Cancer Biomarkers - Volume 28, issue 4

Authors: Fang, Yuan | Long, Fang

Article Type: Research Article

Abstract: BACKGROUND: As the most prevalent primary bone malignancy in children and adolescents, osteosarcoma (OS) has attracted increasing attention. The role of circRNAs in OS has been elucidated in some reports, but many circRNAs remain unexplored. Circ_0000337 has only been revealed as an oncogenic circRNA in esophageal squamous cell carcinoma. Yet whether circ_0000337 exerts any specific function in OS has not been unmasked. METHODS: RT-qPCR was used for measurement of circ_0000337, miR-4458 and BACH1 mRNA levels. Western blot was conducted to detect BACH1 protein. CCK-8 assay, Casepase-3 activity assay and transwell assay were utilized to assess changes …on cellular processes. Cytoplasmic/nuclear fractionation assay was conducted for circ_0000337 localization in OS cells. Luciferase reporter assay and RIP assay were performed to validate the interaction between miR-4458 and circ_0000337 or BACH1. RESULTS: Circ_0000337 expression was upregulated in OS cell lines and it silence hindered OS cell proliferation and migration. MiR-4458 was downregulated in OS cells and miR-4458 upregulation suppressed OS cell growth and migration. Importantly, circ_0000337 sponged miR-4458 to elevate BACH1 expression, thus facilitating OS development. CONCLUSIONS: This research for the first time documented that circ_0000337 promoted OS progression via sponging miR-4458 and thus elevating BACH1 expression, offering rational therapeutic target for OS. Show more

Keywords: circ_0000337, miR-4458, BACH1, osteosarcoma

DOI: 10.3233/CBM-190647

Citation: Cancer Biomarkers, vol. 28, no. 4, pp. 411-419, 2020

Authors: Wang, Zheng | Wang, Qiangwei | Bao, Zhaoshi | Guo, Liemei | Chen, Hongjin | Lv, Tao | Xu, Tianqi | Zhang, Xiaohua | Zhou, Caifang | Sun, Lihua

Article Type: Research Article

Abstract: OBJECTIVE: To investigate the expression pattern, prognostic value and biological functional of LINC00174 in glioma. METHODS: In total, 140 glioma samples were collected as discovery cohort. TCGA RNA sequence dataset was obtained as validation set. Kaplan–Meier survival and multivariate Cox analysis were performed to evaluate survival difference. Furthermore, the biological function of LINC00174 was analyzed by clonogenic and intracranial tumor model assays. RESULTS: Overexpressed LINC00174 was significantly correlated with tumor grade as well as the higher mortality in survival analysis both in the discovery and the validation GBM cohorts. Besides, LINC00174 served as …an independent prognostic indicator in glioblastoma patients. Additionally, knock down of LINC00174 expression significantly suppressed GBM cells’ proliferation both in vitro and vivo . CONCLUSION: LINC00174 acts as an oncogene in glioma and may be a new potential therapeutic target. Show more

Keywords: Gliblastoma, LINC00174, oncogene, prognosis, proliferation

DOI: 10.3233/CBM-191026

Citation: Cancer Biomarkers, vol. 28, no. 4, pp. 421-427, 2020

Authors: Cao, Huifeng | Cheng, Liang | Yu, Junjuan | Zhang, Zhihui | Luo, Zhenguo | Chen, Dayin

