Cancer Biomarkers - Volume 25, issue 4

Authors: Li, Xue-Ting | Li, Jia-Yu | Zeng, Guang-Chun | Lu, Li | Jarrett, Michael J. | Zhao, Ye | Yao, Qing-Zhou | Chen, Xiuwei | Yu, Kai-Jiang

Article Type: Research Article

Abstract: OBJECTIVES: This study was to explore the prognostic value of connective tissue growth factor (CTGF) expression in endometrial cancer (EC). METHODS: We compared CTGF expression in 198 samples from patients with endometrial cancer and 50 samples from patients with healthy endometrial tissues as determined by immunohistochemistry. RESULTS: Expression of CTGF was significantly higher in endometrial cancers as compared to normal endometrial tissues. Positive CTGF expression displayed a strong association with CA125 level, histological grade, depth of myometrial invasion and the International Federation of Gynecology and Obstetrics (FIGO) stage. Our findings revealed histological grade, …depth of myometrial invasion, FIGO stage, vascular/lymphatic invasion, and the CTGF expression are related to 5-year survival in patients with endometrial cancer. Positive CTGF expression, lymph node status, as well as vascular/lymphatic invasion, were identified as independent prognostic factors in endometrial cancer. CONCLUTIONS: Over-expression of CTGF is an independent prognostic factor that will allow the successful differentiation of high-risk population from the group of patients with stage III-IV endometrial cancer. The up-regulation of CTGF may contribute to the progression of endometrial cancer and serve as a new prognostic biomarker in patients with endometrial cancer survival. Show more

Keywords: Endometrial cancer, CTGF, immunohistochemistry, normal endometrial tissues

DOI: 10.3233/CBM-190099

Citation: Cancer Biomarkers, vol. 25, no. 4, pp. 295-302, 2019

Authors: Liu, Deshui | Gao, Zhiying | Yue, Liling

Article Type: Research Article

Abstract: BACKGROUND AND OBJECTIVE: Fucosyltranferase 8 (FUT8), which catalyzes core fucosylation of glycopeptides, plays important roles in cancer development. In this study, we aimed to explore the influence of FUT8 expression on migration ability of human breast cancer cells and its potential mechanisms. METHODS: The core fucosylation levels in normal and FUT8 deficient MCF-7 cells were analyzed by lectin LCA blots. Then, the cell adhesion assay, transwell and wound healing experiments were conducted. The phosphorylation of FAK and core fucosylation of E-cadherin and its downstream integrins in the FAK/integrin pathway were measured. Moreover, the expression levels of …nuclear β -catenin, MMP-2, and MMP-9 were also measured. RESULTS: The core fucosylation levels were significantly reduced by inhibited FUT8. FUT8 deficiency suppressed the adhesion, migration and invasion of MCF-7 cells; the potential mechanisms might involve three aspects. FUT8 deficiency inhibited FAK/integrin pathway by suppressing core fucosylation of E-cadherin. In addition, FUT8 deficiency reduced nuclear β -catenin accumulation. The suppression of MMP-2 and MMP-9 expression also accounted for FUT8 deficiency inhibiting breast cancer cells migration. CONCLUSIONS: FUT8 deficiency suppressed migration of MCF-7 cells by impacting core fucosylation of E-cadherin and the downstream FAK/integrin pathway. Therefore, FUT8 is a potential biomarker for breast cancer detection and treatment. Show more

