Cancer Biomarkers - Volume 32, issue 4

Authors: Arroyo, Esteban | Donís, Sergio Piñeiro | Petronacci, Cintia M. Chamorro | Alves, Monica G. Oliveira | Mendía, Xabier Marichalar | Fernandes, Darcy | Pouso, Alejandro I. Lorenzo | Bufalino, Andreia | Bravo López, Susana | Sayáns, Mario Pérez

Article Type: Systematic Review

Abstract: By using a meta-analytical approach, this study aimed to analyse the diagnostic capacity of protein-based biomarkers in saliva for the differential diagnosis of oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC) from healthy individuals as control group (HCG). Articles on protein-based biomarkers in saliva, which provided quantitative expression in individuals with clinical and histopathological diagnosis of OPMD or oral leukoplakia (OL) were considered eligible. Searches were conducted in eight electronic databases. The methodological quality was assessed using the Quality Assessment of Diagnostic Studies tool (QUADAS-2). Functional analysis was also performed. Meta-analyses were performed using the OpenMeta …tool (Analyst). Meta-analysis was possible for 4 of the 11 biomarkers studied. Only the carcinoembryonic antigen (CEA) and the soluble fragment of cytokeratin 19 (CYFRA21) were significant for the OSCC/OPMD subgroup, both with a very low heterogeneity. CEA had an OE = 25.854 (CI95%: 13.215–38.492, p < 0.001, I2 = 0) and CYFRA21 had an OE = 9.317 (CI95%: 9.014–9.619, p < 0.001, I2 = 0). For the OPMD/HCG subgroup, only CYFRA21 was significant, with an OE = 3.679 (CI95%: 0.663–6.696, p = 0.017) although with high heterogeneity (I2 = 91.24). The CEA and CYFRA21 markers proved very useful when differentiating OSCC from OPMD. The CYFRA21 was the only protein that was capable of distinguishing between OPMD and healthy controls. Show more

Keywords: Systematic review, meta-analysis, protein-based biomarkers, saliva, oral leukoplakia, oral potentially malignant lesions

DOI: 10.3233/CBM-203043

Citation: Cancer Biomarkers, vol. 32, no. 4, pp. 411-424, 2021

Authors: Hua, Hong-Wei | Jiang, Hao-Sheng | Jia, Ling | Jia, Yi-Ping | Yao, Yu-Lan | Chen, Yi-Wen | Jiang, Feng | Lu, Dong-Qing | Zhou, Qing | Jiang, Ma-Wei | Ding, Gang

Article Type: Research Article

Abstract: BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC) is implicated in cancer progression, but its role and associated molecular mechanism in the sorafenib sensitivity of hepatocellular carcinoma cells (HCC) remains elusive. METHODS: Human HCC cell lines Hep3B and HepG2 were treated with sorafenib alone or combined with activator or inhibitor of ferroptosis. Cell viability assay, reactive oxygen species (ROS) assay, lactate dehydrogenase (LDH) assay and western blot were used to study the regulatory mechanism of SPARC on HCC cells. RESULTS: Overexpression of SPARC enhanced the cytotoxic effect of sorafenib in Hep3B and …HepG2 cells compared with parental cells. Depletion of SPARC decreased the cytotoxic effect of sorafenib in Hep3B and HepG2 cells compared with parental cells. Moreover, overexpression of SPARC significantly induced LDH release, whereas depletion of SPARC suppressed the release of LDH in Hep3B and HepG2 cells. Inhibition of ferroptosis exerted a clear inhibitory role against LDH release, whereas activation of ferroptosis promoted the release of LDH in HCC cells, as accompanied with deregulated expression of ferroptosis-related proteins. Furthermore, overexpression of SPARC induced oxidative stress, whereas depletion of SPARC suppressed the production of ROS. Deferoxamine (DFX)-induced inhibition of ferroptosis suppressed the production of ROS, while activation of ferroptosis promoted the contents of ROS in HCC cells exposed to sorafenib. CONCLUSION: Our findings give a better understanding of ferroptosis and its molecular mechanism in HCC cells that is regulated by SPARC in response to sorafenib. Show more

Keywords: Hepatocellular carcinoma, sorafenib, SPARC, ferroptosis

DOI: 10.3233/CBM-200101

Citation: Cancer Biomarkers, vol. 32, no. 4, pp. 425-433, 2021

Authors: Zhao, Hongcan | Sheng, Danli | Qian, Ze | Ye, Sunyi | Chen, Jianzhong | Tang, Zhe