Article Type: Research Article

Abstract: OBJECTIVE: To identify the mRNAs associated with bladder cancer (BC) recurrence. METHODS: The transcription profile of GSE31684 including 39 recurrent BC tumor samples and 54 non-recurrent BC tumor samples as well as transcription profile of GSE13507 including 36 recurrent BC tumor samples and 67 non-recurrent BC tumor samples were downlaoded from the Gene Expression Omnibus. Then, the differentially expressed genes (DEGs) were identified using linear models for microarray data (limma) and the intersections of DEGs from the two datasets were further screened. The weighed gene co-expression network analysis (WGCNA) was used to screen the modules related …to BC recurrence. Protein-protein interaction (PPI) network analysis was used to analyze the genes interaction. Their functions were predicted by Gene Ontology and KEGG pathway enrichment. Moreover, The Comparative Toxicogenomics Database 2017 update (CTD) was used to search the BC related pathway. The univariate cox regression analysis was used to identify DEGs associated to the recurrence. Kaplan-Meier plots were used to illustrate recurrence free survival time (RFS). RESULTS: A total of 692 intersections DEGs were screened. WGCNA showed that 7 modules (2279 genes) were stable in both the datasets. A total of 169 intersection DEGs were mapped to the 7 modules. There existed 149 interaction relationships among 81 proteins (18 down-regulated and 63 up-regulated DEGs) in the PPI network. Two KEGG pathways including Focal adhesion and ECM-receptor interaction were enriched which were also found in the CTD. The univariate cox regression analysis showed that 3 DEGs (COL4A1, COL1A2 and COL5A1) were significant related to the prognosis. Multivariate cox regression analysis revealed that pathologic_N (N0-N1 vs N2-N3, p = 0.033) were independent prognostic factors for overall survival in patients with BC. CONCLUSION: COL4A1, COL1A2 and COL5A1 could be associated with BC recurrence. Show more

Keywords: Biomarker, bladder cancer, recurrence, mRNA, weighed gene co-expression network analysis

DOI: 10.3233/CBM-190617

Citation: Cancer Biomarkers, vol. 28, no. 4, pp. 429-437, 2020

Authors: Chen, Juan | Jiang, Tingting | Yu, Bo | Li, Tao | Zhao, Peige | Yuan, Lindong | Qi, Jun

Article Type: Research Article

Abstract: BACKGROUND: Non-small cell lung cancer (NSCLC) is the major subtype of lung cancer, imposing a huge disease burden worldwide. MicroRNA-1303 (miR-1303) has been demonstrated to be involved in several diseases, including cancers. In this study, we aimed to investigate the role of miR-1303 in NSCLC. METHODS: We quantified the expression levels of miR-1303 in NSCLC tissues and cells using the qRT-PCR assay. Then the association between miR-1303 expression and clinical characteristics of patients was analyzed using the χ 2 test. The Kaplan-Meier and multivariate Cox regression assays were used to investigate the …prognostic value of miR-1303 in NSCLC. Furthermore, the functional proliferation, migration, and invasion assays were used to explore the miR-1303 functions in vitro. RESULTS: The expression of miR-1303 was upregulated in NSCLC tissue samples and cells. The upregulation of miR-1303 was associated with TNM stage and lymph node metastasis. The survival time of NSCLC patients with high expression of miR-1303 was shorter than those with low expression. The functional analyses revealed that overexpression of miR-1303 in H1299 and A549 cells promoted cell proliferation, migration, and invasion. CONCLUSION: These results suggest that miR-1303 may be a potential prognostic biomarker for NSCLC and be involved in the progression of NSCLC. Show more

Keywords: microRNA-1303, NSCLC, proliferation, prognosis, migration, invasion

DOI: 10.3233/CBM-201461

Citation: Cancer Biomarkers, vol. 28, no. 4, pp. 439-446, 2020

Authors: Zhang, Yongjian | Fan, Qiang | Guo, Yingying | Zhu, Koujun

Article Type: Research Article

Abstract: BACKGROUND: Recurrence significantly influences the survival in patients with lung adenocarcinoma (LUAD). However, there are less gene signatures that predict recurrence risk of LUAD. OBJECTIVE: We performed this study to construct a model to predict risk of recurrence in LUAD. METHODS: RNA-seq data from 426 patients with LUAD were downloaded from The Cancer Genome Atlas (TCGA) and were randomly assigned into the training (n = 213) and validation set (n = 213). Differentially expressed genes (DEGs) between recurrent and non-recurrent tumors in the …training set were identified. Recurrence-associated DEGs were selected using multivariate Cox regression analysis. The recurrence risk model that identifies patients at low and high risk for recurrence was constructed, followed by the validation of its performance in the validation set and a microarray dataset. RESULTS: In total, 378 DEGs, including 20 recurrence-associated DEGs, were identified between the recurrent and non-recurrent tumors in the training set. The signatures of 8 genes (including AZGP1, INPP5J, MYBPH, SPIB, GUCA2A, HTR1B, SLC15A1 and TNFSF11) were used to construct the prognostic model to assess the risk of recurrence. This model indicated that patients with high risk scores had shorter recurrence-free survival time compared with patients with low risk scores. ROC curve analysis of this model showed it had high predictive accuracy (AUC > 0.8) to predict LUAD recurrence in the TCGA cohort (the training and validation sets) and GSE50081 dataset. This prognostic model showed high predictive power and performance in predicting recurrence in LUAD. CONCLUSION: We concluded that this model might be of great value for evaluating the risk of recurrence of LUAD in clinics. Show more

