Cancer Biomarkers - Volume 34, issue 4

Authors: Zhu, Longbiao | Zhang, Xinyu | Chen, Yan | Yan, Donglin | Han, Jing

Article Type: Research Article

Abstract: BACKGROUND: Numerous studies reveal the clinical significance of tumor microenvironment (TME) in multiple cancers. The association between TME in oral squamous cell carcinoma (OSCC) and clinical outcomes remains unsolved. OBJECTIVE: This study aims to exhibit the TME of OSCC and identified the prognostic marker. METHODS: Gene expression profile and clinical data OSCC patients were from the TCGA database. The validated stage data was from the Gene Expression Omnibus (GSE65858). Immune/stromal scores of each patient were calculated by ESTIMATE algorithm. Biological functional prediction was conducted. Prognostic genes identified by survival analysis. Nomogram and Receiver …operating characteristic curves were employed to test the predicting power. TIMER database was applied to evaluated the immune infiltrates. RESULTS: Lower immune scores were observed in male patients (P = 0.0107) and different primary tumor sites of oral cavity with different stromal scores (P = 0.0328). The Differentially expressed genes (DEGs) were involved in immune related pathways. HGF gene (hepatocyte growth factor) was prognostic related and with a better prognostic performance when combined with clinical features (AUC= TCGA 0.638, AUC= GEO 0.714). HGF was significantly related with B cell, CD4ï ⁢ ¼ ⁢ ‹ T cell, CD8+ T cell, macrophage, neutrophils, and dendritic cell infiltration. CONCLUSION : The current study analyzed the TME and presented immune related prognostic biomarkers for OSCC. Show more

Keywords: Prognostic genes, cancer, oral, tumor microenvironment

DOI: 10.3233/CBM-210432

Citation: Cancer Biomarkers, vol. 34, no. 4, pp. 523-532, 2022

Authors: Wang, Xinhua | Cui, Zhengfeng | Zeng, Basangdan | Qiong, Zhaxi | Long, Ziwen

Article Type: Research Article

Abstract: Melanoma, a skin cancer derived from malignant melanocytes, is characterized by high aggressiveness and mortality. However, its exact etiology is unknown. Recently, the roles of exosomes and exosomal microRNAs (miRNAs) in the progression and therapy of various disorders, including melanoma, have gained attention. We investigated the impact of miR-138-5p from exosomes released by human mesenchymal stem cells (HMSCs) on the pathogenesis of melanoma. We isolated exosomes from HMSCs (HMSC-exos) by ultracentrifugation and verified them by specific biomarkers and transmission electron microscopy. We used CCK8, flow cytometry, quantitative real-time PCR (qRT-PCR), and Western blots to investigate cell proliferation, apoptosis, and mRNA …and protein levels, respectively. Additionally, we used luciferase assays to examine the relationship between miR-138-5p and SOX4. Administration of HMSC-exos dramatically repressed the growth of melanoma cells. Elevated miR-138-5p levels in HMSC-exos were linked to increased cell apoptosis, and miR-138-5p downregulation had the opposite effects on cells. SOX4 was targeted by miR-138-5p through direct binding to the SOX4 3’UTR. In melanoma tissues, miR-138-5p was downregulated, and SOX4 was upregulated and was negatively correlated. MiR-138-5p plays a crucial role in melanoma progression. The negative regulation of SOX4 transcription mediates the function of miR-138-5p. These findings provide a novel concept of melanoma pathogenesis and identify a valuable target (miR-138-5p/SOX4 axis) in treating this disease. Show more

Keywords: miR-138-5p, human mesenchymal stem cell-derived exosomes, melanoma, SOX4, cellular proliferation, apoptosis

DOI: 10.3233/CBM-210409

Citation: Cancer Biomarkers, vol. 34, no. 4, pp. 533-543, 2022

Authors: Rastorgueva, Eugenia | Liamina, Daria | Panchenko, Ivan | Iurova, Elena | Beloborodov, Evgenii | Pogodina, Evgeniya | Sugak, Dmitrii | Slesarev, Sergei | Saenko, Yury

