threonine kinases which are supposed to regulate tumor generation and progression. Rare study illustrates the roles and functions of RIPKs family in lung adenocarcinoma (LUAD) comprehensively. Our results indicated that the expression of RIPK2 higher in LUAD patients while RIPK5 (encoded by gene DSTYK) expression was lower. Only RIPK2 had a strong correlation with pathological stage in LUAD patients. Kaplan-Meier plotter revealed that LUAD patients with low RIPK2 or RIPK3 level showed better overall survival (OS), but worse when LUAD patients with high RIPK5. Further, lower expression of RIPK2 and higher expression of RIPK1, RIPK4 and RIPK5 prompted a longer disease free survival (DFS). Genetic alterations based on cBioPortal revealing 16% alteration rates of RIPK2, as well as RIPK5. We also found that the functions of RIPKs family were linked to cellular senescence, protein serine/threonine kinase activity, apoptosis process et al. TIMER database indicated that the RIPKs family members had distinct relationships with the infiltration of six types of immune cells (macrophages, neutrophils, CD8+ T-cells, B-cells, CD4+ T-cells and dendritic cells). Moreover, RIPK2 could be observed as an independent prognostic factor with Cox proportional hazard model analysis. DiseaseMeth databases revealed that the global methylation levels of RIPK2 increased in LUAD patients. Thus, the findings above will enhance the understanding of RIPKs family in LUAD pathology and progression, providing novel insights into RIPKs-core therapy for LUAD patients.

Exosome has been demonstrated to be secreted from cells and seized by targeted cells. Exosome could transmit signals and exert biological functions in cancer progression. Nevertheless, the underlying mechanisms of exosome in ovarian cancer (OC) have not been fully explored. In this study, we wanted to explore whether Fibroblast growth factor 9 (FGF9), as an exosome-associated gene, was importantly essential in OC progression and prognosis. Firstly, comprehensive bioinformatics platforms were applied to find that FGF9 expression was lower in OC tissues compared to normal ovarian tissues. Meanwhile, downregulated FGF9 displayed favorable prognostic values in OC patients. The gene enrichment of biological functions indicated that abnormally expressed FGF9 could be involved in the OC-related immune signatures, such as immunoinhibitors and chemokine receptors. Taken together, these findings could provide a novel insight into the significance of FGF9 in OC progress and supply a new destination of FGF9-related immunotherapy in clinical treatment.

Glioma is a highly malignant brain tumor with a poor survival rate. Novel biomarkers that act as prompt indicators of glioma are urgently needed. In this study, we identified and validated prognosis-related differentially expressed genes by datasets of glioma in the GEO and TCGA databases. Ferroptosis is a newly recognized process of cell death playing a vital role in cancer biology. Pearson correlation coefficient were used to discovery the prognosis-related genes which have the highest correlation with ferroptosis. Matrix remodeling-associated protein 8 (MXRA8) was identified as a novel prognosis indicator which may be involved in ferroptosis. The expression of MXRA8 was significantly higher in glioma compared with normal brain tissue, and increased expression of MXRA8 was associated with unfavorable survivals. Furthermore, in vitro analysis showed that knockdown of MXRA8 inhibited the cell viability in T98G and U251 cells and increased the sensitivity of glioma cells to temozolomide. We further observed that downregulation of MXRA8 elevated the levels of intracellular ferrous iron and lipid peroxidation, accompanied by upregulation of NCOA4 and suppression of FTH1. Moreover, co-expression analyses showed that GO term and KEGG pathways were mainly enriched in immunity-related pathways, such as neutrophil-related immunity, adaptive immune response, and cytokine binding. Through ssGSEA algorithm and TISIDB database, immunological analyses showed that MXRA8 was significantly correlated with various immune infiltration cells including NK cells, macrophages, and neutrophils. Meanwhile, MXRA8 was also associated with chemokines and multiple immunoinhibitory molecules, such as TGF-β1, IL-10, PD-L1, and CTLA4. We also found that MXRA8 was positively associated with immune infiltration score, and patients with higher immune score underwent worse overall survivals. Moreover, IHC staining indicated a highly positive correlation of MXRA8 with a macrophage marker CSF1R. The co-cultured models of glioma cells and M2 macrophages showed MXRA8 knockdown glioma cells alleviated the infiltration of M2 macrophage, while the reduced M2 macrophage infiltration generated by MXRA8 could be rescued by Fer-1 treatment. These results suggest that MXRA8 promotes glioma progression and highlight the pivotal role of MXRA8 in ferroptosis and immune microenvironment of glioma. Therefore, MXRA8 may serve as a novel prognostic marker and therapeutic target for glioma.

