Cancer Biomarkers - Volume 33, issue 1

Authors: Záveský, Luděk | Jandáková, Eva | Weinberger, Vít | Hanzíková, Veronika | Slanař, Ondřej | Kohoutová, Milada

Article Type: Review Article

Abstract: Ovarian cancer comprises the most lethal gynecologic malignancy and is accompanied by the high potential for the incidence of metastasis, recurrence and chemotherapy resistance, often associated with a formation of ascitic fluid. The differentially expressed ascites-derived microRNAs may be linked to ovarian carcinogenesis. The article focuses on a number of miRNAs that share a common expression pattern as determined by independent studies using ascites samples and with regard to their functions and outcomes in experimental and clinical investigations. Let-7b and miR-143 have featured as tumor suppressors in ovarian cancer, which is in line with data on other types of …cancer. Although two miRNAs, i.e. miR-26a-5p and miR-145-5p, act principally as tumor suppressor miRNAs, they occasionally exhibit oncogenic roles. The performance of miR-95-3p, upregulated in ascites, is open to debate given the current lack of supportive data on ovarian cancer; however, data on other cancers indicates its probable oncogenic role. Different findings have been reported for miR-182-5p and miR-200c-3p; in addition to their presumed oncogenic roles, contrasting findings have indicated their ambivalent functions. Further research is required for the identification and evaluation of the potential of specific miRNAs in the diagnosis, prediction, treatment and outcomes of ovarian cancer patients. Show more

Keywords: Ovarian cancer, ascites, effusion, microRNA, tumor, tumor suppressor, oncogene

DOI: 10.3233/CBM-210219

Citation: Cancer Biomarkers, vol. 33, no. 1, pp. 1-16, 2022

Authors: Punatar, Sachin | Kandekar, Shruti | Khattry, Navin | Gokarn, Anant | Prabhash, Kumar | Bakshi, Ashish | Rane, Pallavi | Mathew, Libin | Chiplunkar, Shubhada | Kode, Jyoti

Article Type: Research Article

Abstract: BACKGROUND: Allogeneic hematopoietic stem cell transplantation (ASCT) is the preferred treatment option for patients with several hematologic disorders and immunodeficiency syndromes. Graft-versus-host disease (GVHD) is an immune mediated post-transplant complication which has a major impact on long-term transplant outcomes. OBJECTIVE: Current efforts are focused on identification of new markers that serve as potential predictors of GVHD and other post-transplant clinical outcomes. METHODS: This study includes donor harvests collected from twenty-three allogeneic donors during period 2008–2009 and respective transplant recipients followed for clinical outcomes till March 2019. Percent CD26+ and CD34+ cells in donor …harvest were analyzed using flow cytometry. Percent expression and infused dose of CD26+ and CD34+ cells were evaluated for association with various clinical outcomes. RESULTS: Total 23 healthy donors with median age of 28 years (13 males), and transplant recipients with median age of 24 years (17 males) formed the study cohort. The diagnosis included malignant (n = 13) and non-malignant (n = 10) hematological disorders. Median CD34brCD45lo HSC expression was 0.57% (IQR 0.24–1.03) while median CD26 expression was 19.64% (IQR 8.96–33.56) of all nucleated cells. CD26 expression was associated with donor age (P = 0.037). CD26 percent expression correlated with WBC engraftment (P = 0.015) and with acute GVHD (P = 0.023) whereas infused CD26 cell dose correlated with WBC engraftment (P = 0.004) and risk of CMV reactivation (P = 0.020). There was no statistically significant correlation of either CD26 expression or cell dose with chronic GVHD, EFS or OS. CONCLUSIONS: Our findings suggest a role of CD26 expression on human donor harvest as a potential predictor of acute GVHD. This association warrants further exploration. Show more

Keywords: CD26 expression, immuno-ectoenzyme, stem cell transplantation, engraftment, graft-versus-host disease, biomarker, clinical long-term follow-up

