scholarly journals Quiescin Sulfhydryl Oxidase 2 Overexpression Predicts Poor Prognosis and Tumor Progression in Patients With Colorectal Cancer: A Study Based on Data Mining and Clinical Verification

Author(s):  
Tao Jiang ◽  
Li Zheng ◽  
Xia Li ◽  
Jia Liu ◽  
Hu Song ◽  
...  

Background: As a member of the atypical thiol oxidase family, quiescin sulfhydryl oxidase 2 (QSOX2) has been reported to play an important role in several biological processes, but the expression and function of QSOX2 in colorectal cancer (CRC) remains elusive.Methods: The difference of QSOX2 expression, and its relationship with clinicopathological features and prognosis in CRC, was analyzed by bioinformatic analysis and validated by clinical CRC specimen cohort. The functional characterization of QSOX2 was detected via in vitro and vivo experiments in CRC cell lines, while the potential signaling pathways were predicted by Gene Set Enrichment Analysis (GSEA).Results: Our data based on bioinformatical analysis and clinical validation demonstrated that the expression of QSOX2 in CRC tissues was significantly upregulated. Additionally, the chi-square test, logistic regression analysis, and Fisher’s exact test showed that QSOX2 overexpression was significantly correlated with advanced clinicopathological parameters, such as pathological stage and lymph node metastasis. The Kaplan–Meier curves and univariate Cox regression model showed that QSOX2 overexpression predicts poor overall survival (OS) and disease-free survival (DFS) in CRC patients. More importantly, multivariate Cox regression model showed that QSOX2 overexpression could serve as an independent factor for CRC patients. In vitro and vivo data showed that the proliferation and metastasis ability of CRC cells were suppressed on condition of QSOX2 inhibition. In addition, GSEA showed that the QSOX2 high expression phenotype has enriched multiple potential cancer-related signaling pathways.Conclusion: QSOX2 overexpression is strongly associated with malignant progression and poor oncological outcomes in CRC. QSOX2 might act as a novel biomarker for prognosis prediction and a new target for biotherapy in CRC.

Author(s):  
Yuhui Wu ◽  
Xiaojing Liang ◽  
Junjie Ni ◽  
Rongjie Zhao ◽  
Shengpeng Shao ◽  
...  

Background: An increasing number of studies have shown that Isthmin 1 (ISM1), a secreted protein, is important in tumorigenesis and invasion, including in colorectal cancer (CRC). However, the mechanisms are still unclear. This study aims to explore the function and prognosis capacity of ISM1 in CRC.Methods: We investigated the expression of ISM1 in 18 CRC tissues vs. adjacent normal tissues from GSE50760, 473 CRC tissues vs. 41 normal tissues from The Cancer Genome Atlas (TCGA), and across gastrointestinal cancer types. Differences were further confirmed in CRC tissues via quantitative real-time polymerase chain reaction (qRT-PCR). Then, we analyzed correlations between clinicopathologic features and ISM1 expression, including prognostic prediction value, using the Kaplan–Meier method and multivariate Cox regression. Gene set enrichment analysis (GSEA) was performed to identify ISM1-related pathways. In vitro experiments were performed to verify the role of ISM1 in epithelial-mesenchymal transition (EMT) and CRC progression.Results: Multiple datasets showed that ISM1 is upregulated in CRC tissues, which was validated. Patients with higher ISM1 expression had shorter overall survival (OS), and ISM1 expression served as an independent prognostic factor. Enrichment analysis showed that ISM1 upregulation was positively correlated with cancer-related pathways, such as EMT, hypoxia, and the Notch and KRAS signaling pathways. We were exclusively interested in the connection between ISM1 and EMT because 71% of genes in this pathway were significantly positively co-expressed with ISM1, which may account for why patients with higher ISM1 expression are prone to regional lymph node involvement and progression to advanced stages. In addition, we found that ISM1 was positively correlated with multiple immunosuppressive pathways such as IL2/STAT5, TNF-α/NF-κB, and TGF-β, and immune checkpoints, including PD-L1, PD-1, CTLA-4, and LAG3, which may account for upregulation of ISM1 in immunotherapy-resistant patients. Notably, through in vitro experiments, we found that ISM1 promoted EMT and colon cancer cell migration and proliferation.Conclusion: ISM1 is critical for CRC development and progression, which enhances our understanding of the low response rate of CRC to immunotherapy via immunosuppressive signaling pathways.