Transcriptional enhanced associate domain (TEAD) family consists of four members TEAD1/2/3/4 that regulate cell growth, stem cell functions and organ development. As the downstream of Hippo signaling pathway, TEAD family is involved in the progression of several cancers. However, the precise biology functions of TEAD family in hepatocellular carcinoma (HCC) have not been reported yet.We apply bioinformatics analysis based on databases including UALCAN, Oncomine, GEPIA, Kaplan-Meier plotter, WebGestalt, cBioPortal, TIMER2.0, andThe results indicated that TEAD2/4 were significantly upregulated in HCC compared with normal tissues. Downregulated of TEAD2 could promote the death of HCC cells through inducing ferroptosis by iron accumulation and subsequent oxidative damage. According to the Kaplan-Meier plotter database, we found that the high expression of TEAD2 was significantly associated with poor disease-specific survival, overall survival, progression-free survival and relapse-free survival. In aspect of cancer immunity, Tumor Immune Estimation Resource algorithm showed that the expression of TEAD family members was obviously related to multiple of infiltrating immune cells including macrophages, neutrophils, dendritic cells, B cells, CD8+ T cells and CD4+ T cells. Finally, we conducted the functional enrichment analysis including protein-protein interaction network, gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway based on the TEAD family-associated coexpression genes.The study provided deep insight information of TEAD family in the diagnostic and prognostic evaluation of HCC patients.

GSDM family is a group of critical proteins that mediate pyroptosis and plays an important role in cell death and inflammation. However, their specific function in clear cell renal cell carcinoma (ccRCC, KIRC) have not been clarified comprehensively. In this study, we assessed the roles of the GSDM family in expression, prognostic value, functional enrichment analysis, genetic alterations, immune infiltration and DNA methylation in ccRCC patients by using different bioinformatics databases. We found that the expression levels of GADMA-E were significantly higher in ccRCC tissues compared with normal tissues, while the expression level of PJVK was decreased. Moreover, survival analysis indicated that upregulation of GSDME was related to poor overall survival (OS) and recurrence-free survival (RFS) of ccRCC patients. The main function of differentially expressed GSDM homologs was related to ion transport. We also found that the expression profiles of the GSDM family were highly correlated with infiltrating immune cells (i.e., CD8+ T cells, CD4+ T cells, B cells, macrophages, neutrophils and dendritic cells), and there were significant differences in the expression of GSDM family in different ccRCC immune subtypes. Furthermore, DNA methylation analysis indicated that the DNA methylation levels of GSDMA/B/D/E were decreased, while the DNA methylation level of PJVK was increased. In conclusion, this study provides integrated information about abnormal GSDM family members as potential biomarkers for the diagnosis and prognosis of ccRCC. Especially, GSDME was a potential clinical target and prognostic biomarkers for patients with ccRCC.

Ferroptosis is an iron-dependent cell death process that plays important regulatory roles in the occurrence and development of cancers, including hepatocellular carcinoma (HCC). Moreover, the molecular events surrounding aberrantly expressed long non-coding RNAs (lncRNAs) that drive HCC initiation and progression have attracted increasing attention. However, research on ferroptosis-related lncRNA prognostic signature in patients with HCC is still lacking. In this study, the association between differentially expressed lncRNAs and ferroptosis-related genes, in 374 HCC and 50 normal hepatic samples obtained from The Cancer Genome Atlas (TCGA), was evaluated using Pearson’s test, thereby identifying 24 ferroptosis-related differentially expressed lncRNAs. The least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression model were used to construct and validate a prognostic risk score model from both TCGA training dataset and GEO testing dataset (GSE40144). A nine-lncRNA-based signature (CTD-2033A16.3, CTD-2116N20.1, CTD-2510F5.4, DDX11-AS1, LINC00942, LINC01224, LINC01231, LINC01508, and ZFPM2-AS1) was identified as the ferroptosis-related prognostic model for HCC, independent of multiple clinicopathological parameters. In addition, the HCC patients were divided into high-risk and low-risk groups according to the nine-lncRNA prognostic signature. The gene set enrichment analysis enrichment analysis revealed that the lncRNA-based signature might regulate the HCC immune microenvironment by interfering with tumor necrosis factor α/nuclear factor kappa-B, interleukin 2/signal transducers and activators of transcription 5, and cytokine/cytokine receptor signaling pathways. The infiltrating immune cell subtypes, such as resting memory CD4(+) T cells, follicular helper T cells, regulatory T cells, and M0 macrophages, were all significantly different between the high-risk group and the low-risk group as indicated in Spearman’s correlation analysis. Moreover, a substantial increase in the expression of B7H3 immune checkpoint molecule was found in the high-risk group. Our findings provided a promising insight into ferroptosis-related lncRNAs in HCC and a personalized prediction tool for prognosis and immune responses in patients.