DOI: 10.3233/CBM-210137

Citation: Cancer Biomarkers, vol. 33, no. 1, pp. 17-28, 2022

Authors: Lin, Li-Han | Cheng, Hui-Wen | Liu, Chung-Ji

Article Type: Research Article

Abstract: BACKGROUND: TP53 mutation is a driver mutation of oral carcinogenesis. This study investigated cancerous and cell-free DNA (cfDNA) in patients with oral squamous cell carcinoma (OSCC) to detect the target hotspot somatic mutation of TP53. OBJECTIVE: TP53 target hotspot mutations were determined in surgically resected primary tumor samples from 107 OSCC patients. METHODS: Cancerous and cfDNA samples were examined for mutations through droplet digital polymerase chain reaction (ddPCR) by using mutation-specific assays. The ddPCR results were evaluated alongside clinicopathological data. RESULTS: In total, 23 cases had target TP53 mutations in …varying degrees. We found that OSCC had relatively low cfDNA shedding, and mutations were at low allele frequencies. Of these 23 cases, 13 had target TP53 mutations in their corresponding cfDNA. Target somatic mutations in cancerous DNA and cfDNA are related to cervical lymph node metastasis. The cfDNA concentration is related to primary tumor size, lymph node metastasis, and OSCC stage. CONCLUSIONS: Our results show that the detection of TP53 target somatic mutations in OSCC patients by using ddPCR is technically feasible. Low levels of cfDNA may produce different results between cancerous tissue and cfDNA analyses. Future research on cfDNA may quantify diagnostic biomarkers in the surveillance of OSCC patients. Show more

Keywords: cfDNA, ddPCR, oral cancer, tp53, somatic mutation

DOI: 10.3233/CBM-210275

Citation: Cancer Biomarkers, vol. 33, no. 1, pp. 29-41, 2022

Authors: Phanaksri, Teva | Yingchutrakul, Yodying | Roytrakul, Sittiruk | Prasopdee, Sattrachai | Kunjantarachot, Anthicha | Butthongkomvong, Kritiya | Tesana, Smarn | Sathavornmanee, Thanakrit | Thitapakorn, Veerachai

Article Type: Research Article

Abstract: BACKGROUND: Patients infected with a parasite often develop opisthorchiasis viverrini, which often progresses into cholangiocarcinoma (CCA) due to the asymptomatic nature of the infection. Currently, there are no effective diagnostic methods for opisthorchiasis or cholangiocarcinoma. OBJECTIVE: The aim of this study was to identify the host-responsive protein that can be developed as a diagnostic biomarker of opisthorchiasis and cholangiocarcinoma. METHODS: Plasma samples were collected from non-OVCCA, OV, and CCA subjects, and the proteomes were investigated by LC-MS/MS. Venn diagrams and protein network prediction by STITCH were used to identify the potential biomarkers. The …level of candidate protein, the plasma checkpoint protein 1 (Chk1), was measured by indirect enzyme-linked immunosorbent assay (ELISA). RESULTS: Chk1 was present in the center of the protein network analysis in both the OV and CCA groups. In addition, the plasma Chk1 levels were significantly increased in both groups (P < 0.05). The sensitivity of the opisthorchiasis viverrini and cholangiocarcinoma was 59.38% and 65.62%, respectively, while the specificity of both was 85.71%. CONCLUSION: Chk1 was identified by differential plasma proteomes and was increased in O. viverrini -infected and cholangiocarcinoma-derived plasma samples. Higher levels of plasma Chk1 levels may serve as a potential diagnostic biomarker for opisthorchiasis and cholangiocarcinoma. Show more

Keywords: Opisthorchis viverrini, cholangiocarcinoma, checkpoint protein 1, plasma proteome, LC-MS/MS

DOI: 10.3233/CBM-210170

Citation: Cancer Biomarkers, vol. 33, no. 1, pp. 43-55, 2022

Authors: Lu, Yongbin | Su, Fei | Yang, Hui | Xiao, Yi | Zhang, Xiaobin | Su, Hongxin | Zhang, Tao | Bai, Yana | Ling, Xiaoling