Article Type: Research Article

Abstract: In this paper, we have studied the role of chromosomal abnormalities in the expression of small nucleolar RNAs (snoRNAs) of radioresistant (K562) and radiosensitive (HL-60) leukemia cell line. Cells were exposed to an X-ray dose of 4 Gy. SnoRNA expression was investigated using NGS sequencing. The distribution of expressed snoRNAs on chromosomes has been found to be different for two cell lines. The most significant differences in the expression of snoRNAs were found in the K562 cell line based on the analysis of the dynamics of log2fc values. The type of clustering, the number and type of snoRNAs …slightly differed in the chromosomes with trisomy and monosomy and had a pronounced difference in pairs with marker chromosomes in both cell lines. In this study, we have demonstrated that chromosomal abnormalities alter the expression of snoRNA after irradiation. Trisomies and monosomies do not have such a noticeable effect on the expression of snoRNAs as the presence of marker chromosomes. Show more

Keywords: snoRNA, radioresistance, radiosensitivity, cancer cells, marker chromosomes

DOI: 10.3233/CBM-210092

Citation: Cancer Biomarkers, vol. 34, no. 4, pp. 545-553, 2022

Authors: Dobrescu, Ruxandra | Schipor, Sorina | Manda, Dana | Caragheorgheopol, Andra | Badiu, Corin

Article Type: Research Article

Abstract: BACKGROUND: Matrix metalloproteinase-9 (MMP-9) is an important mediator of tumor initiation and progression. The MMP-9 promoter -1562C/T functional polymorphism increases gene expression and was identified as a susceptibility factor for various cancers. OBJECTIVE: To evaluate the influence of the MMP-9 promoter genotype on the risk of developing papillary thyroid cancer (PTC) and to correlate cancer patient genotype with the clinical and pathological phenotype. METHODS: We evaluated 236 patients with nodular thyroid disease pre-thyroidectomy (119 benign disease, 117 PTC). Genomic DNA was isolated from whole blood and the MMP-9 -1562C/T genotype was evaluated by …PCR-RFLP analysis. RESULTS: Genotype frequencies were in Hardy-Weinberg equilibrium for all groups. The T allele was significantly more frequent in cancer compared to benign disease (17.5% vs 10.1%), p = 0.019. Patients with the CT or CT+ TT genotype had an increased risk of developing PTC, specifically micropapillary thyroid carcinoma (MPTC) (CT genotype: OR = 6.467, p = 0.00006; CT+ TT: OR = 6.859, p = 0.00002), but not more advanced stages (CT: p = 0.094; CT+ TT: p = 0.157). The -1562C/T genotype did not significantly correlate with tumor histological subtype, invasion or TNM stage. CONCLUSION: The MMP-9 -1562C/T functional polymorphism may indicate susceptibility to develop thyroid cancer, specifically intrathyroidal clinically non-relevant MPTC. This suggests that although this genotype might be a predisposing factor, other genetic/epigenetic events are needed for cancer progression. Show more

Keywords: Metalloproteinase-9, MMP-9, polymorphism, cancer susceptibility, thyroid cancer

DOI: 10.3233/CBM-203119

Citation: Cancer Biomarkers, vol. 34, no. 4, pp. 555-562, 2022

Authors: Mehravar, Majid | Ghaemimanesh, Fatemeh | Poursani, Ensieh M.