2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Jinpeng Yuan ◽  
Aosi Xie ◽  
Qiangjian Cao ◽  
Xinxin Li ◽  
Juntian Chen

Background. Inhibin subunit beta B (INHBB) is a protein-coding gene that participated in the synthesis of the transforming growth factor-β (TGF-β) family members. The study is aimed at exploring the clinical significance of INHBB in patients with colorectal cancer (CRC) by bioinformatics analysis. Methods. Real-time PCR and analyses of Oncomine, Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) databases were utilized to evaluate the INHBB gene transcription level of colorectal cancer (CRC) tissue. We evaluated the INHBB methylation level and the relationship between expression and methylation levels of CpG islands in CRC tissue. The corresponding clinical data were obtained to further explore the association of INHBB with clinical and survival features. In addition, Gene Set Enrichment Analysis (GSEA) was performed to explore the gene ontology and signaling pathways of INHBB involved. Results. INHBB expression was elevated in CRC tissue. Although the promoter of INHBB was hypermethylated in CRC, methylation did not ultimately correlate with the expression of INHBB. Overexpression of INHBB was significantly and positively associated with invasion depth, distant metastasis, and TNM stage. Cox regression analyses and Kaplan-Meier survival analysis indicated that high expression of INHBB was correlated with worse overall survival (OS) and disease-free survival (DFS). GSEA showed that INHBB was closely correlated with 5 cancer-promoting signaling pathways including the Hedgehog signaling pathway, ECM receptor interaction, TGF-β signaling pathway, focal adhesion, and pathway in cancer. INHBB expression significantly promoted macrophage infiltration and inhibited memory T cell, mast cell, and dendritic cell infiltration. INHBB expression was positively correlated with stromal and immune scores of CRC samples. Conclusion. INHBB might be a potential prognostic biomarker and a novel therapeutic target for CRC.


2019 ◽  
Vol 12 ◽  
pp. 175628481986215 ◽  
Author(s):  
Yuqiang Li ◽  
Lilan Zhao ◽  
Cenap Güngör ◽  
Fengbo Tan ◽  
Zhongyi Zhou ◽  
...  

Background: There is no conclusion about the most important contributor to the upswing of locally advanced colorectal cancer (LACRC) survival. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) database was extracted to identify colorectal adenocarcinoma cancer patients at stage II and III diagnosed in the two periods 1989–1990 and 2009–2010. The statistical methods included Pearson’s chi-squared test, log-rank test, Cox regression model and propensity score matching. Results: The Cox regression model showed that hazard ratio (HR) of non-surgery dropped from 11.529 to 3.469 in right colon cancer (RCC), 5.214 to 2.652 in left colon cancer (LCC) and 3.275 to 3.269 in rectal cancer (RC) from 1989–1990 to 2009–2010. The 95% confidence intervals (CIs) for surgical resection in 2009–2010 were narrower than those in 1989–1990. HR became greater in LACRC without chemotherapy (from 1.337 to 1.779 in RCC, 1.269 to 2.017 in LCC, 1.317 to 1.811 in RC). There was no overlapping about the 95% CI of chemotherapy between the two groups. The progress of surgery was not linked to the improvement of overall survival (OS) of RCC ( p = 0.303) and RC ( p = 0.660). Chemotherapy had a significant association with OS of all colorectal cancer (CRC) patients ( p = 0.017 in RCC; p = 0.006 in LCC; p = 0.001 in RC). Conclusions: Advancements in chemotherapy regimen were the main contributor to the upswing of CRC survival. The improvements in surgery had a limited effect on improvements in CRC survival.


PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6350 ◽  
Author(s):  
Jianfei Fu ◽  
Hang Ruan ◽  
Hongjuan Zheng ◽  
Cheng Cai ◽  
Shishi Zhou ◽  
...  