Keywords: FUT8, breast cancer, cells migration, FAK/integrin pathway

DOI: 10.3233/CBM-190209

Citation: Cancer Biomarkers, vol. 25, no. 4, pp. 303-311, 2019

Authors: Wang, Yu | Fu, Junfeng | Wang, Ze | Lv, Zhenyang | Fan, Zhe | Lei, Ting

Article Type: Research Article

Abstract: BACKGROUND: Lung adenocarcinoma (LUAD) accounts for a significant proportion of lung cancer and there have been few diagnostic and therapeutic targets for LUAD due to the lack of specific biomarker. The aim of this study was to identify key long non-coding RNAs (lncRNAs) for LUAD. METHODS: The lncRNA and mRNA expression profiles of a large group of patients with LUAD were obtained from The Cancer Genome Atlas (TCGA). The differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were identified. The optimal diagnostic lncRNA biomarkers for LUAD were identified by using feature selection procedure and classification model. We …established classification models including random forests, decision tree and support vector machine to distinguish LUAD and normal tissues. The lncRNAs-mRNAs co-expression networks and module identification were established by weighted gene co-expression network analysis (WGCNA). Functional annotation of pink and green modules was performed. The expression of selected DElncRNAs were validated by qRT-PCR. RESULTS: A total of 1364 DEmRNAs (468 down-regulated and 896 up-regulated mRNAs) and 260 DElncRNAs (88 down-regulated and 172 up-regulated lncRNAs) between LUAD and normal tissue were obtained. LANCL1-AS1, MIR3945HG, LINC01270, RP5-1061H20.4, BLACAT1, LINC01703, CTD-2227E11.1 and RP1-244F24.1 were identified as optimal diagnostic lncRNA biomarkers for LUAD. The area under curve (AUC) of the random forests model, decision tree model and SVM model were 0.999, 0.937 and 0.999, and the specificity and sensitivity of the three model were 98.3% and 99.8%, 93.2% and 99% and 100% and 98.4%, respectively. Co-expression networks analysis showed that RP11-389C8.2, CTD-2510F5.4 and TMPO-AS1 were co-expressed with 44, 242 and 241 mRNAs, respectively. Cell cycle, DNA replication and p53 signaling pathway were three significantly enriched pathways. The qRT-PCR results were consistent with our integrated analysis, generally. The GSE32863 and GSE104854 validation was consistent with our integrated analysis, generally. CONCLUSION: Our study identified eight DElncRNAs as potential diagnostic biomarkers of LUAD. Functional annotation of green module provided new evidences for exploring the precise roles of lncRNA in LUAD. Show more

Keywords: Lung adenocarcinoma, machine learning, weighted gene co-expression network analysis, long non-coding RNAs

DOI: 10.3233/CBM-190225

Citation: Cancer Biomarkers, vol. 25, no. 4, pp. 313-324, 2019

Authors: Han, Xia | Du, Chunjuan | Chen, Yinghai | Zhong, Xiaofei | Wang, Feng | Wang, Juan | Liu, Changmin | Li, Mianli | Chen, Shaoshui | Li, Baosheng

Article Type: Research Article

Abstract: BACKGROUND: Lung cancer is the main cancer-related deaths worldwide. In this study, we explored the clinical prognostic significance and functional role of miR-939-3p in lung cancer. METHODS: We analyzed the expression of miR-939-3p in lung cancer tissues and cells by qRT-PCR. The prognostic significance of miR-939-3p was investigated using the Kaplan-Meier survival and Cox regression analyses. The CCK-8 assay was used to determine the role of miR-939-3p in cell proliferation. Transwell assays were used to determine the effects of miR-939-3p on cell migration and invasion abilities. RESULTS: The expression of miR-939-3p was upregulated …in cancer tissues and cell lines compared with adjacent normal tissues and normal cells, respectively. The upregulated miR-939-3p was significantly associated with lymph node metastasis, TNM stage and poor prognosis of lung cancer patients. After the transfection of miR-939 mimic, overexpression of miR-939-3p promoted lung cancer cell proliferation, migration, and invasion. CONCLUSION: These findings suggested that miR-939-3p acts as an oncogene and promotes cell proliferation, migration, and invasion in lung cancer. miR-939-3p may be a potential independent prognostic biomarker in lung cancer. Show more

Keywords: miR-939-3p, lung cancer, prognosis, proliferation, migration, invasion

DOI: 10.3233/CBM-190271

Citation: Cancer Biomarkers, vol. 25, no. 4, pp. 325-332, 2019

Authors: Foda, Abd AlRahman Mohammad | Alam, Mariya Syed | Ikram, Nadeem | Rafi, Samia | Elnaghi, Khaled

Article Type: Research Article

Abstract: BACKGROUND: E-cadherin and Fascin are adhesive proteins that are expressed in many tumors. It was supposed that loss of expression of these proteins is associated with increased aggressiveness of the tumor. Whether spinal and intracranial meningiomas express adhesion proteins in different rates is not yet known. OBJECTIVE: We aimed to investigate the expression of E-cadherin and Fascin in a large number of meningioma specimens and determine if clinical and prognostic significance exists METHODS: One hundred and thirty-four spinal and intracranial meningioma samples were collected. Manual TMA blocks were constructed and immunohistochemistry for E-cadherin …and Fascin was done. Focal or diffuse staining was considered positive. RESULTS: Intracranial meningioma occurred in significantly younger age than spinal ones. Most of spinal meningiomas were of transitional histology. E-cadherin was expressed in 38.8% of cases. Spinal meningiomas showed statistically significant negative expression of E-cadherin than intracranial tumors. All atypical meningiomas showed negative E-cadherin expression. Fascin was expressed in 9% of cases with significant expression in atypical cases. CONCLUSIONS: Aggressive behavior of meningioma could be explained in part by loss of E-cadherin and overexpression of Fascin especially in spinal meningiomas. Further studies are suggested to explore the biological aspects of spinal and intracranial meningiomas for constructing tailored targeted therapies. Show more