Article Type: Research Article

Abstract: BACKGROUND: Secreted phosphoprotein 1 (SPP1), also known as osteopontin (OPN), is a multifunctional protein expressed in diverse normal tissues, and functionally is involved in cellular matrix and signaling processes. Many studies have linked SPP1 to pathophysiological conditions including cancer. OBJECTIVE: The aim of this study is to evaluate the 3’UTR length of SPP1 gene in glioblastoma cell line. METHODS: 3’ Rapid Amplification of cDNA End (3’-RACE) was used to determine the 3’ end of SPP1 gene. APAatlas data base, GEPIA web server, and miRcode were also used to extract related information and bioinformatic …analysis part. RESULTS: In this study we show that SPP1 gene undergoes Alternative cleavage and Polyadenylation (APA) mechanism, by which it generates two 3’ termini, longer isoform and shorter isoform, in glioblastoma derived cell line, U87-MG. Further bioinformatic analysis reveals that SPP1 alternative 3’UTR (aUTR), which is absent in shorter isoform, is targeted by two families of microRNAs-miR-181abcd/4262 and miR-154/872. These miRNAs also target and perhaps negatively regulate NAP1L1 and ENAH genes that are involved in cell proliferation and cell polarity, respectively. Relative expression difference (RED), obtained from RNA-seq data of diverse normal tissues, representing APA usage appears to be negatively correlated with expression of NAP1L1 and ENAH, emphasizing co-expression of SPP1 longer isoform with these two genes, indicating miRNA sponge function of aUTR (longer 3’UTR). Bioinformatic analysis also shows that in normal brain tissue longer APA isoform of SPP1 is expressed; however shorter isoform appears to be expressed in cancer condition. CONCLUSION: Together, this study reveals that SPP1 APA isoforms have different pattern in normal and cancerous conditions, which can be considered as a diagnostic and prognostic marker in cancers. Show more

Keywords: SPP1, OPN, alternative polyadenylation (APA), 3’UTR, glioblastoma

DOI: 10.3233/CBM-210135

Citation: Cancer Biomarkers, vol. 34, no. 4, pp. 563-570, 2022

Authors: Tu, Simei | Zhang, Hao | Qu, Xinjian

Article Type: Research Article

Abstract: BACKGROUND: With the rapid development of genomics and molecular biology, not only have biochemical indicators been used as tumour markers, but many new molecular markers have emerged. Epigenetic abnormalities are a new type of molecular marker, and DNA methylation is an important part of epigenetics. OBJECTIVE: This study used weighted gene coexpression network analysis (WGCNA) to analyse key methylation-driven genes in breast cancer. METHODS: The RNA-seq transcriptome data, DNA methylation data, and clinical information data of breast cancer patients were downloaded from The Cancer Genome Atlas (TCGA) database, and the MethylMix R package …was used to screen methylation-driven genes in breast cancer. The ClusterProfiler package and enrichplot package in R software were used to further analyse the function and signalling pathway of methylation-driven genes. Through univariate and multivariate Cox regression analyses, methylation-driver genes related to prognostic were obtained, a prognostic model was constructed and prognostic characteristics were analysed. RESULTS: The 17 methylation-driven genes related to prognosis were obtained by the WGCNA method in breast cancer, and the prognostic significance of these methylation-driven genes was determined by transcriptome and methylation combined survival analysis. Analysis of functions and signalling pathways showed that these genes were mainly enriched in biological processes and signalling pathway. Through univariate and multivariate Cox regression analyses, a prognostic model of 5 methylation-driven genes was constructed. CONCLUSIONS: The AUC of the receiver operating characteristic (ROC) curve of this model was 0.784, showing that the model had a good prediction effect. Based on WGCNA screening, it was found that only CDO1 was the key methylation-driven gene for prognosis in breast cancer, indicating that CDO1 may be an important indicator of the prognosis of breast cancer patients. Show more

Keywords: Methylation-driven genes, WGCNA, CDO1, prognosis, breast cancer

DOI: 10.3233/CBM-210485

Citation: Cancer Biomarkers, vol. 34, no. 4, pp. 571-582, 2022

Authors: Vural, Fisun | Coşkun, Ayşe Deniz Ertürk | Çıtak, Göksu | Vural, Birol | Köse, Gültekin