Article Type: Research Article

Abstract: BACKGROUND: Colorectal carcinoma (CRC) is one of the most leading cause of cancer death all over the world. The tumor immune microenvironment is illustrated to be necessary for the progress of CRC. And the accumulating evidence indicated that tumor mutation burden (TMB) is effective in differentiating responding population of immune checkpoint inhibitor (ICI) therapies in various cancers. In this study, we aimed to evaluated the potential relationship between TMB and the recurrence risk of CRC. METHODS: The transcriptomic and clinical data of CRC patients were collected from The Cancer Genome Atlas (TCGA) database (n = …382). Then the genomic analysis of tumor mutation burden and tumor purity were conducted by a computational method based on transcriptomic data. RESULTS: Firstly, we accessed the distribution of TMB and preferences at the gene and mutation level using somatic mutation data from TCGA data about CRC. We identified that high TMB predicted better prognosis of CRC patients. Secondly, the differentially expressed genes (DEGs) between the low TMB and high TMB group was clarified. Then the protein-protein interaction (PPI) analysis was performed, and the results confirmed ten hub genes among the DEGs. Utilizing the GEPIA web-tool, we discovered that GNG4 was up-regulated in tumor tissues, and GNG4 was related to the overall survival (OS) and tumor free survival (TFS) of CRC patients. Therefore, we considered GNG4 was essential for the tumor immune microenvironment of CRC. Furthermore, we also accessed the protein level of GNG4 in CRC and liver metastases from CRC. CONCLUSIONS: In this study, GNG4 was demonstrated to be the key element of the CRC TMB, which will be essential for the ICI therapy of CRC. Besides, GNG4 was up-regulated in CRC and liver metastases from CRC tissues. Thus, we thought that GNG4 might play an important role in colorectal cancer TMB and induce its metastasis in liver. Show more

Keywords: CRC, tumor mutation burden, prognosis, GNG4, TCGA

DOI: 10.3233/CBM-203009

Citation: Cancer Biomarkers, vol. 32, no. 4, pp. 435-450, 2021

Authors: Khorshied, Mervat | Soliman, Nohair | Khorshid, Ola | Bakr, Salwa

Article Type: Research Article

Abstract: BACKGROUND: Dysregulated apoptosis is a hallmark of cancer development and progression. TRAIL and its receptors (R1 and R2) are key players in the extrinsic apoptotic pathway. Genetic alteration or blockade of TRAIL-R1 may alter its apoptotic function, and subsequently provide growth advantage to neoplastic cells. OBJECTIVE: to investigate the possible association between -C626G, -A683C and -A1322G single nucleotide polymorphisms (SNPs) of TRAIL-R1 gene and the susceptibility to B-NHL in a cohort of Egyptians. METHODS: Genotypic analysis was performed for 100 newly diagnosed B-NHL patients and 150 age and gender matched healthy controls. …RESULTS: The polymorphic alleles of -C626G and -A1322G conferred almost twofold increased risk of B-NHL (OR = 1.76; 95%CI = 1.01–3.22 and OR = 1.89; 95%CI = 1.01–3.75 respectively). There was no statistical difference in the distribution of TRAIL-R1-A683C alleles/genotypes between B-NHL patients and controls. B-NHL risk increased when -C626G and -A1322G polymorphic genotypes were co-inherited (OR = 3.57; 95%CI = 1.29–9.84). The risk conferred by -C626G SNP increased for DLBCL (OR = 3.39, 95% CI: 1.61–7.16). CONCLUSION: TRAIL-R1–C626G and -A1322G polymorphisms could be considered as molecular risk factors for B-NHL especially DLBCL. The data provided by the current study constitute an initial millstone towards developing a large-scale dataset for genetic variations that could contribute to lymphomagenesis in Egyptian population. Show more

Keywords: B-NHL, TRAIL-R1, C626G, A683C, -A1322G, Egypt

DOI: 10.3233/CBM-201786

Citation: Cancer Biomarkers, vol. 32, no. 4, pp. 451-458, 2021

Authors: Hussan, Syeda Saliah | Maqsood, Neha | Wang, Qingbing | Tao, Sun | Sadaf, Saima

Article Type: Research Article

Abstract: BACKGROUND: Genetic and epigenetic dysregulation of Wnt signaling pathway is widely linked up with abnormal proliferation and/or epithelial-to-mesenchymal transition, in different cancer cell types. OBJECTIVE: In the present research, we have tested whether promoter DNA methylation of a set of Wnt/non-Wnt genes such as [cadherin-2 (CDH2)], “present in circulation”, could serve as “bone-marrow biopsy surrogate” and help in diagnosing the status, sub-type or treatment outcome in pediatric acute lymphoblastic leukemia (ALL) patients. METHODS: Promoter DNA methylation was quantified in the bisulfite modified blood from the pediatric ALL patients (n = …86) in comparison with age-matched cancer-free subjects (n = 28), using real-time methylation specific PCR followed by rigorous statistical validations. RESULTS: The observed methylation index, sensitivity and specificity of selected molecular markers (viz., SALL1, WNT5α , LRP1b, CDH2) in patients’ liquid-biopsies was clinically significant showing high positive correlation in the pre-B ALL cases (p -value < 0.001). A substantial drop in promoter methylation signal of the follow-up/post-treatment patients was also noted (p -value < 0.001), which suggested an impending role of minimally invasive liquid-biopsy approach in the diagnosis and/or therapeutic monitoring of pediatric leukemia. CONCLUSIONS: Whilst the reported metadata provides useful insight into the plausible involvement of epigenetic glitches in leukemogensis, our findings strengthen the remarkable functional consequences of dysregulated Wnt signaling genes in the hematological malignancies besides offering a novel panel of epigenetic marks. Show more