Objective This study was performed to identify a reasonable cutoff age for defining older patients with colorectal cancer (CRC) and to examine whether old age was related with increased colorectal cancer-specific death (CSD) and poor colorectal cancer-specific survival (CSS). Methods A total of 76,858 eligible patients from the surveillance, epidemiology, and end results (SEER) database were included in this study. The Cox proportional hazard regression model and the Chow test were used to determine a suitable cutoff age for defining the older group. Furthermore, a propensity score matching analysis was performed to adjust for heterogeneity between groups. A competing risk regression model was used to explore the impact of age on CSD and non-colorectal cancer-specific death (non-CSD). Kaplan–Meier survival curves were plotted to compare CSS between groups. Also, a Cox regression model was used to validate the results. External validation was performed on data from 1998 to 2003 retrieved from the SEER database. Results Based on a cutoff age of 70 years, the examined cohort of patients was classified into a younger group (n = 51,915, <70 years of old) and an older group (n = 24,943, ≥70 years of old). Compared with younger patients, older patients were more likely to have fewer lymph nodes sampled and were less likely to receive chemotherapy and radiotherapy. When adjusted for other covariates, age-dependent differences of 5-year CSD and 5-year non-CSD were significant in the younger and older groups (15.84% and 22.42%, P < 0.001; 5.21% and 14.21%, P < 0.001). Also an age of ≥70 years remained associated with worse CSS comparing with younger group (subdistribution hazard ratio, 1.51 95% confidence interval (CI) [1.45–1.57], P < 0.001). The Cox regression model as a sensitivity analysis had a similar result. External validation also supported an age of 70 years as a suitable cutoff, and this older group was associated with having reduced CSS and increased CSD. Conclusions A total of 70 is a suitable cutoff age to define those considered as having elderly CRC. Elderly CRC was associated with not only increased non-CSD but also with increased CSD. Further research is needed to provide evidence of whether cases of elderly CRC should receive stronger treatment if possible.


2021 ◽  
Vol 20 ◽  
pp. 153303382110396
Author(s):  
Xiaoshan Wang ◽  
Ru Jia ◽  
Ke Chen ◽  
Jingjing Wang ◽  
Kai Jiang ◽  
...  

Retinoid-related orphan receptor alpha (RORα) and nuclear receptor subfamily 1 group D member 1 (REV-ERBα) play critical roles in many human cancers. Whether RORα and REV-ERBα expression levels are associated with clinical characteristics are poorly understood, and they may be independent predictors of overall survival (OS) and progression-free survival (PFS) in gastric cancer (GC). This study aimed to investigate the correlation of RORα and REV-ERBα expression levels with clinicopathological parameters, OS, and PFS in GC. Immunohistochemistry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were employed to assess the expression levels of RORα and REV-ERBα, which were downregulated in GC tissues compared with normal gastric tissues ( P < .001; P < .001) and were associated with several clinicopathological parameters, including histological grade ( P = .032; P < .001), preoperative carcinoembryonic antigen (CEA) levels ( P = .004; P < .001), and tumor-node-metastasis (TNM) stage ( P = .015; P < .001). Additionally, low RORα and REV-ERBα expression levels were associated with poor OS and PFS in GC patients, respectively ( P < .001; P = .001). Furthermore, univariate Cox regression model analysis showed that histological grade ( P < .001; P < .001), preoperative CEA levels ( P < .001; P = .001), TNM stage ( P < .001; P < .001), lymph node metastasis ( P = .002; P = .002), RORα expression levels ( P = .001; P < .001), and REV-ERBα expression levels ( P < .001; P = .001) were associated with OS and PFS in GC. Multivariate Cox regression model analysis indicated that RORα expression levels and REV-ERBα expression levels are independent factors of OS and PFS in GC. Besides, RORα and REV-ERBα expression may be positively correlated (χ2 = 6.835; P = .009), and GC patients with both high RORα and REV-ERBα expression levels had the best prognosis. In conclusion, RORα and REV-ERBα may coparticipate in tumor activities and show potential to estimate the prognosis of GC.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14163-e14163
Author(s):  
Ikenna Osuorji ◽  
Greg Dyson ◽  
Durga Yerasuri ◽  
Philip Agop Philip ◽  
Anthony Frank Shields ◽  
...  

