Kaplan-Meier Plotter Database Research Articles

Adhesin Component Member STAG2 Enhances Cisplatin Tolerance in Colorectal Cancer Cells through the Epithelial-Mesenchymal Transition Pathway.

Platinum-based compounds are commonly used as an initial treatment for colorectal cancer (CRC). However, the development of drug resistance in patients with CRC necessitates the administration of high drug concentrations during clinical treatment, thereby augmenting the toxicity of platinum-based compounds and increasing the mortality rate. STAG2 is a significantly associated drug-resistance gene in many cancers, but it has not been studied in colorectal cancer. Therefore, the present study aimed to investigate the role and drug sensitivity of the cisplatin-resistant gene STAG2. The effects of STAG2 on drug resistance and survival rates of patients with CRC were examined using the Genomics of Drug Sensitivity in Cancer (GDSC) and Kaplan-Meier (KM) plotter databases. Subsequently, a sh-STAG2-HT-29 cell line was generated using a knockdown test of STAG2, and the half-maximal inhibitory concentration (IC50) of the two cell lines was determined using a cell viability test. We then used various techniques, including the Cell Counting Kit-8 (CCK-8), plate cloning, 5-ethynyl-2'-deoxyuridine (EdU) fluorescence staining, flow cytometry for cell cycle detection, the scar assay, the Transwell invasion assay, and Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) fluorescence staining for apoptosis detection, to investigate the functionality of the four subgroups of cancer cell lines. Additionally, Western blotting (WB) was used to identify the potential pathways associated with the observed functional alterations. Finally, the phenotype, tumor weight, mouse weight, tumor volume, and tumor tissue structure of the developed tumors were assessed using the subcutaneous tumor formation method. Database analysis indicated that STAG2 plays a role in facilitating drug resistance among individuals with CRC. Furthermore, mutations in this gene lead to increased sensitivity to cisplatin, and its overexpression was associated with an unfavorable prognosis. Following the successful development of STAG2 knockdown cells, differences in IC50 concentrations were observed between HT-29 and sh-STAG2-HT-29 cells. A treatment concentration of 10 μM cisplatin was selected, and the proliferation, migration, and invasion capabilities of cancer cells decreased after STAG2 knockdown. Additionally, the sensitivity of the cells to cisplatin therapy was increased, which was potentially mediated by the epithelial-mesenchymal transition (EMT) pathway. In mice, the tumorigenic potential of HT-29 cells was reduced by STAG2 knockdown, accompanied by a decrease in resistance to cisplatin therapy. STAG2 acts as a proto-oncogene in CRC, and its resistance to cisplatin therapy is more prominent. This study confirmed the role of STAG2 in CRC and provided a theoretical basis for the further development of STAG2 as an auxiliary criterion for determining dosage when patients are treated with platinum drugs.

Comprehensive analysis of the prognostic value of glutathione S-transferases Mu family members in breast cancer.

Breast cancer (BC) remains a significant public health concern globally, with a high number of reported cases and a substantial number of deaths every year. Accumulating reactive oxygen species (ROS) and oxidative stress are related to BC and the Glutathione S-transferases Mu (GSTM) family is one of the most important enzymatic detoxifiers associated with many cancers. In this study, UALCAN, Kaplan-Meier plotter, bc-GenExMiner, cBioPortal, STRING, Enrichr, and TIMER databases were employed to carry out a comprehensive bioinformatic analysis and provide new insight into the prognostic value of GSTMs in BC. GSTM2-5 genes in mRNA and protein levels were found to be expressed at lower levels in breast tumors compared to normal tissues, and reduction in mRNA levels is linked to shorter overall survival (OS) and relapse-free survival (RFS). The lower mRNA levels of GSTMs were strongly associated with the worse Scarff-Bloom-Richardson (SBR) grades (p < 0.0001). The mRNA levels of all five GSTMs were substantially higher in estrogen receptor (ER)-positive and progesterone receptor (PR)-positive compared to ER-negative and PR-negative BC patients. As well, when nodal status was compared, GSTM1, GSTM3, and GSTM5 were significantly higher in nodal-positive BC patients (p < .01). Furthermore, GSTM4 had the most gene alteration (4%) among other family members, and GSTM5 showed the strongest correlation with CD4+ T cells (Cor= .234, p = 2.22e-13). In conclusion, our results suggest that GSTM family members may be helpful as biomarkers for prognosis and as therapeutic targets in BC.

FTO is Associated with Patient Prognosis and Immune Infiltrates in Gastric Cancer and Regulates TGF-β Expression.