Article Type: Research Article

Abstract: BACKGROUND: The inflammatory markers are associated with adverse clinical outcomes in endometrial cancers (EC), but hematopoietic aging may affect the results. OBJECTIVE: To compare inflammatory markers in geriatric and nongeriatric EC. METHODS: This study included 342 women with endometrial cancers (n: 171) and age-matched controls (n: 171). Geriatric (⩾ 65 years old) and nongeriatric women in each group was compared for inflammatory markers, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), mean platelet volume (MPV), and platelet distribution width (PDW). RESULTS: Geriatric EC had more common nonendometrioid tumors, myometrial …invasion, lymph node metastasis, advanced stage, and low overall survival (OS). Nongeriatric EC had low MPV, high NLR, and PDW compared to nongeriatric control. Geriatric EC had low MPV, lymphocyte, and high NLR, PLR compared to geriatric control (p < 0.05). Geriatric EC had significantly low PDW and high NLR, PLR compared to nongeriatric EC in early stages, not in advanced stages. Lymphocyte count was significantly low in geriatric EC with all stages (p < 0.05). In nongeriatric EC, stage was related to platelet count (r: 0.341, p: 0.0019), and PLR (r: 0.252, p: 0.01). OS was negatively related to PLR (r: - 0.267, p: 0.007) and NLR (r: - 0.353, p: 0.000). In geriatric EC, myometrium invasion was negatively related to lymphocyte count (r: - 0.268, p: 0.035). OS was related to neutrophil count (p: 0.352, p: 0.01). MPV was negatively related to stage (r: - 0.335, p: 0.01) and OS (r: - 0.337, p: 0.02). CONCLUSIONS: The inflammatory responses of geriatric and nongeriatric EC were different in the early and advanced stages. Geriatric EC had low PDW and high NLR, PLR compared to nongeriatric EC in early stages. Decreased lymphocyte count was the most prominent feature of geriatric EC in the early and advanced stages. These results suggested that decreased lymphocyte count may reflect an aggressive course of disease in the elderlies. Future inflammation studies may direct anticancer treatment strategies in geriatric EC. Further research on inflammaging and geriatric EC is needed to increase our understanding of aging and carcinogenesis. Show more

Keywords: Endometrial cancer, inflammation, geriatric cancers, lymphocyte count, platelet count, hematologic markers

DOI: 10.3233/CBM-210215

Citation: Cancer Biomarkers, vol. 34, no. 4, pp. 583-590, 2022

Authors: Robinson, Irina | Bertsch, Alexandra | Leithner, Katharina | Stiegler, Philipp | Olschewski, Horst | Hrzenjak, Andelko

Article Type: Research Article

Abstract: BACKGROUND: The potential of microRNAs (miRNAs) as molecular tumor biomarkers for early diagnosis and prognosis in lung cancer is still unclear. OBJECTIVE: To analyze expression of miRNAs in A549 lung adenocarcinoma (LUAD) cells and in primary, non-malignant bronchial epithelial (BE) cells from healthy donors. To analyze the most prominently deregulated miRNAs in plasma samples of LUAD patients and healthy donors. MATERIALS AND METHODS: The expression of 752 miRNAs in LUAD and BE cells was assessed by RT-qPCR with mean-centering restricted normalization. The relative plasma levels of 18 miRNAs in LUAD patients and healthy …donors were analyzed using RT-qPCR and normalized to miR-191-5p and miR-16-3p. Putative interactions between miRNAs and their target genes were investigated in silico . RESULTS: Out of 752 miRNAs, 37 miRNAs were significantly deregulated in A549 cells compared to BE cells. MiR-15b-3p, miR-148a-3p, miR-193b-3p, and miR-195-5p were significantly deregulated in plasma samples of LUAD patients compared to donors. The target genes of those four miRNAs are involved in essential mechanisms in cancer development and progression. CONCLUSIONS: There are substantial differences between cancer and control miRNA expression in vitro and in plasma samples of LUAD patients compared to healthy donors. Four deregulated miRNAs are promising as a diagnostic biomarker for adenocarcinoma of the lung. Show more

Keywords: Lung adenocarcinoma, A549 cells, bronchial epithelial cells, microRNA, plasma samples

DOI: 10.3233/CBM-210205

Citation: Cancer Biomarkers, vol. 34, no. 4, pp. 591-606, 2022

Authors: Abou-Fadel, Johnathan | Grajeda, Brian | Jiang, Xiaoting | Cailing-De La O, Alyssa-Marie D. | Flores, Esmeralda | Padarti, Akhil | Bhalli, Muaz | Le, Alexander | Zhang, Jun