Keywords: E-cadherin, Fascin, spinal meningioma, intracranial meningioma

DOI: 10.3233/CBM-190164

Citation: Cancer Biomarkers, vol. 25, no. 4, pp. 333-339, 2019

Authors: Wu, Yibo | Zhao, Jiangman | Dong, Shu | Wang, Yu | Li, Ailu | Jiang, Yancheng | Chen, Zixuan | Li, Chunxiao | Wang, Wei | Zhang, Zhishan

Article Type: Research Article

Abstract: BACKGROUND: Worldwide, cervical cancer is the fouth leading cause of deaths in gynecological oncology. Although the causes of cervical cancer have been extensively investigated, understanding of its exact pathogenesis remains incomplete. OBJECTIVE: This study aimed to identify alterations of genome and transcriptome of HPV associated cervical cancer pathogenesis using multi-omics approaches. METHODS: Cervical cancer and matched adjacent non-tumor specimens of one HPV16+ and two HPV- patients were sampled for whole-exome sequencing (WES) and RNA sequencing to characterize DNA mutations and gene expression profiles. WES and Affymetrix SNP 6.0 arrays data were analyzed from …6 HPV- and 93 HPV16+ cervical cancer patients in the cancer genome atlas (TCGA) database, as an independent validation group. RESULTS: WES identified 64 somatic mutation genes in tumors of 3 patients. HPV16+ tumor got fewer somatic mutated genes than HPV- tumors, which was validated by TCGA results. In this study, somatic mutated profile, CNV and gene expression heat map presented that HPV16+ tumors was distinct with HPV- tumors. The most significant altered pathways and GO terms were both related with cell cycle. Integrated analysis of multi-omics showed positive correlation between gene expression level and copy numbers. CONCLUSIONS: The results of this study provided novel insights into the pathogenesis of HPV associated cervical cancer. Show more

Keywords: Cervical carcinoma, HPV, Whole-exome sequencing, RNA sequencing

DOI: 10.3233/CBM-190055

Citation: Cancer Biomarkers, vol. 25, no. 4, pp. 341-350, 2019

Authors: Zhang, Liang | Huang, Yu | Ling, Junjun | Xiang, Ying | Zhuo, Wenlei

Article Type: Research Article

Abstract: BACKGROUND: Evidence indicates that inorganic arsenic (iAs) can directly damage cells and result in malignant transformation with unclear complicated mechanisms. In the present study, we aimed to explore the possible molecules, pathways and therapeutic agents by using bioinformatics methods. METHODS: Microarray-based data were retrieved and analyzed to screen the differentially expressed genes (DEGs) between iAs-treated lung cells and controls. Then, the functions of DEGs were annotated and the hub genes were filtrated. The key genes were selected from the hub genes through validation in The Cancer Genome Atlas (TCGA) cohorts. Possible drugs were predicted by using …CMAP tool. RESULTS: Two datasets (GSE33520 and GSE36684) were retrieved, and 61 up-regulated and 228 down-regulated DEGs were screened out, which were enriched in various pathways, particularly metabolism-related pathways. Among the DEGs, four hub genes including MTIF2, ACOX1, CAV1, and MRPL17, which might affect lung cancer prognosis, were selected as the key genes. Interestingly, Quinostatin was predicted to be a potential agent reversing iAs-induced lung cell malignant transformation. CONCLUSION: The present study sheds novel insights into the mechanisms of iAs-induced lung cell malignant transformation and identified several potential small agents for iAs toxicity prevention and therapy. Show more

Keywords: Arsenic, differentially expressed genes, TCGA, lung carcinoma, bioinformatics

DOI: 10.3233/CBM-182333

Citation: Cancer Biomarkers, vol. 25, no. 4, pp. 351-360, 2019

Authors: Wang, Lihong | Lv, Xiuyun | Fu, Xiuhua | Su, Liqing | Yang, Ting | Xu, Peng