Keywords: 8-gene signature, lung adenocarcinoma, prognostic model, recurrence, The Cancer Genome Atlas

DOI: 10.3233/CBM-190329

Citation: Cancer Biomarkers, vol. 28, no. 4, pp. 447-457, 2020

Authors: Miao, Wei | Lu, Tanmin | Liu, Xiaolin | Yin, Weiyang | Zhang, Hui

Article Type: Research Article

Abstract: Ovarian carcinoma ranks fifth in the leading causes of cancer-relevant deaths among the female, with the highest fatality rate in all gynecological malignant tumors and the rising incidence worldwide. Mounting evidence has unveiled that lncRNAs are implicated in the tumorigenesis and cancer development. Several studies have proven the carcinogenic role of SNHG8 in various malignancies, but the physiological functions of SNHG8 in ovarian carcinoma need more detailed explanations. The present study certified that inhibition of SNHG8 executed suppressive activities in ovarian carcinoma by obstructing cell proliferation, migration, EMT process and stemness as well as driving cell apoptosis. Moreover, SNHG8 bound …with CAPRIN1 and positively modulated the expression of CAPRIN1. Further experiments manifested that CTNNB1 and Axin1 displayed a binding affinity with CAPRIN1. Knockdown of CAPRIN1 promoted the mRNA degradation of CTNNB1 and Axin1. Finally, we corroborated that CTNNB1 (or Axin1) ectopic expression or activation of Wnt/β -catenin pathway abrogated the effects of SNHG8 downregulation on the cellular process of ovarian carcinoma cells. To summarize, SNHG8 acted as an oncogene in ovarian carcinoma via targeting Wnt/β -catenin pathway, providing a new insight into understanding ovarian carcinoma at the molecular level. Show more

Keywords: Ovarian carcinoma, lncRNA, SNHG8, CAPRIN1, Wnt/β-catenin

DOI: 10.3233/CBM-190640

Citation: Cancer Biomarkers, vol. 28, no. 4, pp. 459-471, 2020

Authors: Fan, Xiangyu | Sun, Yingying | Guo, Xu | He, Chunbo | Han, Beiqiu | Sun, Xilin

Article Type: Research Article

Abstract: This article has been retracted, and the online PDF replaced with this retraction notice.

Keywords: LINC01116, miR-744-5p, SCN1B, LUSC

DOI: 10.3233/CBM-190945

Citation: Cancer Biomarkers, vol. 28, no. 4, pp. 473-482, 2020

Authors: Zhang, Linshen | Jiang, Hongjun | Zhang, Yufan | Wang, Chenrong | Xia, Xixi | Sun, Yi