Xinxin Ren,1 Xiang Wang,2 Bi Peng,3 Qiuju Liang,2 Yuan Cai,3 Kewa Gao,3 Yongbin Hu,3 Zhijie Xu,3,4 Yuanliang Yan2 1Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3Department of Pathology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Yuanliang YanDepartment of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of ChinaEmail yanyuanliang@csu.edu.cnPurpose: To explore the molecular profiles of transcriptional enhanced associate domain (TEAD) family in ovarian serous carcinoma (OSC).Methods: In this study, we use bioinformatics methods including GEPIA, GE-mini, Oncomine 3.0, Kaplan–Meier plotter, cBioPortal, WebGestalt, TIMER2.0 and DiseaseMeth2.0, and in vitro experimental RT-PCR to assess the expression profiles and prognostic significance of TEAD family in OSC.Results: According to the bioinformatics analysis, TEAD family was abnormally expressed in OSC. In terms of prognosis, Kaplan–Meier plotter indicated that OSC patients with high level of TEAD4 showed poor overall survival (OS), progression-free survival (PFS) and post progression survival (PPS). TEAD family also had significantly diagnostic values for OSC patients. Tumor Immune Estimation Resource (TIMER) algorithm indicated that TEAD family was significantly associated with different types of infiltrating immune cells, including B cells, macrophages, dendritic cells, neutrophils, CD8+ T cells and CD4+ T cells. Gene set enrichment analysis of TEAD family-associated coexpression genes was further explored. In in vitro experiments, the RT-PCR results showed the upregulated TEAD2/4 in OSC tissues and cells (A2780 and TOV112D). Moreover, decreased expression of TEAD2 could induce the ferroptosis through increasing the ROS accumulation.Conclusion: Thus, TEAD family correlated with the diagnosis, prognosis and immune infiltration in OSC. These results could provide comprehensive understanding of TEAD family in the diagnosis and prognosis of OSC patients.Keywords: TEAD family, Hippo pathway, ovarian serous carcinoma, expression profiles, prognosis, immune infiltration

Six Gasdermins (GSDM) family members participate in various biological processes especially pyroptosis, as well as in the initiation and development of many types of cancer. However, the systematic analysis of the GSDM family in hepatocellular carcinoma (HCC) is lacking. In this study, several bioinformatics databases were recruited to analyze the roles of the GSDMs in differential expression, prognostic correlation, functional enrichment exploration, immune modulation, genetic alterations, and methylated modification in patients with HCC. Consequently, the mRNA expression of all the six GSDMs was accordantly increased in HCC, while only the protein expressions of GSDMB, GSDMD, and GSDME were apparently increased in HCC tissue. The expression of all the GSDMs (except GSDMA) was significantly higher in tumor stage 1-3 subgroups, compared with that in normal subgroups. Higher GSDME expression was significantly associated with shorter overall survival (OS) and disease specific survival (DSS) in patients with HCC. GSDMD had the highest genetic alteration rate among the GSDMs. The three signal pathways which were most likely related to GSDMs-associated molecules were the cell adhesion, growth regulation, and hormone metabolic process. The majority of GSDMs members were positively correlated with the infiltration of B cells, neutrophils, and dendritic cells, however negatively correlated with macrophage. All of the six GSDM members showed remarkably decreased methylation levels in HCC tissues. In conclusion, the GSDM family (especially GSDME) had the potential to become essential biomarkers to better improve the diagnosis and prognosis of HCC, as well as provided insight for the development of therapeutic targets.