Article Type: Research Article

Abstract: BACKGROUND: Triple-negative breast cancer (TNBC) is a highly malignant breast cancer subtype with a poor prognosis. The cell cycle regulator cyclin A2 (CCNA2 ) plays a role in tumor development. Herein, we explored the role of CCNA2 in TNBC. METHODS: We analyzed CCNA2 expression in 15 pairs of TNBC and adjacent tissues and assessed the relationship between CCNA2 expression using the tissue microarray cohort. Furthermore, we used two TNBC cohort datasets to analyze the correlation between CCNA2 and E2F transcription factor 1 (E2F1) and a luciferase reporter to explore their association. Through …rescue experiments, we analyzed the effects of E2F1 knockdown on CCNA2 expression and cellular behavior. RESULTS: We found that CCNA2 expression in TNBC was significantly higher than that in adjacent tissues with similar observations in MDA-MB-231 and MDA-MB-468 cells. E2F1 was highly correlated with CCNA2 as observed through bioinformatics analysis (R = 0.80, P < 0.001) and through TNBC tissue verification analysis (R = 0.53, P < 0.001). We determined that E2F1 binds the + 677 position within the CCNA2 promoter. Moreover, CCNA2 overexpression increased cell proliferation, invasion, and migration owing to E2F1 upregulation in TNBC. CONCLUSION: Our data indicate that E2F1 promotes TNBC proliferation and invasion by upregulating CCNA2 expression. E2F1 and CCNA2 are potential candidates that may be targeted for effective TNBC treatment. Show more

Keywords: TNBC, E2F1, CCNA2, tumorigenicity

DOI: 10.3233/CBM-210149

Citation: Cancer Biomarkers, vol. 33, no. 1, pp. 57-70, 2022

Authors: Zhu, Li-Rong | Yuan, Rong-Xia | Xia, Xian-Bin | Wang, Yi | Zhu, Yu-Min | Fi, Ling | Li, Jian

Article Type: Research Article

Abstract: BACKGROUND: Differential diagnosis between malignant pleural effusion (MPE) and benign pleural effusion (BPE) remains a clinical challenge. OBJECTIVE: The aim of the study is to assess the efficacy of the serum and pleural fluid (PF) miRNA panels in distinguishing MPE from BPE. METHODS: Fourteen candidate miRNAs which were shown aberrant expression in lung cancer based on previous studies were tested by quantitative real-time PCR (qRT-PCR) in 20 MPE patients and 20 BPE patients. Significantly aberrantly expressed miRNAs were further assessed by qRT-PCR in all patients enrolled in this study. A receiver operating characteristic …(ROC) curve was constructed, and the area under the ROC curve (AUC) was calculated to evaluated the diagnostic performance of the miRNAs. RESULTS: miR-21, miR-29c and miR-182 were found to be significantly aberrantly expressed in the serum and PF of MPE patients. The AUCs for the combination of miR-21, miR-29c and miR-182 in serum and PF were 0.832 and 0.89 respectively in distinguishing MPE from infection-associated PE including tuberculous pleurisy and parapneumonia PE, and 0.866 and 0.919 respectively for differentiating MPE from heart failure-associated PE, which were superior to AUC of each individual miRNAs. CONCLUSIONS: miR-21, miR-29c and miR-182 in serum and PF could be useful biomarkers for diagnosis of MPE. Show more

Keywords: Pleural effusion, differential diagnosis, biomarkers, miR-21, miR-29c, miR-182

DOI: 10.3233/CBM-210090

Citation: Cancer Biomarkers, vol. 33, no. 1, pp. 71-82, 2022

Authors: Santos, Everton Cruz | Binato, Renata | Fernandes, Priscila Valverde | Ferreira, Maria Aparecida | Abdelhay, Eliana