This study aimed to examine the associations of FTO expression with prognosis, tumor microenvironment (TME), immune cell infiltration, immune checkpoint genes, and relevant signaling pathways in GC. Furthermore, the relationship between FTO and TGF-β was studied in GC. The mRNA expression and clinical survival data of GC samples were obtained from The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD). TIMER2, TNM plot, and GEPIA database were used to analyze FTO expression. The associations of FTO with prognosis and clinicopathologic features were assessed using the Kaplan-Meier plotter and UALCAN database, respectively. The R software was employed to analyze its related signaling pathways and the associations with TME, immune cell infiltration, and immune checkpoint genes. GEPIA and ENCORI were used to examine the association of FTO with TGF-β expression. The SRAMP website was utilized to predict m6A modification of TGF-β. IHC, Western blot, and qPCR were used to analyze the expression levels of FTO and TGF-β in clinical gastric cancer tissue samples or gastric cancer cell lines. In addition, a m6A RNA methylation assay kit was used to determine m6A levels in gastric cancer cells. FTO mRNA and protein levels were significantly elevated in GC compared to normal gastric tissues. Kaplan-Meier survival analysis suggested that upregulated FTO was associated with a worse prognosis in GC. Upregulated FTO was markedly correlated with differentiation degree, lymph node metastasis, and clinical TNM stage. GO and KEGG pathway analyses revealed that FTO-associated molecules were enriched in neuroactive ligand-receptor interaction, calcium signaling, PI3k-Akt signaling, cAMP signaling pathways, and TGF-β signaling pathways, among others. The TME score was remarkably higher in the high-FTO group than in the low-FTO group. Furthermore, FTO expression had positive correlations with different types of immune cells and immune checkpoint genes. Moreover, FTO may regulate TGF-β in an m6A RNA modification manner in GC. FTO may become an independent predictive prognostic biomarker correlating with TME, immune cell infiltration, and immune checkpoint genes in gastric cancer and might influence GC progression by regulating TGF-β expression.

ANGPTL3 diminishes the resistance of ovarian cancer to paclitaxel by blocking the PI3K-AKT-mTOR signaling pathway

Angiopoietin-like protein 3 (ANGPTL3) is key in ovarian cancer (OC) cell growth and metastasis, notably by enhancing natural killer cells' capacity for inducing cell toxicity and apoptosis. However, its role in influencing chemotherapy resistance in OC remains ambiguous. In this study, we discovered a correlation between reduced ANGPTL3 levels and a less favorable outcome in OC patients using the Kaplan-Meier Plotter database. Lower levels of ANGPTL3 were detected in paclitaxel (PTX)-resistant OC tissues and cell lines via western blotting and immunohistochemistry. To investigate ANGPTL3's effects, we established SKOV3/PTX and 2780/PTX as PTX-resistant OC cell lines by incrementally increasing PTX exposure and then transfecting them with overexpress ANGPTL3 (OE-ANGPTL3) lentivirus. We conducted various assays such as CCK-8, colony formation, Edu staining, flow cytometry, and transwell to investigate the impact of ANGPTL3 on PTX resistance. Additionally, this effect was examined in a mouse subcutaneous xenograft model. Both in vitro and in vivo experiments demonstrated that ANGPTL3 overexpression mitigated PTX resistance in OC cells by inactivating the PI3K-AKT-mTOR pathway. In summary, our research reveals that ANGPTL3 enhances PTX sensitivity in OC by downregulating the PI3K-AKT-mTOR pathway. The study of this study suggest that ANGPTL3 could serve as a valuable therapeutic target for OC, signifying its clinical relevance in OC management.

Abstract PO5-02-10: Favorable effect of HER2-low expression on prognosis for breast cancers after neoadjuvant chemotherapy

Abstract [Background] The clinicopathological characteristics, pathological complete response and survival outcomes of HER2-low, HER2-zero and HER2-positive breast cancers are yet to be elucidated in Chinese patients especially those administered neoadjuvant chemotherapy. [Methods] We retrospectively identified 259 patients with different HER2 statuses (zero, low and positive) who underwent surgery as planned after neoadjuvant chemotherapy from a prospectively maintained institutional cohort database in Renji Hospital, School of Medicine, Shanghai Jiao Tong University between 2014 and 2019. Overall survival (OS) denoted the time from surgery to death, irrespective of cause. Locoregional relapse-free survival (LRFS) was estimated from surgery to first occurrence of locoregional, ipsilateral relapse, or death, irrespective of cause. We defined pathologic complete response (pCR) as ypT0 ypN0 (absence of cancer in the breast and axillary nodes). The definition of ypT0/is ypN0 (absence of invasive cancer in the breast and axillary nodes, irrespective of ductal carcinoma in situ) was evaluated as an additional endpoint. [Results] A total of 89 (34.36%), 66 (25.48%) and 104 (40.16%) HER2-low, HER2-zero and HER2-positive breast cancers were enrolled in this analysis, respectively. The median follow-up interval was 5.74 years. Hormone receptor(HR) expression was numerically more common in HER2-low breast cancers than the other two subgroups (83.15% in HER2-low vs 72.73% in HER2-zero vs 77.88% in HER2-positive, P &amp;gt;0.05). The level of Ki-67 index was significantly lower in the HER2-low tumors than that of HER2-zero tumors (P=0.023). HER2-positive tumors had the highest proportion of histological grade III (P=0.005). The HER2-low breast cancers showed significantly better OS (P=0.0056) and LRFS (P=0.002) than HER2-zero counterparts. Subgroup analysis revealed the similar benefit in LRFS (P=0.018) rather than OS (P=0.055) for patients with HR positive/HER2-negative tumors. When the HER2-positive tumors was combined together for comparison, the OS (P=0.016) and LRFS (P=0.0062) also significantly differed among patients with HER2-low, HER2-zero, and HER2-positive tumors. Additionally, the HR negative patients had analogous OS outcome to the entire population according to different HER2 status (P=0.041). Multivariable Cox-regression analysis and external validation in the TCGA database as well as Kaplan-Meier plotter database supported that HER2-low tumors and HER2-positive tumors treated with HER2-directed therapy may have similar survival outcomes, while HER2-zero peers may have the worst outcome compared with the above two groups. There were no remarkable differences in pCR rates between HER2-low and HER2-zero tumors after neoadjuvant chemotherapy (ypT0ypN0 and ypT0/isypN0, P=0.452 and P=0.777, respectively). HER2-positive tumors had a significantly higher pCR rate, especially compared to HER2-low tumors in the entire population (both P&amp;lt; 0.001) as well as in the HR positive subgroup (both P&amp;lt; 0.0001). The pCR status affected survival outcomes for breast cancers with different HER2 status. As for those without pCR, the HER2-low subgroup showed a remarkably better performance compared with HER2-zero patients in terms of OS (P=0.018) and LRFS (P=0.005), while little difference was found for patients who achieved pCR. [Conclusion] Our study demonstrated that HER2-low breast cancer may be a different entity from HER2-zero or HER2-positive tumors, which provide illuminating evidence in view of patients receiving neoadjuvant treatment. Citation Format: Yingying Zhao, Wenjin Yin, Xinru Chen, Jingsong Lu. Favorable effect of HER2-low expression on prognosis for breast cancers after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-02-10.