e14163 Background: Metastatic colorectal disease is generally incurable and treatment is palliative with the intent to balance toxicity with quality of life. Coin 3 trial showed that pre-chemotherapy platelet counts > 400,000 per μL were associated with poor survival when intermittent chemotherapy was used, whereas patients with lower platelet counts did not have any significant difference between the intermittent and continuous chemotherapy arms. Methods: We reviewed retrospectively 775 stage IV colorectal cancer patients at Karmanos Cancer Center over a 10 year period to see if high platelet count was associated with a poor outcome irrespective of treatment. Our analysis included 480 patients with adenocarcinoma who had not received chemotherapy prior to referral, and where information on the baseline platelet count, race, and age was available. We also analyzed the impact of race, age and bevacizumab use. We used Cox regression model for analysis. Results: Among the patients 48.3% were African American (AA) and 51.7% were Caucasians (C). 34.4 % had had PLT > 400,000 per μL. For those with lower platelet counts the median survival was 26.2 months in the C and 14.1 months in the AA groups respectively. Patients with platelet above 400,000 had a median survival of 15.2 months for C and 12.6 months for AA. Cox regression analysis, showed hazard ratios for outcome of death were; 1.16(1.07-1.26) p<0.001 for age (per 10 yrs), 1.60(1.31-1.94) [AA versus C(ref)] p< 0.001 for race and 1.35(1.10-1.65)[>400 versus <] p<0.004 for platelet count. In subset analysis, 296(61.7%) patients who received chemotherapy had data regarding use of bevacizumab (B). Among the 31.7% who received B, the median survival was 25.6 months compared to14.1 months in the no B arm. A Cox regression model using B as a stratification variable showed that the impact of race {hazard ratio = 1.32 (1.02-1.69) p =0.03} and platelet count {hazard ratio = 1.27(0.97-1.65) p =0.08} were much less. Conclusions: Pre-chemotherapy Platelet count< 400,000, C race and younger age are associated with improved survival. Use of bevacizumab may mitigate the impact of these factors.


2004 ◽  
Vol 19 (1) ◽  
pp. 32-37 ◽  
Author(s):  
C. Arun ◽  
N.J.M. London ◽  
D.M. Hemingway

Background Prognostic factors from clinical, laboratory and pathological data of patients with colorectal cancer are essential to identify high-risk groups to whom beneficial adjuvant therapy could be given. Endothelin-1, a growth factor, has been associated with the development and spread of solid tumours. This prospective study was performed to determine whether preoperative plasma big ET-1 levels might be useful as a prognostic indicator in patients with colorectal carcinoma. Method Sixty-five consecutive patients with colorectal cancer confirmed by biopsy were included prospectively into this study over a 12-month period. Plasma samples from a peripheral vein were obtained prior to surgery. Univariate analysis of survival using age (< or > 70 years), sex, Dukes’ stage (A&B versus C), tumour size (< or > 50 mm), vascular invasion and plasma big ET-1 levels was performed and significant factors were then analysed with the Cox regression model. Results Three variables, age, Dukes’ tumour stage and plasma big ET-1 levels, were found to have prognostic significance (p<0.05). Factors associated with a poorer prognosis were age >70 years (p=0.02), Dukes’ C tumours (p=0.04) and plasma big ET-1 levels >4.2 pg/mL (p=0.02). The Cox regression model identified the same three variables as having independent prognostic value for overall survival. Conclusion Preoperative plasma big ET-1 levels may be useful in predicting overall survival in patients with colorectal cancer. Plasma big ET-1 levels may be useful in the selection of high-risk lymph node-negative patients with colorectal cancer for adjuvant therapy.


2021 ◽  
Author(s):  
Sha Tian ◽  
Shang qing Wang ◽  
Piao Zheng ◽  
Xu Zhu ◽  
Huan Han ◽  
...  

Abstract Background: The FK506-binding protein 4 ( FKBP4 ), a tumor-related gene, plays a vital role in tumorigenesis and cancer progression. The study is aimed to clarify the effect of FKBP4 in lung adenocarcinoma (LUAD). Methods: Relying on The Cancer Genome Atlas (TCGA) cohort, the FKBP4 expression difference between LUAD tissues and non-tumor tissues was first detected, and verified with public tissue microarrays (TMAs), clinical LUAD specimen cohort and Gene Expression Omnibus (GEO) cohort. Then, logistic regression analysis and chi-square test were applied to detect the correlation between FKBP4 expression and clinicopathological parameters. Kaplan-Meier survival analysis and Cox regression model were utilized to evaluate the effect of FKBP4 expression on survival. Signaling pathways related to LUAD were obtained via employing Gene Set Enrichment Analysis (GSEA). Results: The FKBP4 expression level in LUAD samples was dramatically higher than that in non-tumor samples. High FKBP4 expression in LUAD is associated with gender, pathological stage, T classification, lymph node metastasis and distant metastasis. The Kaplan-Meier curve indicated a poor prognosis for LUAD patients with high FKBP4 expression. Multivariate analysis suggested that the high FKBP4 expression was a vital independent predictor of poor overall survival (OS). GSEA showed that a total of 15 signaling pathways were enriched in samples with high FKBP4 expression phenotype. Conclusions: FKBP4 may be an oncogene in LUAD, and is promised to become a prognostic indicator and therapeutic target for LUAD.