Keywords: Acute lymphoblastic leukemia, biomarker, bisulfite conversion, CpG island, diagnosis, promoter hypermethylation, Wnt signaling pathway

DOI: 10.3233/CBM-200814

Citation: Cancer Biomarkers, vol. 32, no. 4, pp. 459-470, 2021

Authors: Celik, Zeliha Esin | Demir, Fatih | Yonar, Harun | Ugras, Serdar

Article Type: Research Article

Abstract: BACKGROUND: Breast cancer (BC) is a common malignancy in women. Some molecules, including endocan, are still under investigation as potential prognostic factors in BC. OBJECTIVE: In the present study, we aimed to determine the relationship between endocan expression and clinicopathological prognostic parameters in BC. METHODS: Two hundred and fifty-five patients diagnosed with BC were included in the present study. The immuno-reactivity scoring (IRS) system was used to reveal the tissue endocan expression levels. RESULTS: We found that endocan expression is associated with tumor necrosis, tumor size, and the presence of …lobular carcinoma in situ (LCIS) in BC. There was no relationship between endocan expression and survival as well as other clinicopathological prognostic parameters. CONCLUSION: Endocan overexpression in BC is associated with some prognostic parameters, including tumor necrosis, tumor size, and the presence of LCIS. Further studies with larger series are needed to reveal the clinical and therapeutic implications of endocan in BC. Show more

Keywords: Breast cancer, pathology, Endocan, immunohistochemistry, prognosis

DOI: 10.3233/CBM-201026

Citation: Cancer Biomarkers, vol. 32, no. 4, pp. 471-477, 2021

Authors: Wei, Min | Chen, Youguo | Du, Wensheng

Article Type: Research Article

Abstract: BACKGROUND: Cervical cancer (CC) is the most common form of gynecological malignancy. Long intergenic non-protein coding RNA 858 (LINC00858) has been identified to participate in multiple cancers. However, the role and mechanism of LINC00858 in CC cells are still elusive. AIM: The aim of this study is to explore the biological functions and mechanisms of LINC00858 in CC cells. METHODS: RT-qPCR analysis was used to examine the expression of LINC00858 in CC cells. EdU and colony formation assay were utilized to assess cell proliferation. TUNEL assay and flow cytometry assay were conducted to …assess cell apoptosis. The mechanism regarding LINC00858 was certified through RNA pull down, RIP and luciferase reporter assays. RESULTS: The up-regulated LINC00858 was detected in CC cells. Reduction of LINC00858 effectively subdued CC cells proliferation and stimulated cell apoptosis. LINC00858 was determined to bind with miR-3064-5p and up-regulate VMA21 in CC cells. In rescue assays, miR-3064-5p down-regulation and VMA21 up-regulation were able to counteract the effect caused by LINC00858 decrease on CC cell proliferation and apoptosis. CONCLUSION: LINC00858 enhances cell proliferation, while restraining cell apoptosis in CC through targeting miR-3064-5p/VMA21 axis, implying that LINC00858 may serve as a promising therapeutic target for CC. Show more

Keywords: LINC00858, miR-3064-5p, VMA21, cervical cancer

DOI: 10.3233/CBM-200033

Citation: Cancer Biomarkers, vol. 32, no. 4, pp. 479-489, 2021

Authors: Topno, Rachel | Nazam, Nazia | Kumari, Pallawi | Kumar, Manoj | Agarwal, Pallavi