Comprehensive Analysis of the Expression, Prognosis, and Immune Infiltrates for Chromodomain-Helicase-DNA-Binding Proteins in Breast Tumor.

Several recent studies suggest that chromodomain-helicase -DNA-binding domains (CHDs) are linked with cancers. We explored the association between chromodomain-Helicase-DNA-binding domain proteins and breast cancer (BrCa) and introduced potential prognostic markers using various databases. We analyzed the expression of the CHD family and their prognostic value in BrCa by mining UALCAN, TIMER, and Kaplan-Meier plotter databases. The association of CHD expression and immune infiltrating abundance was studied via the TIMER database. In addition, microRNAs related to the CHD family were identified by using the MirTarBase online database. The present study indicated that compared to normal tissues, BrCa tissues showed increased mRNA levels of CHD3/4/7 but decreased CHD2/5/9 expression. Interestingly, We also found a positive correlation between CHD gene expression and the infiltration of macrophage, neutrophil, and dendritic cells in BrCa, except CHD3/5. The Kaplan-Meier Plotter analysis suggested that high expression levels of CHD1/2/3/4/6/8/9 were significantly related to shorter relapse-free survival (RFS), while higher mRNA expression of CHD1, CHD2, CHD8, and CHD9 was significantly associated with longer overall survival of BrCa patients. The miRNAs of hsa-miR-615-3p and hsa-let-7b-5p were identified as being more correlated with the CHD family. The altered expression of some CHD members was significantly related to clinical cancer outcomes, and CHD1/2/8/9 could serve as potential prognostic biomarkers to improve the survival of BrCa patients. However, to evaluate the studied CHD members in detail are needed further investigations including experimental validation.

Toxoplasma gondii suppresses proliferation and migration of breast cancer cells by regulating their transcriptome

BackgroundBreast cancer is the most common cancer in women worldwide. Toxoplasma gondii (T. gondii) has shown anticancer activity in breast cancer mouse models, and exerted beneficial effect on the survival of breast cancer patients, but the mechanism was unclear.MethodsThe effect of tachyzoites of T. gondii (RH and ME49 strains) on human breast cancer cells (MCF-7 and MDA-MB-231 cells) proliferation and migration was assessed using cell growth curve and wound healing assays. Dual RNA-seq was performed for T. gondii-infected and non-infected cells to determine the differentially expressed genes (DEGs). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein–Protein Interaction Networks analysis (PPI) were performed to explore the related signaling pathway and hub genes. Hub genes were validated using the Kaplan–Meier plotter database, and Pathogen Host Interaction (PHI-base) database. The results were verified by qRT-PCR.ResultsThe tachyzoites of T. gondii decreased the expression of Ki67 and increased the expression of E-cadherin, resulting in suppressing the proliferation and migration of infected human breast cancer cells. The inhibitory effect of T. gondii on breast cancer cells showed a significant dose–response relationship. Compared with the control group, 2321 genes were transcriptionally regulated in MCF-7 cells infected with T. gondii, while 169 genes were transcriptionally regulated in infected MDA-MB-231 cells. Among these genes, 698 genes in infected MCF-7 cells and 67 genes in infected MDA-MB-231 cells were validated by the publicly available database. GO and KEGG analyses suggested that several pathways were involved in anticancer function of T. gondii, such as ribosome, interleukin-17 signaling, coronavirus disease pathway, and breast cancer pathway. BRCA1, MYC and IL-6 were identified as the top three hub genes in infected-breast cancer cells based on the connectivity of PPI analysis. In addition, after interacting with breast cancer cells, the expression of ROP16 and ROP18 in T. gondii increased, while the expression of crt, TgIST, GRA15, GRA24 and MIC13 decreased.ConclusionsT. gondii transcriptionally regulates several signaling pathways by altering the hub genes such as BRCA1, MYC and IL-6, which can inhibit the breast tumor growth and migration, hinting at a potential therapeutic strategy.