Ovarian cancer is a significant clinical challenge as no effective treatments are available to enhance patient survival. Recently, N6-methyladenosine (m6A) RNA modification has been demonstrated to play a pivotal role in tumorigenesis and progression. However, the roles of m6A target genes in ovarian cancer haven’t been clearly illustrated. In this study, we presented a comprehensive bioinformatics and in vitro analysis to evaluate the roles of m6A target genes. Cell division cycle 42 effector protein 3 (CDC42EP3), one probable m6A target gene, was identified to be down-regulated in ovarian cancer tissues and cells. Meanwhile, quantitative PCR (qPCR) and western blot were used to confirm the down-regulated CDC42EP3 in ovarian cancer cells A2780 and TOV112D. The biological function of CDC42EP3 in ovarian cancer was further validated with several algorithms, such as PrognoScan, K-M plotter, LinkedOmics and TISIDB. These findings indicated that lower expression of CDC42EP3 was correlated with poor prognosis in patients with ovarian cancer. In addition, CDC42EP3 expression was significantly associated with a diverse range of tumor-infiltrating immune cells, including natural killer cells (NK), T central memory cells (Tcm), T gamma delta cells (Tgd), etc. Taken together, this study uncovered the potential roles of m6A target gene CDC42EP3 in the regulation of immune microenvironment in the ovarian cancer, and identified CDC42EP3 as a novel prognostic target.

Background Serving as N6-methyladenosine demethylases, the AlkB family is involved in the tumorigenesis of hepatocellular carcinoma (HCC). However, the molecular profiles and clinical values of the AlkB family in HCC are not well known. Methods Several bioinformatics tools and in vitro experiments were used to identify the immune-related profiles and prognostic values of AlkB family in HCC. Results In this study expression levels of ALKBH1/2/3/4/7 were all remarkably increased in HCC tissues when compared with normal tissues. Quantitative PCR (qPCR) and immunohistochemistry were used to validate the expression of AlkB family members in HCC tissues and normal liver tissues. In addition, high expression levels of ALKBH4 were negatively correlated with overall survival (OS) and disease-free survival (DFS) in patients with HCC. Increased ALKBH4 was also associated with pathological stage in HCC patients. The molecular profiles of AlkB family in HCC were mainly associated with peptidyl-serine modification, peptidyl-tyrosine modification, regulation of metal ion transport, etc. Furthermore, tumor-infiltrating immune cell analysis indicated that ALKBH1/2/3/4/5/6/7/8 and FTO were related to the infiltration of different immune cell, such as CD8+ T cells, macrophages, neutrophils, dendritic cells and CD4+ T cells. We also discovered that the methylation levels of ALKBH1/2/4/5/6/8 and FTO were remarkably reduced in HCC tissues. Conclusions Collectively, our findings may deepen the understanding of specific molecular profiles of the AlkB family in HCC pathology. In particular, ALKBH4 could serve as a promising prognostic candidate for treating HCC, and these results might potentiate the development of more reliable therapeutic strategies for patients with HCC.

Carbamoyl phosphate synthetase-1 (CPS1), the first rate-limiting mitochondrial enzyme in the urea cycle, regulates proliferation and differentiation during tumor progression. However, the detailed function of CPS1 in glioblastoma Multiforme (GBM) is still unclear. Here, we highlight mechanisms for CPS1 upregulation and the effects of upregulated CPS1 on GBM tumorigenesis. The transcriptome data from several public databases, such as Oncomine and GEPIA, revealed that CPS1 transcriptional level was significantly upregulated in GBM tissues and cells. Moreover, CPS1 was hypomethylated in GBM tissues. The Wanderer database, linked to the Cancer Genome Atlas (TCGA), showed the association between CPS1 expression or its methylation values and the clinicopathological parameters in GBM patients. Our work fully demonstrated that CPS1 expression was upregulated in GBM and this gene could be used as a potential diagnostic and prognosis indicator for GBM.