Article Type: Research Article

Abstract: BACKGROUND: Gefitinib-resistance in lung cancers has become an intractable clinical problem. However, the mechanisms underlying this resistance are not fully understood. OBJECTIVE: Present study aims to investigate the roles and underlying mechanism of miR-153 in modulating gefitinib resistance in lung cancers. METHODS: In the present study, genes expression of miR-153, MDR-1 and ABCE1 were detected by qRT-PCR and western blot. The cell viability was examined by MTT assays. The regulation of miR-153 on ABCE1 was examined by luciferase reporter gene assays. The interaction of miR-153 and ABCE1 was detected by gene over-expression and …siRNA interference technology. RESULTS: The mRNA level of miR-153 was significantly down-regulated in gefitinib-resistance (GR) tissues and HCC827 cells, while the protein level of ABCE1 was up-regulated in GR tissues and HCC827 cells. Besides, miR-153 over-expression evidently increased miR-153 level and suppressed cell viability and multi drug resistance gene (MDR-1) expression in HCC827/Gef cells, while silence of miR-153 caused adverse alterations in HCC827 cells. Luciferase reporter assay results showed that miR-153 directly targeted ABCE1. Further studies showed that ABCE1 over-expression improved the expression of ABCE1 and MDR-1 and increased cell viability in HCC827/Gef cells, while ABCE1 silencing resulted in contrary trends in HCC827 cells. What’s more, miR-153 over-expression inhibited tumorigenesis and ABCE1 expression, while increased miR-153 level in tumor tissues. CONCLUSIONS: MiR-153 regulates gefitinib resistance by modulating expression of ABCE1 in lung cancers. Our findings may provide a worthwhile therapeutic target to reverse gefitinib resistance in lung cancers in the future. Show more

Keywords: Gefitinib-resistant, non-small cell lung cancer, ABCE1, miR-153

DOI: 10.3233/CBM-190094

Citation: Cancer Biomarkers, vol. 25, no. 4, pp. 361-369, 2019

Authors: Zahran, Asmaa M. | Rayan, Amal | Sayed, Heba Abdel Razik | Sobhy, Ali | Solimn, Ahmed | Darwish, Abeer M.

Article Type: Research Article

Abstract: BACKGROUND AND AIM: We aimed to quantify monocyte subsets in newly diagnosed pediatric patients with solid tumors at South Egypt Cancer Institute (SECI) and Assiut University Hospital (AUH), and investigate their roles in the treatment outcomes. PATIENTS AND METHODS: This is a prospective case-controlled study included 100 patients with de novo solid tumors and forty age and sex matched healthy children to provide blood samples as control subjects to determine normal count of monocyte subsets, blood samples were collected from cancer patients before the first cycle of chemotherapy, these blood samples were subjected to routine laboratory …tests and assessment of monocyte subsets using flow cytometry. RESULTS: Significant accumulations of intermediate monocytes and non classical monocytes (P < 0.000) in pediatric cases compared to controls were detected, there was a significant impact of non classical and intermediate monocytes on the type of response (P < 0.008, P < 0.4 respectively), The median OS for 100 patients with pediatric solid tumors involved in our study was 27 ± 0.589 months with 95% CI = 25.846–28.154, while the median PFS was 26 ± 0.610 months with 95% CI = 24.805–27.195, significant positive correlation between non-classical monocytes and OS (r = + 0.659, P < 0.041). CONCLUSION: Solid conclusion regarding the impact of monocyte classes in pediatric tumors is premature, although, in this study, non-classical and intermediate monocytes were associated with better response to treatment in pediatric solid tumors and non-classical monocytes were correlated with higher overall survival; further studies are needed for better understanding and specification of monocyte functions in different pediatric tumors. Show more

Keywords: Monocytes, pediatric solid tumors, progression free survival, overall survival

DOI: 10.3233/CBM-182212

Citation: Cancer Biomarkers, vol. 25, no. 4, pp. 371-379, 2019

Authors: Sun, Haijun | Wang, Lei | Zhao, Qingqing | Dai, Jianhua

Article Type: Research Article

Abstract: BACKGROUND: It is well known that some circulating microRNAs (miRNAs) are highly stable and might serve as promising biomarkers for many types of human cancer including esophageal squamous cell carcinoma (ESCC). However, the potential clinical significance of serum miR-1290 in ESCC remained unknown. OBJECTIVE: The aim of this study was to investigate the diagnostic and prognostic value of serum miR-1290 for ESCC. METHODS: The expression levels of serum miRNA-1290 in patients with ESCC and healthy controls were detected, and their potential diagnostic and prognostic value was analyzed. RESULTS: Our results …showed that tissue and serum miR-1290 levels were both significantly elevated in ESCC compared to their respective controls. Tissue miR-1290 levels were highly correlated with serum miR-1290 levels. High serum miR-1290 levels were significantly associated with worse clinicopathological characteristics. Patients with high serum miR-1290 levels had significantly worse survival. Further multivariate analysis showed that serum miR-1290 was an independent risk factor for ESCC. Serum miR-1290 could effectively discriminate ESCC cases from normal controls. CONCLUSIONS: The level of serum microRNA-1290 in ESCC patients increased significantly, and its expression level could reflect the progress of ESCC, suggesting that serum microRNA-1290 might be a useful diagnostic and prognostic marker of ESCC. Show more

Keywords: MiRNA, serum, esophageal squamous cell carcinoma, prognosis, diagnosis

DOI: 10.3233/CBM-190007

Citation: Cancer Biomarkers, vol. 25, no. 4, pp. 381-387, 2019