Analysis of cancer-associated fibroblasts related genes identifies COL11A1 associated with lung adenocarcinoma prognosis

BackgroundThe treatment of lung adenocarcinoma is difficult due to the limited therapeutic options. Cancer-associated fibroblasts play an important role in the development of cancers. This study aimed to identify a promising molecular target associated with cancer-associated fibroblasts for the treatment of lung adenocarcinoma.MethodsThe Cancer Genome Atlas lung adenocarcinoma dataset was used to screen hub genes associated with cancer-associated fibroblasts via the EPIC algorithm and Weighted Gene Co-expression Network Analysis. Multiple databases were used together with our data to verify the differential expression and survival of COL11A1. Functional enrichment analysis and the single-cell TISCH database were used to elucidate the mechanisms underlying COL11A1 expression. The correlation between COL11A1 and immune checkpoint genes in human cancers was also evaluated.ResultsUsing the EPIC algorithm and Weighted Gene Co-expression Network Analysis, 13 hub genes associated with cancer-associated fibroblasts in lung adenocarcinoma were screened. Using the GEPIA database, Kaplan-Meier Plotter database, GSE72094, GSE75037, GSE32863, and our immunohistochemistry experiment data, we confirmed that COL11A1 overexpresses in lung adenocarcinoma and that high expression of COL11A1 is associated with a poor prognosis. COL11A1 has a genetic alteration frequency of 22% in patients with lung adenocarcinoma. COL11A1 is involved in the extracellular matrix activities of lung adenocarcinoma. Using the TISCH database, we found that COL11A1 is mainly expressed by cancer-associated fibroblasts in the tumor microenvironment rather than by lung adenocarcinoma cells. Finally, we found that COL11A1 is positively correlated with HAVCR2(TIM3), CD274 (PD-L1), CTLA4, and LAG3 in lung adenocarcinoma.ConclusionCOL11A1 may be expressed and secreted by cancer-associated fibroblasts, and a high expression of COL11A1 may result in T cell exhaustion in the tumor microenvironment of lung adenocarcinoma. COL11A1 may serve as an attractive biomarker to provide new insights into cancer therapeutics.

The prognostic and antitumor roles of key genes of ferroptosis in liver hepatocellular cancer and stomach adenocarcinoma.

Liver hepatocellular cancer (LIHC) and stomach adenocarcinoma (STAD) are common malignancies with high lethal ratios worldwide. Great progress has been achieved by using diverse therapeutic strategies; however, these diseases still have an unfavourable prognosis. Ferroptosis inducer drugs, unlike apoptosis-related drugs, can overcome the resistance to cancer therapy caused by traditional chemicals. However, the relationship between overall survival (OS) and ferroptosis-related genes, as well as the mechanisms involved, are largely unclear. The expression levels of AIFM2, GPX4, ACSL4, FTH1, NOS1, and PTGS2 in LIHC and STAD were obtained from UALCAN. The correlations of OS with these gene expression levels were obtained using the Kaplan-Meier Plotter database. The OS associated with genetic mutations of those genes compared to that of unchanged genes was analysed using the TIMER website. GO and KEGG enrichment analyses of ferroptosis-related genes and their coexpressed genes in LIHC and STAD were conducted using the STRING and DAVID databases. The relationship of PTGS2 and ACSL4 to immune cell infiltration was analysed using the TIMER website. The viability and GPX5 expression levels in LIHC cells treated with RSL3 and As2O3 were detected by MTT methods and western blotting, respectively. Our results showed that GPX4, FTH1 and AIFM2 were overexpressed in LIHC and STAD. High levels of GPX4, FTH1 and AIFM2 were prominently correlated with better prognosis in LIHC. However, GPX and FTH1 in STAD did not show significant correlations with OS. AIFM2 in STAD had the opposite trend with OS compared with that in LIHC. Moreover, a high mutation rate of these genes (35.74%) was also observed in LIHC patients, and genetic mutation of these genes was correlated with shorter OS. In contrast, the genetic mutation of these genes did not change OS in STAD. Enrichment analysis showed that the respiratory electron transport chain, cell chemotaxis and T-cell migration were related to ferroptosis. ASCL4 and PTGS2 coexpressed with cytokines associated with immune cell infiltration. Compared to RSL3 or As2O3 alone, As2O3 plus RSL3 significantly inhibited the growth of Huh7 cells. GPX4 was downregulated to an undetectable level when in combination with RSL3. Our results indicated that ferroptosis-related genes might play an important role in LIHC and STAD and might be risk factors for overall survival in LIHC and STAD.