The gasdermin (GSDM) superfamily has been demonstrated to consist of several important molecules that modulate multifunctional signal processes, such as cell pyroptosis. In this research, the roles of the GSDM superfamily on the occurrence and prognosis of lung adenocarcinoma (LUAD) were evaluated using integrative bioinformatic analyses and in vitro methods. Here, data from several bioinformatic platforms revealed that GSDMC is significantly upregulated in LUAD tissues and cell lines. Real-time fluorescence quantitative PCR (qPCR) demonstrated that GSDMC was obviously upregulated in radio-resistant LUAD cells, compared with their parental cells. Moreover, upregulated GSDMC expression was confirmed to be an independent indicator of poor first progression (FP) and overall survival (OS) in LUAD patients. DNA methylation analysis showed an evidently negative correlation between GSDMC expression and methylation status of one CpG site (cg05316065) in its DNA sequence. Patients with high methylation values had significantly higher Karnofsky performance scores (KPSs) and prolonged OS rates. Together, we confirmed that overexpression of GSDMC acts as a promising predictive factor for the poor prognosis of LUAD patients.

Background The methylated septin 9 (mSEPT9) assay was the first blood-based test approved by the United States Food and Drug Administration as a colorectal screening test. However, the diagnostic and prognostic role of preoperative mSEPT9 for colorectal cancer (CRC) in Chinese patients is still unknown. Aim To improve the understanding of diagnostic and prognostic factors, serum mSEPT9 was detected in Chinese CRC patients. Methods A retrospective analysis of 354 cases, of which 300 had CRC and 54 were normal, was performed in China. Patients' characteristics, treatments, and laboratory data, including age, the date of surgery, Union for International Cancer Control (UICC) stages, distant metastasis (M), and so on, were collected. Methylation levels of SEPT9 were quantified by quantitative, methylation-specific polymerase chain reaction before surgery. In addition, the effects of mSEPT9 on the occurrence and prognosis of 330 CRC cases from The Cancer Genome Atlas (TCGA) database were evaluated using bioinformatics analyses. Potential prognostic factors for overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier univariate analysis. Results In Chinese CRC patients, positive mSEPT9 was strongly associated with advanced UICC stages, deeper invasion by the primary tumor, and more distant metastasis. Methylation levels of SEPT9 were stage-dependent and showed a stepwise increase in UICC stages (I-IV), primary tumor categories (T1-T4), regional node categories (N0-N2), and distant metastasis categories (M0-M1). The patients with positive mSEPT9 showed a tendency toward lower PFS. After analyzing TCGA clinical data, the high mSEPT9 group was found to be obviously correlated only with more distant metastasis. The patients with high mSEPT9 levels showed a tendency toward lower OS. Besides, nine meaningful mSEPT9 sites were found to provide guidance for the follow-up studies. Conclusion MSEPT9 analysis may add valuable information to current tumor staging. Serum mSEPT9 in Chinese CRC patients appears to offer promising novel prognostic markers and might be considered for monitoring CRC recurrence.

Objective Sirtuins (SIRT) are NAD+-dependent protein deacetylases that are involved in the regulation of cancer-associated pathways. However, the biological role of these deacetylases remains elusive in glioblastoma (GBM). Here, we evaluated the effects of 7 sirtuins regarding their occurrence and prognostic value for GBM. Methods In this research, the effects of SIRT5 on the occurrence and prognosis of GBM were evaluated using integrative bioinformatics analyses. Results Based on comprehensive analyses of data obtained from web-based bioinformatics platforms, the data demonstrate that only SIRT5 expression is statistically decreased in GBM tissues. The clinical relevance analysis shows that downregulation of SIRT5 is significantly correlated with a shorter survival time. Moreover, the expression levels of SIRT5 were confirmed to be negatively associated with DNA methylation status. In addition, a protein-protein interaction network was constructed to determine the relationship of genes coexpressed with SIRT5. Functional enrichment analysis revealed that SIRT5 was potentially involved in epithelial-mesenchymal transition and in regulating cell communications. Conclusions Collectively, our results indicate that SIRT5 acts as a potential suppresser during tumorigenesis, and suggest that SIRT5 may be a promising prognostic biomarker of GBM.