2022 ◽  
Vol 12 ◽  
Author(s):  
Chenshen Huang ◽  
Na Zhang ◽  
Hao Xiong ◽  
Ning Wang ◽  
Zhizhong Chen ◽  
...  

BackgroundCurrently, a comprehensive method for exploration of transcriptional regulation has not been well established. We explored a novel pipeline to analyze transcriptional regulation using co-analysis of RNA sequencing (RNA-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq).MethodsThe G protein-coupled receptors (GPCRs) possibly associated with macrophages were further filtered using a reduced-Cox regression model. ATAC-seq profiles were used to map the chromatin accessibility of the GPRC5B promoter region. Pearson analysis was performed to identify the transcription factor (TF) whose expression was correlated with open chromatin regions of GPRC5B promoter. ChIP-seq profiles were obtained to confirm the physical binding of GATA4 and its predicted binding regions. For verification, quantitative polymerase chain reaction (qPCR) and multidimensional database validations were performed.ResultsThe reduced-Cox regression model revealed the prognostic value of GPRC5B. A novel pipeline for TF exploration was proposed. With our novel pipeline, we first identified chr16:19884686-19885185 as a reproducible open chromatin region in the GPRC5B promoter. Thereafter, we confirmed the correlation between GATA4 expression and the accessibility of this region, confirmed its physical binding, and proved in vitro how its overexpression could regulate GPRC5B. GPRC5B was significantly downregulated in colon adenocarcinoma (COAD) as seen in 28 patient samples. The correlation between GPRC5B and macrophages in COAD was validated using multiple databases.ConclusionGPRC5B, correlated with macrophages, was a key GPCR affecting COAD prognosis. Further, with our novel pipeline, TF GATA4 was identified as a direct upstream of GPRC5B. This study proposed a novel pipeline for TF exploration and provided a theoretical basis for COAD therapy.


2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S448-S449
Author(s):  
Jongtak Jung ◽  
Pyoeng Gyun Choe ◽  
Chang Kyung Kang ◽  
Kyung Ho Song ◽  
Wan Beom Park ◽  
...  

Abstract Background Acinetobacter baumannii is one of the major pathogens of hospital-acquired infection recently and hospital outbreaks have been reported worldwide. On September 2017, New intensive care unit(ICU) with only single rooms, remodeling from old ICU with multibed bay rooms, was opened in an acute-care tertiary hospital in Seoul, Korea. We investigated the effect of room privatization in the ICU on the acquisition of carbapenem-resistant Acinetobacter baumannii(CRAB). Methods We retrospectively reviewed medical records of patients who admitted to the medical ICU in a tertiary care university-affiliated 1,800-bed hospital from 1 January 2015 to 1 January 2019. Patients admitted to the medical ICU before the remodeling of the ICU were designated as the control group, and those who admitted to the medical ICU after the remodeling were designated as the intervention group. Then we compared the acquisition rate of CRAB between the control and intervention groups. Patients colonized with CRAB or patients with CRAB identified in screening tests were excluded from the study population. The multivariable Cox regression model was performed using variables with p-values of less than 0.1 in the univariate analysis. Results A total of 1,105 cases admitted to the ICU during the study period were analyzed. CRAB was isolated from 110 cases in the control group(n=687), and 16 cases in the intervention group(n=418). In univariate analysis, room privatization, prior exposure to antibiotics (carbapenem, vancomycin, fluoroquinolone), mechanical ventilation, central venous catheter, tracheostomy, the presence of feeding tube(Levin tube or percutaneous gastrostomy) and the length of ICU stay were significant risk factors for the acquisition of CRAB (p&lt; 0.05). In the multivariable Cox regression model, the presence of feeding tube(Hazard ratio(HR) 4.815, 95% Confidence interval(CI) 1.94-11.96, p=0.001) and room privatization(HR 0.024, 95% CI 0.127-0.396, p=0.000) were independent risk factors. Table 1. Univariate analysis of Carbapenem-resistant Acinetobacter baumannii Table 2. Multivariable Cox regression model of the acquisition of Carbapenem-resistant Acinetobacter baumannii Conclusion In the present study, room privatization of the ICU was correlated with the reduction of CRAB acquisition independently. Remodeling of the ICU to the single room would be an efficient strategy for preventing the spreading of multidrug-resistant organisms and hospital-acquired infection. Disclosures All Authors: No reported disclosures


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