Systematic analysis of expression and prognostic significance for MCM family in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSC) is a common malignant tumor in the world and has a poor prognosis. The family of minichromosome maintenance proteins (MCM) improves the stability of genome replication by inhibiting the rate of DNA replication in eukaryotic cells, thus, small changes in physiological MCM levels would increase the instability of gene replication and increase the incidence of tumor formation, most of which are significantly elevated in multiple cancers. However, the expression of different MCM families in HNSC and their prognostic value remain unclear. ONCOMINE and GEPIA databases were used to analyze the expression of MCMs in HNSC. The Kaplan-Meier plotter database was used to identify molecules with prognostic values. We collected 77 HNSC tissues and 50 normal tissues to validate the results of the bioinformatics analysis by immunohistochemical staining. The expression of MCM3, MCM5 and MCM6 in mRNA and protein levels were higher in HNSC. Moreover, the increased expression of MCM3, MCM5 and MCM6 in mRNA and protein levels predicted better prognosis of HNSC patients. Furthermore, multivariate analysis showed that high expressions of MCM3, MCM5 and MCM6 in protein level may be independent prognostic factors for HNSC patients. The results of this study indicated that MCM3, MCM5 and MCM6 play an important role in occurrence and development in HNSC and might be risk factors for the survival of HNSC patients.

HIF1A-dependent overexpression of MTFP1 promotes lung squamous cell carcinoma development by activating the glycolysis pathway

IntroductionMitochondrial fission process 1 (MTFP1) is an inner mitochondrial membrane (IMM) protein implicated in the development and progression of various tumors, particularly lung squamous cell carcinoma (LUSC). This study aims to provide a more theoretical basis for the treatment of LUSC. MethodsThrough bioinformatics analysis, MTFP1 was identified as a novel target gene of HIF1A. MTFP1 expression in LUSC was examined using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Proteomics Data Commons (PDC) databases. The Kaplan-Meier plotter (KM plotter) database was utilized to evaluate its correlation with patient survival. Western blot and chromatin immunoprecipitation (ChIP) assays were employed to confirm the regulatory relationship between MTFP1 and HIF1A. Additionally, cell proliferation, colony formation, and migration assays were conducted to investigate the mechanism by which MTFP1 enhances LUSC cell proliferation and metastasis. ResultsOur findings revealed that MTFP1 overexpression correlated with poor prognosis in LUSC patients(P < 0.05). Moreover, MTFP1 was closely associated with hypoxia and glycolysis in LUSC (R = 0.203; P < 0.001, R = 0.391; P < 0.001). HIF1A was identified as a positive regulator of MTFP1. Functional enrichment analysis demonstrated that MTFP1 played a role in controlling LUSC cell proliferation. Cell proliferation, colony formation, and migration assays indicated that MTFP1 promoted LUSC cell proliferation and metastasis by activating the glycolytic pathway (P < 0.05). ConclusionsThis study establishes MTFP1 as a novel HIF1A target gene that promotes LUSC growth by activating the glycolytic pathway. Investigating MTFP1 may contribute to the development of effective therapies for LUSC patients, particularly those lacking targeted oncogene therapies.

Abstract B028: Unraveling the role of matrix metalloproteinase 3 (mmp3) in cisplatin resistance of ovarian cancer

Abstract B028: Unraveling the role of matrix metalloproteinase 3 (mmp3) in cisplatin resistance of ovarian cancer

The Prognostic Value and Clinical Significance of lncRNA SNHG5 Expression in Patients with Multiple Malignancies: A Bioinformatic and Meta-Analysis.

Long non-coding RNA small nucleolar RNA host gene 5 (lncRNA SNHG5) has been identified as both a promising target for treatment and a predictor of prognosis in diverse types of cancer. The objective of this study was to assess whether lncRNA SNHG5 expression can be utilized as a prognostic biomarker for human cancer. To ensure a thorough search of the literature for relevant English studies published before July 2023, several databases were searched, including PubMed, Web of Science, ProQuest, Cochrane Library, and Google Scholar. The study evaluated the impact of lncRNA SNHG5 on the overall survival (OS) of cancer by calculating the pooled hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CIs). To further confirm the accuracy of the findings, the study investigated the expression profile and prognostic significance of lncRNA SNHG5 through the use of GenomicScape, OncoLnc, Kaplan-Meier plotter, and GEPIA databases. In this study, 995 patients were examined across a total of fourteen original studies. The findings indicated that there was a significant relationship between heightened lncRNA SNHG5 expression and reduced OS, as evidenced by both univariate and multivariate analyses (HR = 1.89; 95% CI, 1.44-2.49; p < 0.001; HR = 3.97; 95% CI, 1.80-8.73; p < 0.001, respectively). Pooled OR analysis showed a significant association between over-expression of lncRNA SNHG5 with advanced histological grade (OR = 0.28; 95% CI, 0.11-0.71; p = 0.007), present lymph node metastasis (LNM; OR = 4.28; 95% CI, 2.47-7.43; p < 0.001), and smoking history (OR = 0.27; 95% CI, 0.15-0.49; p < 0.001). Bioinformatic databases confirmed that elevated SNHG5 expression was significantly linked to poor prognosis in cancer patients, including colorectal cancer (CRC), acute myeloid leukemia (AML), and esophageal adenocarcinoma (ESAD), and a longer OS in patients with uterine corpus endometrial carcinoma (UCEC). These results suggest that lncRNA SNHG5 may serve as an adverse prognostic biomarker in several human cancers. Further investigations are needed to better understand the underlying mechanisms that link lncRNA SNHG5 to multiple malignancies.