Article Type: Research Article

Abstract: BACKGROUND: Gastric cancer (GC) is the third leading cause of cancer worldwide. According to the Lauren classification, gastric adenocarcinoma is divided into two subtypes: diffuse and intestinal. The development of intestinal gastric cancer (IGC) can take years and involves multiple factors. OBJECTIVE: To investigate the protein profile of tumor samples from patients with IGC in comparison with adjacent nontumor tissue samples. METHODS: We used label-free nano-LC-MS/MS to identify proteins from the tissues samples. The results were analyzed using MetaCore™ software to access functional enrichment information. Protein-protein interactions (PPI) were predicted using STRING analysis. …Hub proteins were determined using the Cytoscape plugin, CytoHubba. Survival analysis was performed using KM plotter. We identified 429 differentially expressed proteins whose pathways and processes were related to protein folding, apoptosis, and immune response. RESULTS: The PPI network of these proteins showed enrichment modules related to the regulation of cell death, immune system, neutrophil degranulation, metabolism of RNA and chromatin DNA binding. From the PPI network, we identified 20 differentially expressed hub proteins, and assessed the prognostic value of the expression of genes that encode them. Among them, the expression of four hub genes was significantly associated with the overall survival of IGC patients. CONCLUSIONS: This study reveals important findings that affect IGC development based on specific biological alterations in IGC patients. Bioinformatics analysis showed that the pathogenesis of IGC patients is complex and involves different interconnected biological processes. These findings may be useful in research on new targets to develop novel therapies to improve the overall survival of patients with IGC. Show more

Keywords: Protein-protein interaction, intestinal gastric cancer, proteomics, hub proteins

DOI: 10.3233/CBM-203225

Citation: Cancer Biomarkers, vol. 33, no. 1, pp. 83-96, 2022

Authors: Khalighfard, Solmaz | Kalhori, Mohammad Reza | Amiriani, Taghi | Poorkhani, Amirhoushang | Khori, Vahid | Esmati, Ebrahim | Lashkari, Marzieh | Najafi, Ali | Alizadeh, Ali Mohammad

Article Type: Research Article

Abstract: BACKGROUND: The discovery of miRNA/mRNA interactions in several biological samples prompted the researchers to explore new biomarkers in tumors. OBJECTIVE: We aimed to investigate the interactions of miRNA/mRNA in response to radiotherapy in the plasma samples of rectal cancer patients. METHODS: Five microarray datasets related to cancerous and non-cancerous individuals were first used to construct networks. The databases of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were applied to analyze pathway enrichment. The plasma samples were then collected from 55 patients with recently diagnosed rectal cancer and 10 healthy …subjects. For radiotherapy courses, the patients have consecutively received 30 sessions of local radiation for six weeks. At last, the expression of selected genes and miRNAs was experimentally measured before and after radiotherapy by qPCR, and the protein levels of the target genes were measured by ELISA assay. We evaluated the therapeutic responses based on the tumor regression grade of the Dworak classification. RESULTS: We identified 5 up-regulated and 5 down-regulated miRNAs and 8 up-regulated and 3 down-regulated genes of the databases. There was a significant increase in tumor suppressor miRNAs, including miR-101-3p, miR-145-5p, miR-26a-5p, miR-34a-5p, and a significant decrease in oncomiRs, including miR-221-3p and miR-17-5p, after radiotherapy compared to the pre-treatment. Moreover, the up-regulated miR-17-5p and miR-221-5p and the down-regulated miR-101-3p and miR-145-5p were directly related to rectal cancer through the interaction with the Wnt, RAS, PI3K, and TGF-β signaling pathways. An analysis of receiver operating characteristics showed that miRNAs 221, 17, and 23 were response-related in locally advanced rectal cancer patients. CONCLUSIONS: It seems that monitoring the miRNA/mRNA interactions during radiotherapy can be an appropriate diagnostic tool to track the recovery process and respond to standard therapies. Show more

Keywords: Radiotherapy, rectal cancer, gene, protein, microarray, microRNA

DOI: 10.3233/CBM-210079

Citation: Cancer Biomarkers, vol. 33, no. 1, pp. 97-110, 2022

Authors: Rashid, Faiza A. | Khan, Mosin S. | Tabassum, Sobia | Aiman, Aiffa | Jadoon, Maharij H.