Article Type: Research Article

Abstract: BACKGROUND: Despite notable progression from a therapeutic point of view, castration resistant prostate cancer (CRPC) remains a clinical significant stumbling block. The current study aimed to elucidate the functional role of the gene glucocorticoid receptor (GR) in CRPC, and identify the contributions of the GR gene in CRPC in connection with microRNA-143-3p (miR-143-3p)/Jagged1 (JAG1)/NOTCH2. METHODS: The expression of GR and miR-143-3p in CRPC tissues and cells as well as JAG1/NOTCH2 expression in CRPC tissues was initially determined by quantitative polymerase chain reaction and Western blot analyses. The relationship among GR, JAG1, NOTCH2 and miR-143-3p was subsequently …verified using the dual-luciferase reporter gene assay. ChIP assay confirmed the binding of GR to miR-143-3p promoter. Gain- and loss-function approaches were applied to ascertain the role of GR and miR-143-3p in progression of CRPC. Additionally, xenograft tumor models in nude mice were established to further confirm our results. RESULTS: GR was found to be highly expressed while miR-143-3p was lowly expressed in the CRPC tissues and cells. Silencing GR reduced migration, invasion, proliferation and increased apoptosis of CRPC cells. GR was enriched in the miR-143-3p promoter region and could down-regulate miR-143-3p expression. The overexpression of miR-143-3p led to a reduction in the migration, invasion, proliferation and increased apoptosis of CRPC cells. JAG1 and NOTCH2 were the target genes of miR-143-3p, and GR up-regulated the JAG1/NOTCH2 expression by down-regulating miR-143-3p. Silencing JAG1/NOTCH2 inhibited epithelial-mesenchymal transition and CRPC progression in vitro . Furthermore, the in vitro findings were reproduced in the in vivo experiments. CONCLUSION: The key findings of the current study demonstrated that silencing GR suppressed the progression of CRPC through the JAG1/NOTCH2 pathway via up-regulation of miR-143-3p. Show more

Keywords: Glucocorticoid receptor, microRNA-143-3p, JAG1, NOTCH2, castration-resistant prostate cancer, migration, invasion

DOI: 10.3233/CBM-191271

Citation: Cancer Biomarkers, vol. 28, no. 4, pp. 483-497, 2020

Authors: Gissi, Davide B. | Gabusi, Andrea | Tarsitano, Achille | Asioli, Sofia | Rossi, Roberto | Marchetti, Claudio | Montebugnoli, Lucio | Foschini, Maria P. | Morandi, Luca

Article Type: Research Article

Abstract: BACKGROUND: A non-invasive sampling procedure for the early detection of Oral Squamous Cell Carcinoma (OSCC) based on DNA methylation analysis of a panel of 13 genes was applied in 4 different OSCC risk-group of patients. Aim of the study is to evaluate the between-group differences and the variables related to the methylation profile of each group. METHODS: Oral brushing samples were collected from 54 healthy subjects, 31 Oral Leukoplakia (OL) patients, 18 Oral Lichen Planus (OLP) patients and 26 patients previously treated for OSCC. Each sample was considered positive or negative in relation to a predefined …cut-off value. RESULTS: None of the samples from 54 healthy subjects were positive, whereas 22/31 OL, 3/18 OLP and 8/26 surgically treated OSCC samples showed positive values with respect to the cut-off. In OL patients, dysplasia was the only variable significantly related to positive values: 10/10 OLs with high-grade dysplasia were positive with respect to 12/21 OLs without dysplasia (Chi 6.039, p < 0.05). CONCLUSION: DNA methylation analysis in epithelial cells collected by oral brushing seems to be a promising genetic method to distinguish lesions at high risk of developing OSCC. Larger population studies and an adequate follow-up period are necessary to confirm these preliminary data. Show more

Keywords: Bisulfite sequencing, quantitative DNA methylation analysis, algorithm, oral brushing, oral carcinoma, oral leukoplakia, oral lichen planus