Anti-cancer effects of Coix seed extract through KCTD9-mediated ubiquitination of TOP2A in lung adenocarcinoma

BackgroundCoix seed extract (CSE), a traditional Chinese medicine, has been reported as an adjunctive therapy in cancers. However, the molecular targets are largely unclear. The study is designed to unveil its function in lung adenocarcinoma (LUAD) and the possible molecular mechanism.MethodsThe HERB database was utilized to predict the molecular targets of the Coix seed, followed by prognostic value prediction in the Kaplan–Meier Plotter database. LUAD cells were infected with sh-KCTD9 after co-culture with CSE, and cell viability, growth, proliferation, and apoptosis were determined. The substrates of KCTD9 were predicted using a protein–protein interaction network and verified. The expression of PD-L1, the contents of TNF-α, IFN-γ, CXCL10, and CXCL9 in the co-culture system of LUAD cells and T cells and the proliferation of T cells were evaluated to study the immune escape of LUAD cells in response to CSE and sh-KCTD9. Lastly, tumor growth and immune escape were observed in tumor-bearing mice.ResultsCSE inhibited malignant behavior and immune escape of LUAD cells, and the reduction of KCTD9 reversed the inhibitory effect of CSE on malignant behavior and immune escape of LUAD cells. Knockdown of KCTD9 expression inhibited ubiquitination modification of TOP2A, and knockdown of TOP2A suppressed immune escape of LUAD cells in the presence of knockdown of KCTD9. CSE exerted anticancer effects in mice, but the reduction of KCTD9 partially compromised the anticancer effect of CSE.ConclusionCSE inhibits immune escape and malignant progression of LUAD through KCTD9-mediated ubiquitination modification of TOP2A.

Overexpression of BZW1 promotes invasion and metastasis of gastric cancer cells by regulating Wnt/β-catenin signaling and promoting epithelial-mesenchymal transition

To investigate the expression level of basic leucine zipper and W2 domain-containing protein 1 (BZW1) in gastric cancer, its impact on patient prognosis and the underlying mechanisms. TIMER, UALCAN and Kaplan-Meier Plotter databases were used for analyzing BZW1 expression level gastric cancer tissues and its correlation with tumor grade and stage and the patients' prognosis. We further analyzed BZW1 expressions, disease progression, and postoperative 5-year survival in 102 patients undergoing radical surgery for gastric cancer at our hospital between January, 2014 and December, 2016. Gastric cancer MGC803 cells were examined for changes in migration, invasion, and epithelial-mesenchymal transition (EMT) following lentivirus-mediated BZW1 overexpression or knockdown. The protein and mRNA expressions of BZW1 in gastric cancer tissues were 3.30 and 6.54 times of those in adjacent tissues, respectively (P < 0.01). BZW1 expression in gastric cancer tissues were positively correlated with peripheral blood CEA and CA199 levels (P < 0.01). A high BZW1 expression was an independent risk factor for 5-year survival of gastric cancer patients after radical surgery (P < 0.05, HR=2.070, 95%CI: 1.021-4.196). At the cut-off value of 3.61, BZW1 expression had a sensitivity of 75.56% and a specificity of 71.93% for predicting postoperative 5-year mortality (P < 0.01). In MGC803 cells, BZW1 overexpression obviously promoted cell migration and invasion (P < 0.05), enhanced cellular expressions of N-cadherin and vimentin (P < 0.05) and inhibited the expression of E-cadherin (P < 0.05). Enrichment analysis suggested the involvement of BZW1 in the Wnt/β-catenin signaling pathway. Western blotting confirmed that BZW1 overexpression promoted while BZW1 knockdown inhibited the expressions of Wnt3a, β-catenin and C-myc in MGC803 cells (P < 0.05). BZW1 is highly expressed in gastric cancer tissues to affect the patient prognosis possibly by activation the Wnt/β-catenin signaling pathway to promote EMT of gastric cancer cells.

