Search

Fangteng Liu,1,2 Hengyu Wu1 1Department of Breast Surgery, The Third Hospital of Nanchang, Nanchang, Jiangxi, 330009, People’s Republic of China; 2Faculty of Medicine, University of Munich, Munich, 80336, GermanyCorrespondence: Hengyu Wu Tel +86-15270280590Email why_wuhengyu0590@163.comBackground: Lung adenocarcinoma (LUAD) is the most common type of lung cancer with a high incidence and increased mortality. CC chemokine receptors were participating in the modulation of the tumor microenvironment and involved in carcinogenesis and tumor development. However, the potential mechanistic values of CC chemokine receptors as clinical biomarkers and therapeutic targets in LUAD have not been fully clarified.Methodology: ONCOMINE, UALCAN, GEPIA, Kaplan–Meier Plotter, SurvExpress, MethSurv, SurvivalMeth, cBioPortal, String, GeneMANIA, DAVID, Metascape, TRRUST, LinkedOmics, and Timer were applied in this work.Results: The transcriptional levels of CCR1/10 in LUAD tissues were significantly reduced while the transcriptional levels of CCR3/6/7/8 were significantly elevated, and the expression of CCR1 was the highest in LUAD among these CC chemokine receptors. A significant correlation was found between the expression of CCR2/4/6/7 and the pathological stage of LUAD patients. There were significant associations between CCR2/3/4/5/6/10 expression levels and OS in LUAD, and LUAD patients with high transcriptional levels of CCR3/4 had inferior first-progression survival. In addition, the prognostic values of CC chemokine receptors signature in LUAD were explored in three independent cohorts, the high-risk group displayed unfavorable OS compared with the low-risk group, and the LUAD cases in the high-risk group also suffered inferior RFS than that in the low-risk group. And for the prognostic value of the DNA methylation of CC chemokine receptors, we found 1 CpG of CCR2, 2 CpGs of CCR3, 1 CpG of CCR4, 3 CpGs of CCR6, 3 CpGs of CCR7, 1 CpG of CCR8, and 3 CpGs of CCR9 were significantly associated with prognosis in LUAD patients. However, the DNA methylation signature analysis showed there was no statistically significant association between the high- and low-risk group. For potential mechanism, the neighbor gene networks, interaction analyses, functional enrichment analyses of CC chemokine receptors in LUAD were performed, the transcription factor targets, kinase targets, and miRNA targets of CC chemokine receptors were also identified in LUAD. We also found significant correlations among CC chemokine receptors expression and the infiltration of immune cells, the tumor infiltration levels among LUAD with different somatic copy number alterations of these chemokine receptors were also assessed. Moreover, the Cox proportional hazard model showed that CCR1/2/10, B_cell, CD4_Tcell were significantly related to the clinical outcome of LUAD patients.Conclusion: CC chemokine receptors might serve as immunotherapeutic targets and prognostic biomarkers in LUAD.Keywords: CC chemokine receptors, lung adenocarcinoma, prognostic biomarker, immunotherapeutic target, bioinformatics analysis

Fangteng Liu,1,2 Hengyu Wu1 1Department of Breast Surgery, The Third Hospital of Nanchang, Nanchang 330009, Jiangxi, People’s Republic of China; 2Faculty of Medicine, University of Munich, Munich 80336, GermanyCorrespondence: Hengyu Wu Tel +86-15270280590Email why_wuhengyu0590@163.comBackground: Janus kinases (JAKs) are a family of non-receptor tyrosine kinases involved in multiple malignancies. However, clinical values of JAKs as prognostic markers and potential mechanism as molecular targets in breast invasive carcinoma (BC) are not completely clarified.Methodology: TIMER, UALCAN and GEPIA were used to assess the expression and methylation levels of JAKs in BC. Kaplan–Meier Plotter, bc-GenExMiner, SurvExpress, TRGAted, MethSurv, and SurvivalMeth were used to assess the multilevel prognostic significance of JAKs in breast cancer patients. And cBioPortal, TIMER, STRING, GeneMANIA, NetworkAnalysis, LinkedOmics, DAVID 6.8, and Metascape were applied for multilayer networks and functional enrichment analyses. Correlations between immune cell infiltrates/their gene markers and JAKs were evaluated by TIMER.Results: We first explored the expression and methylation level of JAKs in breast cancer and found significantly reduced JAK1 and JAK2 expression at mRNA and protein levels, significantly higher JAK3 protein expression, and significantly increased TYK2 expression at mRNA level but decreased at protein level. In addition, hypermethylation of JAK3 and TYK2 and hypomethylation of JAK1 were found in tumor samples. In terms of prognostic values of JAKs in BC patients, low transcriptional levels of JAK1, JAK2, JAK3, and TYK2 indicated worse OS/DMFS/PPS/RFS/DFS, inferior DFS, worse RFS, and shorter OS/DMFS/RFS, respectively. The mRNA signature analysis showed that high-risk group had unfavorable OS/RFS/MFS. Low JAK2 protein level indicated unfavorable DSS/PFS in BC patients. Five CpGs of JAK1, four CpGs of JAK2, 20 CpGs of JAK3, and 13 CpGs of TYK2 were significantly associated with prognosis in BC patients. The DNA methylation signature analysis also suggested worse prognosis in the high-risk group. For potential biological roles of JAKs, interaction analyses, functional enrichment analyses for biological process, cellular component, molecular function, and KEGG pathway analyses of JAKs and their neighbor genes in BC were conducted. Kinase targets, gene–miRNA interactions, and transcription factor–gene interactions of JAKs were also identified. Furthermore, JAKs were found to be significantly related to immune infiltrates as well as the expression levels of multiple immune markers in BC.Conclusion: JAKs showed multilevel prognostic value and important biological roles in BC. They might serve as promising prognostic markers and possible targets in breast cancer.Keywords: Janus kinase, breast cancer, prognosis, immunity, biomarker, target