DOI: 10.3233/CBM-190422

Citation: Cancer Biomarkers, vol. 28, no. 4, pp. 499-510, 2020

Authors: Zhang, Yong | Zhang, Wei

Article Type: Research Article

Abstract: BACKGROUND: Foxhead box D1 (FOXD1) is validated to be over-expressed in a variety of human malignancies and promotes cancer progression. Nevertheless, the role of FOXD1 and the associated mechanism in nasopharyngeal carcinoma (NPC) remain largely unknown. METHODS: A total of seventy-five cases of NPC tissue samples were collected. FOXD1 expression in NPC tissues and cells (SUNE1, CNE1, CNE2, and HONE1) was detected using immunohistochemistry and Western blot, respectively. The relationship between FOXD1 expression and clinicopathological parameters of NPC patients was analyzed. FOXD1 mRNA and miR-186 expression in NPC tissues and cells was detected using quantitative polymerase …chain reaction (qPCR). The cell viability of NPC cells was detected using CCK-8 assay. Colony survival of NPC cells exposed to different doses of radiation was detected using colony formation assay. Transwell assay was used to evaluate the migration and invasion of NPC cells. The dual-luciferase reporter gene assay was employed to verify the targeting relationship between miR-186 and FOXD1. RESULTS: FOXD1 was over-expressed in NPC tissues (average fold change on mRNA level = 4.72), and its high expression was correlated to NPC positive lymph node metastasis and tissue differentiation. The over-expression of FOXD1 promoted the proliferation, migration, invasion and radio-resistance of NPC cells. On the contrary, the knock-down of FOXD1 inhibited the malignant phenotypes of the above cells. It was verified that FOXD1 was one of the downstream targets of miR-186 and was negatively regulated by it. CONCLUSION: FOXD1, which is negatively regulated by miR-186, acts as a novel oncogene in NPC and serves as potential biomarker and therapeutic target for NPC. The research will provide great theoretical basis for further clinical diagnosis and therapy. Show more

Keywords: NPC, FOXD1, miR-186

DOI: 10.3233/CBM-191311

Citation: Cancer Biomarkers, vol. 28, no. 4, pp. 511-521, 2020

Authors: Barsoum, Ihab | Elgohary, Marwan N. | Bassiony, Mohamed A.A.

Article Type: Research Article

Abstract: BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Viral hepatitis, alcoholism and non-alcoholic steatohepatitis are the most common risk factors. Despite the advances in HCC screening and treatment options, HCC still has a high mortality rate and a high rate of recurrence after treatment. Lipocalin-2 (LCN-2) is a glycoprotein transporter that is highly expressed in HCC tissues. OBJECTIVE: To evaluate serum LCN-2 as a diagnostic marker for HCC. METHODS: The study was carried out in Zagazig university hospitals. It included 210 HCC patients (subdivided in three subgroups), 72 …liver cirrhosis patients without HCC and 18 normal control persons (the total is 300 subjects). All the study subjects were evaluated by history taking, physical examination, routine laboratory investigations, alpha-fetoprotein (AFP) and LCN-2 in addition radiology. RESULTS: In comparison between HCC and control, there was a statistically significant difference in hemoglobin percent (HB%), platelet count, serum ALT, AST, ALP, bilirubin, albumin and creatinine. In comparison to AFP, LCN-2 > 225 ng/ml had a higher diagnostic performance in HCC patients and was more accurate in differentiation between cirrhosis and HCC patients. CONCLUSION: LCN-2 is a good candidate for HCC diagnosis and screening. Show more

Keywords: Hepatocellular carcinoma, alpha-fetoprotein, lipocalin-2, screening, cirrhosis, hepatitis

DOI: 10.3233/CBM-190084

Citation: Cancer Biomarkers, vol. 28, no. 4, pp. 523-528, 2020

Authors: Pi, Hongquan | Huang, Libing | Liu, Huifang | Liang, Shulan | Mei, Juanjuan

Article Type: Research Article

Abstract: OBJECTIVE: To explore the effects of the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) signaling pathway on the intestinal flora in patients with colorectal cancer (CRC). METHODS: A total of 30 CRC patients treated with PD-1 monoclonal antibody therapy in the Oncology Department of our hospital from January 2018 to January 2019, and another 30 patients treated with routine non-immune therapy were enrolled. The feces specimens were collected for sequencing, the CRC model was established, and the 16S rRNA gene sequences in intestinal flora in feces specimens of mice were analyzed. RESULTS: The 3-month progression-free survival …could not be predicted through the gene count or abundance of metagenomic species (MGS) in intestinal microflora of patients. The gene count or MGS abundance was related to the clinical progression-free response. There were abundant unclassified Escherichia coli, s_lactobacillus and s_unclassified parasutterella in patients treated with PD-1. The reflection curve of microbiota had an obvious difference in richness (Chao1), but had no apparent difference in diversity (Shannon). CONCLUSION: The PD-1/PD-L1 signaling pathway can regulate the metabolic activity of intestinal flora, thereby promoting immune surveillance of tumors. Show more