High expression of COX6B2 in gastric cancer is associated with poor long-term prognosis and promotes cell proliferation and cell cycle progression by inhibiting p53 signaling

To investigate the effect of COX6B2 expression in gastric cancer tissues on the patients' long-term prognosis and its underlying mechanism. Based on the public databases and the medical records of patients, we analyzed the expression level of COX6B2 in gastric cancer and adjacent tissues and its influence on long-term prognosis of the patients. Enrichment analysis were used to predict the possible role of COX6B2 in gastric cancer. The effects of lentivirusmediated COX6B2 knockdown on biological behaviors of gastric cancer cells were examined using CCK-8 assay, flow cytometry, and Western blotting. TCGA database and the results of immunohistochemistry, Western blotting and realtime PCR all demonstrated a significantly higher expression of COX6B2 in gastric cancer tissues (P < 0.05). Kaplan-Meier plotter database and Kaplan-Meier curves showed that the patients with high COX6B2 expression had significantly shorter postoperative survival (P < 0.05). A high expression of COX6B2 in gastric cancer tissues was closely correlated with clinicopathologic stage, CEA and CA19-9 (P < 0.05). A high expression of COX6B2, CEA level≥5 μg/L and CA19-9 level≥37 kU/L were independent risk factors affecting postoperative 5-year survival rate of gastric cancer patients (P < 0.05), and COX6B2 expression level had a predictive value for long-term prognosis of the patients (P < 0.05). GO and KEGG enrichment analyses showed that COX6B2 was mainly involved in the regulation of cell cycle. In the in vitro cell experiment, COX6B2 overexpression significantly promoted gastric cancer cell proliferation, increased the percentage of G1/S phase cells and inhibited the cellular expressions of p53 and p21 (P < 0.05). s COX6B2 is highly expressed in gastric cancer and is closely correlated with a poor long-term prognosis of the patients possibly by promoting gastric cancer cell proliferation and regulating cell cycle.

CCDC71L as a novel prognostic marker and immunotherapy target via lipid metabolism in head and neck squamous cell carcinoma

BackgroundHead and neck squamous cell carcinoma (HNSCC) is the sixth most widespread cancer globally with high rate and poor prognosis. Coiled-coil domain containing 71 like (CCDC71L) exerts an important role in cellular lipid metabolic process. However, its function in HNSCC remains unclear. To this end, we examined the CCDC71L implications for prognosis and tumor microenvironment in HNSCC. Materials and methodsFirst, CCDC71L expression was explored through The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), the Gene Expression Profiling Interactive Analysis 2 (GEPIA2), Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Gene Expression Omnibus (GEO) databases. The clinicpathological information were obtained from the dataset of TCGA. The Kaplan–Meier Plotter databases and Cox model were performed for the determination of prognostic values of CCDC71L, including the overall survival (OS), progress free interval (PFI), recurrence-free survival (RFS) and disease specific survival (DSS). Then, the potential mechanism of CCDC71L in HNSCC development was elucidated by means of Gene set enrichment analysis (GSEA) and Metascape databases. Furthermore, the relevance of CCDC71L to immune cells infiltration and immune checkpoints was assessed. The correlations among CCDC71L expression, mutational landscape and genome heterogeneity [mutant-allele tumor heterogeneity (MATH) and tumor purity] were detected by the data in TCGA. ResultsCCDC71L expression was significantly upregulated in HNSCC, and positively associated with age, gender and N stage. Higher CCDC71L expression resulted in poor OS, RFS, DSS and PFI. Multivariate Cox regression analysis showed CCDC71L would be an independent prognostic marker in patients with HNSCC. Moreover, CCDC71L and the level of macrophage and neutrophil cells infiltration were significantly correlated in HNSCC. High expression of CCDC71L was related to immune checkpoint genes, oncogene mutations and genome heterogeneity markers. ConclusionThese results implied that CCDC71L plays vital roles in HNSCC progression, which could be used as a underlying biomarker for the diagnosis and prognosis of HNSCC. Meanwhile, CCDC71L participates in immune regulation, which has a potential value for the immunotherapy of HNSCC patients.

Periostin is associated with prognosis and immune cell infiltration in pancreatic adenocarcinoma based on integrated bioinformatics analysis.

Pancreatic cancer is one of the most aggressive human malignancies. Previous research has shown that periostin (POSTN) promotes pancreatic cancer cell proliferation, migration, and invasion. Further, POSTN is involved in tumor microenvironment remodeling during tumor progression. However, the relationship between POSTN expression, immune cell infiltration, and the efficacy of immunotherapy in pancreatic cancer is unclear. We conducted a comprehensive evaluation of POSTN differential expression, examining mRNA and protein levels. To gather data, we utilized various databases including gene expression profiling interactive analysis 2 (GEPIA2), gene expression omnibus (GEO), and the human protein atlas (HPA). To investigate the correlation between POSTN expression and clinical characteristics, we analyzed data from the Kaplan-Meier plotter database and clinical data sourced from the cancer genome atlas (TCGA). Furthermore, we performed gene ontology (GO) analysis, Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis, and gene set enrichment analysis (GSEA). Additionally, we explored the relationship between POSTN expression and immune cell infiltration, as well as the immunophenoscore (IPS), by leveraging the cancer immunome atlas (TCIA) database. Lastly, we examined the tumor mutational burden (TMB) in pancreatic cancer in relation to POSTN expression. When compared with healthy pancreatic tissues, pancreatic cancer tissues displayed significantly higher levels of POSTN, which was indicative of a worse prognosis. POSTN expression was closely associated with extracellular matrix (ECM) organization, ECM-receptor interaction, and focal adhesion by GO, KEGG pathway, and GSEA analyses. Higher expression of POSTN was associated with increased infiltration of M2 macrophages. Additionally, increased IPS was linked to lower POSTN expression. IPS scores for CTLA4, PD-1/PDL1, and CTLA4/PD-1/PDL1 immune checkpoint inhibitors were also higher in the POSTN-low expression group, suggesting that lower expression of POSTN is associated with a better outcome with checkpoint inhibitor treatment. POSTN is related to pancreatic cancer prognosis, and may influence immune cell infiltration. High expression of POSTN is predicted to correlate with lower sensitivity to immunotherapy with checkpoint inhibitors in pancreatic cancer.