Background Phosphoribosylaminoimidazole carboxylase (PAICS), a de novo purine metabolic enzyme, has been identified as an oncogene in several tumor types, including breast cancer and prostate cancer. However, the role of PAICS in human lung adenocarcinoma (LADC) requires further study. Methods In this research, the effects of PAICS on the occurrence and prognosis of LADC were evaluated using integrative bioinformatics analyses. Results By employing the bioinformatics analyses of several public databases, PAICS, which is overexpressed in the LADC tissues, was identified as a potential tumor-promoting gene in LADC biology. Several relevant clinical studies indicated that the upregulation of PAICS was statistically correlated with a shorter overall survival time. Moreover, the carcinogenic function of PAICS in LADC was validated by the further protein-protein interactions (PPI) and biological process annotation analysis. Mechanistically, we found that the PAICS methylation level was significantly lower in the LADC tissues compared to the normal lung tissues. Furthermore, using the MEXPRESS web tool, we predicted 15 possible DNA methylation sites in the nucleotide sequences of PAICS, which could explain the alteration in the PAICS expression levels in LADC. Conclusions Our work demonstrates that high levels of PAICS are found in LADC and that this gene may be a potential therapeutic target for this subset of lung cancers. Determining the detailed roles of PAICS in LADC biology may provide useful information for further investigations.

PrimPol has been recently identified as a DNA damage tolerant polymerase that plays an important role in replication stress response. However, the regulatory mechanisms of PrimPol are not well defined. In this study, we identify that the deubiquitinase USP36 interferes with degradation of PrimPol to regulate the replication stress response. Mechanistically, USP36 is deubiquitinated following DNA replication stress, which in turn facilitates its upregulation and interaction with PrimPol. USP36 deubiquitinates K29-linked polyubiquitination of PrimPol and increases its protein stability. Depletion of USP36 results in replication stress-related defects and elevates cell sensitivity to DNA-damage agents, such as cisplatin and olaparib. Moreover, USP36 expression positively correlates with the level of PrimPol protein and poor prognosis in patient samples. These findings indicate that the regulation of PrimPol K29-linked ubiquitination by USP36 plays a critical role in DNA replication stress and chemotherapy response.

Non‑small cell lung cancer (NSCLC) is prevalent worldwide. Lung squamous cell carcinoma (LUSC) is one of the main subtypes of NSCLC yet, currently, few biomarkers are available for the diagnosis of LUSC. The present study aimed to investigate the expression and role of adenosine deaminase RNA specific B1 (ADARB1) in lung squamous cell carcinoma (LUSC). Integrative bioinformatics analysis was used to identify the effects of ADARB1 expression on the occurrence and prognosis of LUSC. The expression of ADARB1 was further examined by immunohistochemistry (IHC). Bioinformatics analysis suggested that ADARB1 was downregulated in LUSC, serving as a potential tumor suppressor, and these results were verified by IHC performed on a lung cancer tissue array. Clinical studies suggested that ADARB1 expression and methylation levels were significantly associated with patient characteristics in LUSC. Moreover, ADARB1 global methylation levels were upregulated in LUSC tissues compared with normal lung tissues. Higher methylation levels of cg24063645 were associated with shorter overall survival time of patients with LUSC. A negative correlation was identified between ADARB1 and epidermal growth factor receptor (EGFR) expression in LUSC. Using the Gene Expression Omnibus database, it was suggested that the expression of ADARB1 in LUSC was significantly different compared with that in lung adenocarcinoma. Furthermore, protein‑protein interactions were studied and a biological process annotation analysis was conducted. The present study suggested that ADARB1 was downregulated in LUSC; therefore, ADARB1 may serve as a specific biomarker and a potential therapeutic target for LUSC.

The purpose of this study was to identify a vital gene signature that has prognostic value for pancreatic cancer based on gene expression datasets from the Cancer Genome Atlas and Gene Expression Omnibus. A total of 34 genes were obtained by the univariate analysis, which were significantly associated with the overall survival of PC patients. After further analysis, Anillin (ANLN) and Histone H1c (HIST1H1C) were identified and considered to be the most significant prognostic genes among the 34 genes. A prognostic model based on these two genes was constructed, and successfully distinguished pancreatic cancer survival into high-risk and low-risk groups in the training set and testing set. Subsequently, independent predictive factors, including the age, margin condition and risk score, were then employed to construct the nomogram model. The area under curve for the nomogram model was 0.826 at 0.5 years and 0.726 at 1 year, and the C-index of the nomogram model was 0.664 higher than the others variables alone. These findings have indicated that high expression of ANLN and HIST1H1C predicted poor outcomes for patients with pancreatic cancer. The nomogram model based on the expression of two genes could be valuable for the guidance of clinical treatment.