Keywords: PD-1/PD-L1 signaling pathway, colorectal cancer, intestinal flora

DOI: 10.3233/CBM-201606

Citation: Cancer Biomarkers, vol. 28, no. 4, pp. 529-535, 2020

Authors: Wang, Lei | Zhou, Yehui | Xia, Suhua | Lu, Linlin | Dai, Tiantian | Li, Aoshuang | Chen, Yan | Gao, Erli

Article Type: Research Article

Abstract: BACKGROUND: The new systemic inflammation response index (SIRI) constructed based on neutrophil, monocyte and lymphocyte counts in peripheral blood is considered to be related to the prognosis of a variety of tumours. OBJECTIVE: To evaluate the prognostic value of the SIRI in operable breast cancer patients and establish a nomogram to predict the survival of breast cancer patients. METHODS: A total of 949 patients with operable breast cancer were enrolled in the present study. RESULTS: The overall survival (OS) of breast cancer patients with SIRI ⩽ 0.65 …was significantly higher than that of breast cancer patients with SIRI > 0.65 (P < 0.001). A nomogram generated based on SIRI, grade and TNM stage and SIRI predicted the 5- and 10-year survival rates of breast cancer patients more accurately than TNM stage alone. In addition, the change in SIRI relative to baseline at 4 weeks after surgery was closely related to the survival of breast cancer patients. Compared with those with no SIRI changes (absolute value of variation < 25%), breast cancer patients with an increase in SIRI > 75% or 25–75% had worse OS (P < 0.001). CONCLUSIONS: The SIRI before and after surgery is closely related to the prognosis of breast cancer patients. Show more

Keywords: SIRI, breast cancer, prognosis

DOI: 10.3233/CBM-201682

Citation: Cancer Biomarkers, vol. 28, no. 4, pp. 537-547, 2020

Authors: Wang, Guoan | Zhou, Yingyan | Chen, Weizhuang | Yang, Yiming | Ye, Jiankui | Ou, Huilin | Wu, Hongcheng

Article Type: Research Article

Abstract: OBJECTIVE: Studies have suggested that miR-21-5p and WWC2 are key players in most cancer types, yet the underlying mechanisms in lung adenocarcinoma (LUAD) remain elusive. This study made in-depth research on the two factors-dependent mechanisms underlying LUAD occurrence and development. METHODS: Bioinformatics methods were employed to identify the miRNA and its target gene of interest. In all, 20 pairs of LUAD tumor tissue samples and matched adjacent normal samples along with 5 LUAD cell lines were collected for evaluating the aberrant expression of miR-21-5p and WWC2. Dual-luciferase reporter assay was performed to validate the targeted relationship …between miR-21-5p and WWC2. A series of in vitro experiments including colony formation assay, EdU, wound healing assay and Transwell were conducted for assessment of the LUAD cell biological behaviors. In addition, Western blot was carried out to determine the protein expression of epithelial-mesenchymal transition (EMT)-related proteins. RESULTS: miR-21-5p was found to be considerably increased in LUAD tissue and cells relative to that in the adjacent tissue and the human bronchial epithelial cells, whereas WWC2 was significantly decreased. Dual-luciferase reporter assay revealed that miR-21-5p targeted WWC2 and down-regulated its expression. Besides, silencing miR-21-5p or overexpressing WWC2 played an inhibitory role in PC-9 cancer cell proliferation, migration and invasion, but such effect was suppressed when miR-21-5p was overexpressed. Furthermore, Western blot uncovered that WWC2 overexpression impeded the EMT process in LUAD cells. CONCLUSION: miR-21-5p facilitates LUAD cell proliferation, migration and invasion through targeting WWC2, which provides a novel therapeutic target for LUAD treatment. Show more

Keywords: Lung adenocarcinoma, WWC2, miR-21-5p, proliferation, migration, invasion

DOI: 10.3233/CBM-201489

Citation: Cancer Biomarkers, vol. 28, no. 4, pp. 549-559, 2020