Crocin enhances the sensitivity to paclitaxel in human breast cancer cells by reducing BIRC5 expression.

Paclitaxel (PTX) is one of the first-line chemotherapeutic agents for treating breast cancer. However, PTX resistance remains a major hurdle in breast cancer therapy. Crocin, the main chemical constituent of saffron, shows anti-cancer activity against various types of cancer. However, the effect of crocin on the resistance of PTX in breast cancer is still unknown. CCK-8 and TUNEL assays were employed to detect cell viability and apoptosis, respectively. The targets of crocin were predicted using HERB database and the targets associated with breast cancer were acquired using GEPIA database. The Venn diagram was utilized to identify the common targets between crocin and breast cancer. Baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) expression was detected by qRT-PCR and western blot analysis. The correlation between BIRC5 expression and survival was analyzed by Kaplan-Meier plotter and PrognoScan databases. Our data suggested that crocin aggravated PTX-induced decrease of viability and increase of apoptosis in MCF-7 and MCF-7/PTX cells. BIRC5 was identified as the target of crocin against breast cancer. Crocin inhibited BIRC5 expression in MCF-7 and MCF-7/PTX cells. BIRC5 is overexpressed in breast cancer tissues, as well as PTX-sensitive and PTX-resistant breast cancer cells. BIRC5 expression is related to the poor survival of patients with breast cancer. Depletion of BIRC5 strengthened PTX-induced viability reduction and promotion of apoptosis in MCF-7 and MCF-7/PTX cells. Moreover, BIRC5 overexpression reversed the inhibitory effect of crocin on PTX resistance in breast cancer cells. In conclusion, crocin enhanced the sensitivity of PTX in breast cancer cells partially through inhibiting BIRC5 expression.

TRIP13 Enhances Radioresistance of Lung Adenocarcinoma Cells through the Homologous Recombination Pathway

Radiation therapy is one of the most common treatments for non-small cell lung cancer (NSCLC). However, the insensitivity of some tumor cells to radiation is one of the major reasons for the poor efficacy of radiotherapy and the poor prognosis of patients, and exploring the underlying mechanisms behind radioresistance is the key to solving this clinical challenge. This study aimed to identify the molecules associated with radioresistance in lung adenocarcinoma (LUAD), identified thyroid hormone receptor interactor 13 (TRIP13) as the main target initially, and explored whether TRIP13 is related to radioresistance in LUAD and the specific mechanism, with the aim of providing theoretical basis and potential targets for the combination therapy of LUAD patients receiving radiotherapy in the clinic. Three datasets, GSE18842, GSE19188 and GSE33532, were selected from the Gene Expression Omnibus (GEO) database and screened for differentially expressed genes (|log FC|>1.5, P<0.05) in each of the three datasets using the R 4.1.3 software, and then Venn diagram was used to find out the differentially expressed genes common to the three datasets. The screened differential genes were then subjected to protein-protein interaction (PPI) analysis and module analysis with the help of STRING online tool and Cytoscape software, and survival prognosis analysis was performed for each gene with the help of Kaplan-Meier Plotter database, and the TRIP13 gene was identified as the main molecule for subsequent studies. Subsequently, the human LUAD cell line H292 was irradiated with multiple X-rays using a sub-lethal dose irradiation method to construct a radioresistant cell line, H292DR. The radioresistance of H292DR cells was verified using cell counting kit-8 (CCK-8) assay and clone formation assay. The expression levels of TRIP13 in H292 and H292DR cells were measured by Western blot. Small interfering RNA (siRNA) was used to silence the expression of TRIP13 in H292DR cells and Western blot assay was performed. The clone formation ability and migration ability of H292DR cells were observed after TRIP13 silencing, followed by the detection of changes in the expression levels of proteins closely related to homologous recombination, such as ataxia telangiectasia mutated (ATM) protein. Screening of multiple GEO datasets, validation of external datasets and survival analysis revealed that TRIP13 was highly expressed in LUAD and was associated with poor prognosis in LUAD patients who had received radiation therapy. And the results of gene set enrichment analysis (GSEA) of TRIP13 suggested that TRIP13 might be closely associated with LUAD radioresistance by promoting homologous recombination repair after radiation therapy. Experimentally, TRIP13 expression was found to be upregulated in H292DR, and silencing of TRIP13 was able to increase the sensitivity of H292DR cells to radiation. TRIP13 is associated with poor prognosis in LUAD patients treated with radiation, possibly by promoting a homologous recombination repair pathway to mediate resistance of LUAD cells to radiation.