Article Type: Research Article

Abstract: Breast cancer is the most diagnosed cancer worldwide and remains the second leading cause of cancer death. While breast cancer mortality has steadily declined over the past decades through medical advances, an alarming disparity in breast cancer mortality has emerged between African American women (AAW) and Caucasian American women (CAW). New evidence suggests more aggressive behavior of triple-negative breast cancer (TNBC) in AAW may contribute to racial differences in tumor biology and mortality. Progesterone (PRG) can exert its cellular effects through either its classic, non-classic, or combined responses through binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane …PRG receptors (mPRs), warranting both pathways equally important in PRG-mediated signaling. In our previous report, we demonstrated that the CCM signaling complex (CSC) consisting of CCM1, CCM2, and CCM3 can couple both nPRs and mPRs signaling cascades to form a CSC-mPRs-PRG-nPRs (CmPn) signaling network in nPR positive(+ ) breast cancer cells. In this report, we furthered our research by establishing the CSC-mPRs-PRG (CmP) signaling network in nPR(- ) breast cancer cells, demonstrating that a common core mechanism exists, regardless of nPR(+ ⁣ / ⁣ - ) status. This is the first report stating that inducible expression patterns exist between CCMs and major mPRs in TNBC cells. Furthermore, we firstly show mPRs in TNBC cells are localized in the nucleus and participate in nucleocytoplasmic shuttling in a coordinately synchronized fashion with CCMs under steroid actions, following the same cellular distribution as other well-defined steroid hormone receptors. Finally, for the first time, we deconvoluted the CmP signalosome by using systems biology and TNBC clinical data, which helped us understand key factors within the CmP network and identify 6 specific biomarkers with potential clinical applications associated with AAW-TNBC tumorigenesis. These novel biomarkers could have immediate clinical implications to dramatically improve health disparities among AAW-TNBCs. Show more

Keywords: Triple negative breast cancers, African American women, classic nuclear progesterone receptors, non-classic membrane progesterone receptors, cytoplasmic-nuclear trafficking, biomarkers, cancer therapy, CCM signaling complex, tumorigenesis, progesterone, mifepristone

DOI: 10.3233/CBM-210351

Citation: Cancer Biomarkers, vol. 34, no. 4, pp. 607-636, 2022

Authors: Yang, Bin | Miao, Shuai

Article Type: Research Article

Abstract: BACKGROUND: More novel biomarkers need to be discovered to improve the therapeutic efficiency of non-small cell lung cancer (NSCLC). lncRNA ELFN1-AS1 (ELFN1-AS1) was proved to play crucial roles in numerous diseases, its intention in NSCLC remains unclear. OBJECTIVE: This study aimed to investigate the function of ELFN1-AS1 and its potential mechanism in NSCLC development. METHODS: A total of 117 NSCLC patients were recruited and provided paired NSCLC tissues and normal tissues. The expression of ELFN1-AS1 was analyzed by PCR. The biological function of ELFN1-AS1 was estimated by CCK8 and Transwell assay. Additionally, the …potential mechanism underlying the function of ELFN1-AS1 was explored by the dual-luciferase reporter assay and western blotting. RESULTS: The significant upregulation of ELFN1-AS1 was found in NSCLC tissues and cells, which was closely associated with the TNM stage, lymph node metastasis status, and overall survival of patients. The knockdown of ELFN1-AS1 was found to inhibit the cellular processes and EMT of NSCLC. Moreover, ELFN1-AS1 was found to serve as a sponge to binding with miR-497, and CCNE1 was demonstrated to be the downstream target of miR-497, which was speculated as the potential mechanism underlying the function of ELFN1-AS1. CONCLUSIONS: ELFN1-AS1 acts as an independent prognostic biomarker and tumor promoter of NSCLC by sponging miR-497/CCNE1 axis. Show more

Keywords: lncRNA ELFN1-AS1, non-small lung cancer, miR-497, CCNE1, EMT, prognosis, tumor progression

DOI: 10.3233/CBM-210393

Citation: Cancer Biomarkers, vol. 34, no. 4, pp. 637-646, 2022