Background GKN2, as a secretory protein, is involved in the inflammation and immune modulation, and its aberrant expression is closely related to tumorigenesis. However, integrated studies on the value of GKN2 as a promising clinical biomarker and immunotherapy target in multiple tumors are still rare. Methodology Multiple online databases, including ONCOMINE, SEGreg, UALCAN, GEPIA, K-M Plotter, cBioPortal, MethSurv, CellMarker, and Timer, were applied to assess the clinical significance of GKN2 and its correlation with tumor-infiltrating immune cells in differentially expressed cancers. Results Several databases confirmed that GKN2 was significantly down-regulated in lung and gastric cancers compared that in normal samples. GKN2 was altered in 3%, 5%, and 4% of the LUAD, LUSC, and STAD samples, respectively. Hyper-methylation of GKN2 was found in LUAD and LUSC samples. For the clinical values of GKN2, we found that the low transcription level of GKN2 was associated with worse OS in lung cancer, and inferior FP and PPS in gastric cancer, and the relationships between GKN2 expression and clinical variables regarding OS/FP/PPS in lung and gastric cancers were assessed. Moreover, the prognostic value of the DNA methylation patterns of GKN2 in LUAD, LUSC, and STAD was identified. Furthermore, GKN2 expression was found to be significantly correlated with the infiltrating multiple tumor immune cells, and statistically significant differences in the correlation between GKN2 expression and multiple markers of neutrophils and macrophage polarization were observed in LUAD, LUSC, and STAD. Conclusion The study revealed the prognosis and risk factors for deterioration in patients with low expression of GKN2. GKN2 may be used as a valuable prognostic biomarker and therapeutic target in lung and gastric cancers.

Objective. Systemic inflammation response index (SIRI) is a new inflammation-based evaluation system that has been reported for predicting survival in multiple tumors, but the prognostic significance of SIRI in cancers has not been evinced. Methods. Eligible studies updated on December 31, 2019, were selected according to inclusion criteria, the literature searching was performed in PubMed, Web of Science, Google Scholar, and Cochrane. Hazard ratios (HRs), and 95% confidence intervals (CIs) were extracted and pooled by using Stata/SE 14.1. Results. 11 publications involving 19 cohort studies with a total of 5,605 subjects were included. Meta-analysis results evinced that high SIRI was associated with worse OS (HR=2.30, 95% CI: 1.87-2.83, p≤0.001), poor CSS/DSS (HR=2.83, 95% CI: 1.98-4.04, p≤0.001), and inferior MFS/DFS/PFS/RFS/TTP (HR=1.88, 95% CI: 1.65-2.15, p≤0.001). The association of SIRI with OS was not significantly affected when stratified by diverse confounding factors. It was suggested that tumor patients with high pretreatment SIRI levels would suffer from adverse outcomes. Conclusion. High SIRI is associated with unfavorable clinical outcomes in human malignancies; pretreatment SIRI level might be a useful and promising predictive indicator of prognosis in cancers.

Background/Aims. Calpain small subunit 1 (Capn4) is implicated in tumorigenesis and plays a key role in multiple tumors. This study aimed to fully illustrate the prognostic value of Capn4 protein in cancer patients. Methods. A systematic search was conducted against several online databases. Hazard ratios (HRs) or odds ratio (ORs) were used to investigate the relationship between Capn4 protein expression and prognosis as well as clinical parameters in cancer survivors. Results. Eleven studies involving 1775 patients were identified. Overall, the results showed that Capn4 protein was associated with poor prognosis of overall survival (OS) (HR=1.74; 95% CI:1.47-2.01; p p p=0.01), venous invasion (OR=2.34; 95% CI: 1.07-5.13; p=0.03), lymph node metastasis (2.74; 95% CI: 1.98-3.79; p p p p=0.47) and tumor differentiation (OR=1.16; 95% CI: 0.90-2.23; p=0.25). Conclusions. Expression of Capn4 protein is associated with cancer survival and clinicopathologic characteristics in patients.

Recent studies have reported that the lncRNA-LET was down-regulated in several cancers.The current meta-analysis aims to determine whether lncRNA-LET can be used as a potential biomarker for metastasis and prognosis.We collected all relevant papers by searching multiple electronic databases(Pubmed,EMBASE,Google Scholar,CNKI,Wanfang database) and explored the association between the expression levels of lncRNA-LETand lymph node metastasis (LNM),distant metastasis (DM) and overall survival (OS).A total of 383 patients from four studies were finally included.The meta-analysis results showed that LNM occurred more frequently in patients with low lncRNA-LET expression group than in patients with high lncRNA-LET expression group(OR=4.56,95%CI:2.92-7.12,p0.00001),and a similar result was observed between lncRNA-LET expression and DM,the OR was 4.77(95%CI:2.29-9.94, p0.0001).Additionally,we found that patient with low lncRNA-LET expression had a poorer OS than those high lncRNA-LET expression (HR=2.39,95 %CI:1.57-3.21,p = 0.000).LncRNA-LETmay serve as a common molecular marker for metastasis and prognosis in human cancers.