Article Type: Research Article

Abstract: BACKGROUND: Somatic variations in rearranged during transfection (RET) proto-oncogene acts to influence Thyroid cancer (TC) in a low penetrance manner, but their effects tend to vary between different populations. OBJECTIVE: This case-control study was aimed to evaluate effect of RET G691S, S904S and L769L single nucleotide polymorphisms (SNPs) on the risk for differentiated thyroid carcinoma (DTC). METHODS: A total of 180 patients and 220 controls were genotyped by Polymerase chain reaction – restriction fragment length polymorphism (PCR-RFLP). Di-Deoxy Sanger sequencing was performed on 100 samples with variations and 20 wild samples for …each amplified exon. In addition, In Silico tools were used to evaluate structural and functional impact of individual SNPs in disease progression. RESULTS: In RET G691S/L769L/S904S SNPs, frequency of variant genotypes in DTC cases was 61.1%, 54.4% and 76.6% as compared to 45.9%, 43.6% and 89.09% in controls respectively (P ⩽ 0.05). In Silico analysis revealed that different protein formed due to G691S substitution decreases the stability of 3D structure of protein. The RET G691S and L769L SNP followed “Dominant” but RET S904S SNP confirmed an “Additive” mode of inheritance. CONCLUSION: RET G691S/L769L/S904S SNPs are significantly associated with DTC with G691S SNP declining the stability of final protein product. Show more

Keywords: Thyroid cancer, RET, DTC, SNP, PTC

DOI: 10.3233/CBM-210088

Citation: Cancer Biomarkers, vol. 33, no. 1, pp. 111-121, 2022

Authors: Huang, Lili | Zhou, Yan | Sun, Qiuwei | Cao, Lei | Zhang, Xueguang

Article Type: Research Article

Abstract: BACKGROUND and OBJECTIVE: Gastric adenocarcinoma (GAC) is one of the most common malignancies. Increasing data have indicated a correlation between soluble B7-H3 (sB7-H3) levels and tumor malignancies. In this study, we aim to investigate the level of soluble B7-H3 in serum of GAC patients. Further, we analyze the correlation between sB7-H3 level and tissue B7-H3 expression and explore the clinical evaluation value of sB7-H3 associated with pathological characteristics and prognosis of GAC patients. METHODS: One hundred and twenty-eight serum and tissue samples of GAC, 20 serum and tissue samples of gastritis patients and 77 serum, 5 …tissue samples of healthy controls were collected. The serum levels of sB7-H3 were detected by Enzyme-linked immunosorbent assay (ELISA), while the expression of membrane B7-H3 (mB7-H3) and Ki67 were evaluated by immunohistochemistry. The correlation between sB7-H3 and mB7-H3, sB7-H3 and Ki67, sB7-H3 or mB7-H3 and clinical features were analyzed by Pearson’s Chi-square test. RESULTS: Both serum level of sB7-H3 and tissue B7-H3 of GAC patients were significantly higher than those of gastritis patients and healthy controls. sB7-H3 level was correlated with total B7-H3 expression in tissues (r = 0.2801, P = 0.0014). Notably, the concentration of sB7-H3 was correlated with its expression of membrane form in tumor cells (r = 0.3251, P = 0.002) while not in stromal cells (r = 0.07676, P = 0.3891). Moreover, the levels of sB7-H3 in patients with TNM stage III/IV or with infiltration depth T3/T4 or with lymph node metastasis were significantly higher than those of patients with TNM stage I/II (P = 0.0020) or with Infiltration depth T1/T2 (P = 0.0169) or with no lymph node metastasis (P = 0.0086). Tumor B7-H3 score, but not stromal B7-H3 score, in patients with TNM stage III/IV or with lymph node metastasis was significantly higher than those with TNM stage I/II (P = 0.0150) or with no lymph node metastasis (P = 0.182). CONCLUSIONS: Soluble B7-H3 level may reflect the tissue B7-H3 expression on tumor cells of GAC tissues. Elevated level of sB7-H3 in serum suggests poor clinical pathological characteristics of GAC patients. Show more

Keywords: Gastric adenocarcinoma, soluble B7-H3, membrane B7-H3, prognosis

DOI: 10.3233/CBM-210178

Citation: Cancer Biomarkers, vol. 33, no. 1, pp. 123-129, 2022