IMPORTANCE: In observational studies, higher plasma 25-hydroxyvitamin D (25[OH]D) levels have been associated with improved survival in metastatic colorectal cancer (CRC). OBJECTIVE: To determine if high-dose vitamin D(3) added to standard chemotherapy improves outcomes in patients with metastatic CRC. DESIGN, SETTING, AND PARTICIPANTS: Double-blind phase 2 randomized clinical trial of 139 patients with advanced or metastatic CRC conducted at 11 US academic and community cancer centers from March 2012 through November 2016 (database lock: September 2018). INTERVENTIONS: mFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high-dose vitamin D(3) (n = 69) or standard-dose vitamin D(3) (n = 70) daily until disease progression, intolerable toxicity, or withdrawal of consent. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS) assessed by the log-rank test and a supportive Cox proportional hazards model. Testing was 1-sided. Secondary end points included tumor objective response rate (ORR), overall survival (OS), and change in plasma 25(OH)D level. RESULTS: Among 139 patients (mean age, 56 years; 60 [43%] women) who completed or discontinued chemotherapy and vitamin D(3) (median follow-up, 22.9 months), the median PFS for high-dose vitamin D(3) was 13.0 months (95% CI, 10.1 to 14.7; 49 PFS events) vs 11.0 months (95% CI, 9.5 to 14.0; 62 PFS events) for standard-dose vitamin D(3) (log-rank P = .07); multivariable hazard ratio for PFS or death was 0.64 (1-sided 95% CI, 0 to 0.90; P = .02). There were no significant differences between high-dose and standard-dose vitamin D(3) for tumor ORR (58% vs 63%, respectively; difference, −5% [95% CI, −20% to 100%], P = .27) or OS (median, 24.3 months vs 24.3 months; log-rank P = .43). The median 25(OH)D level at baseline for high-dose vitamin D(3) was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D(3) (difference, −2.6 ng/mL [95% CI, −6.6 to 1.4], P = .30); at first restaging, 32.0 ng/mL vs 18.7 ng/mL (difference, 12.8 ng/mL [95% CI, 9.0 to 16.6], P

There is increasing evidence that human complement factor H‑related protein 1 (CFHR1) plays a crucial role in the development of malignant diseases. However, few studies have identified the roles of CFHR1 in the occurrence and prognosis of lung adenocarcinoma (LADC). In the present study, comprehensive bioinformatic analyses of data obtained from the Oncomine platform, UALCAN and Gene Expression Profiling Interactive Analysis (GEPIA) demonstrated that CFHR1 expression is significantly reduced in both LADC tissues and cancer cells. The patients presenting with downregulation of CFHR1 had significantly lower overall survival (OS) and post progression survival (PPS) times. Through analysis of the datasets from Gene Expression Omnibus database, we found that the compound actinomycin D promoted CFHR1 expression, further displaying the cytotoxic effect in the LADC cell line A549. In addition, the expression level of CFHR1 in the cisplatin‑resistant LADC cell line CDDP‑R (derived from H460) was also significantly reduced. Our research demonstrated that low levels of CFHR1 are specifically found in LADC samples, and CFHR1 could serve as a potential therapeutic target for this subset of lung cancers. Determination of the detailed roles of CFHR1 in LADC biology could provide insightful information for further investigations.

Neurotrophic receptor tyrosine kinase 2 (NTRK2) is a member of the tropomyosin receptor kinase family associated with the tumor development. However, the detailed function of NTRK2 in lung cancer, especially in lung adenocarcinoma (LUAD), is still not fully understood. Here, we investigated the effects of NTRK2 on LUAD biology. Through analyzing bioinformatics data derived from several databases, such as Oncomine, Gene Expression Profiling Interactive Analysis and UALCAN, we found that NTRK2 expression was significantly decreased in LUAD tissues. Clinical data acquired from Wanderer database, which is linked to The Cancer Genome Atlas database, demonstrated that the expression and methylation site of NTRK2 were significantly related to the clinical characteristics and prognosis of LUAD. Furthermore, NTRK2 expression was increased remarkably after treatment with the protein kinase B (AKT) inhibitor MK2206 and the anticancer agent actinomycin D. Functional enrichment analysis of NTRK2-associated coexpression genes was further conducted. Together, our results suggested that downregulated NTRK2 might be used in the diagnostic and prognostic evaluation of LUAD patients, or as a potential therapeutic target for the treatment of LUAD.