Article Type: Research Article

Abstract: BACKGROUND: The breast cancer subtype deficient in estrogen receptor and human epidermal growth factor receptor-2 (ER-/HER2-) displays enhanced aggressiveness, metastasis and disease relapse due to chemoresistance. ER-/HER2- patients lack molecularly targeted treatment hence, new therapeutic and prognostic biomarkers are required for better patient management. OBJECTIVES: To investigate the prognostic role of protein tyrosine phosphatase genes in Breast Cancer and their relevance as predictive markers for chemoresistance. METHODS: We examined the expression of 114 protein tyrosine phosphatase (PTP) genes in 1700 breast cancer patient’s tumor samples with respect to ER-/HER2- subtype. Correlation of relevant …candidates with chemoresistance was analyzed in breast cancer cells resistant to taxane/anthracycline based drugs. The prognostic value of key candidates was assessed using Kaplan Meier plots and Nottingham prognostic index and expression pattern was confirmed using qRT-PCR. The epigenetic regulation was analyzed using ChIP-Seq datasets. By plotting ROC plots, clinical outcome after treatment with taxane and anthracycline was established. RESULTS: Overexpression of CDC25A and CDC25C and under-expression of DUSP16 was observed in tumor samples of ER-/HER2- patients and breast cancer cells. Similar expression patterns of these candidate genes were observed in MCF7 cells resistant to paclitaxel and adriamycin and also correlated with poor prognosis of breast cancer patients. Increased CDC25A and CDC25C in ER-/HER2- cells was found to be regulated epigenetically by histone H3K4 methylation. Overall, the present study establishes increased expression of protein tyrosine phosphatase CDC25C as a poor prognostic marker for breast cancer. CONCLUSION: Our study highlights the role of CDC25C in chemoresistance to taxane and anthracycline based therapy and proposes CDC25C as a potential predictive marker for these cancer therapies. Show more

Keywords: Breast cancer, chemoresistance, protein tyrosine phosphatase, ER-/HER2-, DUSP16, CDC25C

DOI: 10.3233/CBM-200858

Citation: Cancer Biomarkers, vol. 32, no. 4, pp. 491-504, 2021

Authors: Khadirnaikar, Seema | Chatterjee, Annesha | Shukla, Sudhanshu Kumar

Article Type: Research Article

Abstract: BACKGROUND: Leukocyte infiltration plays an critical role in outcome of various diseases including Lung adenocarcinoma (LUAD). OBJECTIVES: To understand the genetic and epigenetic factors affecting leukocyte infiltration and identification and validation of immune based biomarkers. METHOD: Correlation analysis was done to get the associations of the factors. CIBERSORT analysis was done for immune cell infiltration. Genetic and epigenetic analysis were performed. Cox regression was carried out for survival. RESULTS: We categorized the TCGA-LUAD patients based on Leukocyte fraction (LF) and performed extensive immunogenomic analysis. Interestingly, we showed that LF has …a negative correlation with copy number variation (CNV) but not with mutational load. However, several individual genetic mutations, including KRAS and KEAP1, were significantly linked with LF. Also, as expected, patients with high LF showed significantly increased expression of genes involved in leukocyte migration and activation. DNA methylation changes also showed a strong association with LF and regulated a significant proportion of genes associated with LF. We also developed and validated an independent prognostic immune signature using the top six prognostic genes associated with LF. CONCLUSION: Together, we have identified clinical, genetic, and epigenetic variations associated with LUAD LF and developed an immune gene-based signature for disease prognostication. Show more

Keywords: Lung adenocarcinoma, Immune landscape, leukocyte fraction, prognosis

DOI: 10.3233/CBM-203071

Citation: Cancer Biomarkers, vol. 32, no. 4, pp. 505-517, 2021

Authors: Caner, Vildan | Cetin, Gokhan Ozan | Hacioglu, Sibel | Baris, Ikbal Cansu | Tepeli, Emre | Turk, Nilay Sen | Bagci, Gulseren | Yararbas, Kanay | Cagliyan, Gulsum

Article Type: Research Article

Abstract: BACKGROUND: Due to the heterogeneous nature of Diffuse Large B-cell Lymphoma (DLBCL), the mechanisms underlying tumor development and progression have not yet been fully elucidated. OBJECTIVE: This study aimed to compare the characteristics of plasma exosomes of DLBCL patients and healthy individuals and to evaluate the exosomal interactions between DLBCL cell lines and normal B-cells. METHODS: Exosome isolation was performed using an ultracentrifugation-based protocol from plasma of 20 patients with DLBCL and 20 controls. The expression of miRNAs from exosome samples was analyzed using a miRNA expression microarray. The presence of exosome-mediated communication …between the lymphoma cells and normal B-cells was determined by the co-culture model. RESULTS: A significant increase in plasma exosome concentrations of DLBCL patients was observed. There was also a significant decrease in the expression of 33 miRNAs in plasma exosomes of DLBCL patients. It was determined that normal B-cells internalize DLBCL-derived exosomes and then miRNA expression differences observed in normal B-cells are specific to lymphoma-subtypes. CONCLUSIONS: MiR-3960, miR-6089 and miR-939-5p can be used as the miRNA signature in DLBCL diagnosis. We suppose that the exosomes changed the molecular signature of the target cells depending on the genomic characterization of the lymphoma cells they have originated. Show more

Keywords: Diffuse large B-cell lymphoma, exosomes, miRNA, B-cells, cellular uptake

DOI: 10.3233/CBM-210110

Citation: Cancer Biomarkers, vol. 32, no. 4, pp. 519-529, 2021