Cancer Biomarkers - Volume 34, issue 3

Authors: Wang, Chunhui | Che, Jizhong | Jiang, Ying | Chen, Ping | Bao, Guochang | Li, Chunsheng

Article Type: Research Article

Abstract: BACKGROUND: CDT1 is the essential regulator of the initiation of DNA replication. Overexpressed CDT1 can cause DNA damage through re-replication. However, the function of CDT1 in prostate cancer (PCa) development has not been established. METHODS: Through bioinformatics, expression levels of CDT1 were found to be higher in metastatic PCa when compared to primary PCa. Then, immunohistochemical staining confirmed that the expression of CDT1 was significantly correlated with the occurrence of distant metastasis. For PCa cells, we established a stable clones knockdown CDT1. MTT was used in analyzing the proliferation ability of cells. Migration as well as …invasion assays were performed. Effects of CDT1 knockdown on the cell cycle were evaluated by flow cytometry. Expression levels of EMT-associated markers in PCa cells were determined by Western blotting. And PI3K/AKT/GSK3β , a signaling molecule recognized in PCa that can regulate EMT, was detected in protein level. RESULTS: Over expression of CDT1 in PCa cells enhanced cell migration, invasion, tumor metastasis and was correlated with cell cycle regulation. Our results showed that knockdown of CDT1 inhibited G1 to S phase transition and induced the G1 phase cell cycle arrest in PCa cells. Moreover, it upregulated the expressions of epithelial markers (E-cadherin) and down-regulated mesenchymal markers (including Slug, N-cadherin, MMP2, vimentin, Snail, and MMP9) via regulating the phosphorylation level of PI3K, AKT and GSK3β . CONCLUSIONS: CDT1 promotes PCa cell metastasis by promoting cell cycle and PI3K/AKT/GSK3β mediated epithelial-mesenchymal transition (EMT) progression and may be a therapeutic target for metastatic PCa. Show more

Keywords: CDT1, cell cycle, EMT, metastasis, prostate cancer

DOI: 10.3233/CBM-210389

Citation: Cancer Biomarkers, vol. 34, no. 3, pp. 459-469, 2022

Authors: Liu, Cheng | Zou, Xuan | Song, Guoxin | Fan, Xingchen | Peng, Shuang | Zhang, Shiyu | Geng, Xiangnan | zhou, Xin | Wang, Tongshan | Cheng, Wenfang | Zhu, Wei

Article Type: Research Article

Abstract: BACKGROUND: Several studies have demonstrated that microRNAs (miRNAs) and target mRNAs are associated with different frequencies of microsatellite instability. OBJECTIVE: The study aimed to elucidate the profiles of miRNAs and target mRNAs expression and their associations with the phenotypic hallmarks of microsatellite instability in colorectal cancers (CRC) by integrating transcriptomic, immunophenotype, methylation, mutation, and survival data. METHODS: Differentially expressed miRNAs (DEmiRNAs) and mRNAs (DEmRNAs) were screened out and then the miRNA-mRNA regulatory pairs were identified through two databases. We verified that the expression levels were detected in 40 microsatellite instable (MSI) and 40 …microsatellite stable (MSS) CRC samples and used the logistic regression and the Cox regression method to evaluate the diagnostic and prognostic value of negative regulatory pairs respectively. RESULTS: The best diagnostic model that combines miR-31-5p, PLAGL2, miR-361-5p, and RAB27B, which were associated with immune microenvironment, tumor mutation burden (TMB), and overall DNA methylation, could significantly predict microsatellite instability in colon tissues. MiR-31-5p and RAB27B could also predict the overall survival of MSS CRCs. CONCLUSION: This study generated a predictive model of the combination of miRNAs and mRNAs to distinguish MSI versus MSS CRCs and elaborated their potential molecular mechanisms and biological functions. Show more

Keywords: miRNA, miRNA-mRNA networks, microsatellite instability, colorectal cancer

DOI: 10.3233/CBM-210408

Citation: Cancer Biomarkers, vol. 34, no. 3, pp. 471-483, 2022

Authors: Majek, Pavel | Sovova, Zofie | Pecankova, Klara | Cermak, Jaroslav | Gasova, Zdenka | Pecherkova, Pavla | Ignjatovic, Vera | Dyr, Jan E.

Article Type: Research Article

Abstract: BACKGROUND: Leucine-rich alpha-2-glycoprotein (LRG) has been repeatedly proposed as a potential plasma biomarker for myelodysplastic syndrome (MDS). OBJECTIVE: The goal of our work was to establish the total LRG plasma level and LRG posttranslational modifications (PTMs) as a suitable MDS biomarker. METHODS: The total plasma LRG concentration was determined with ELISA, whilst the LRG-specific PTMs and their locations, were established using mass spectrometry and public mass spectrometry data re-analysis. Homology modelling and sequence analysis were used to establish the potential impact of PTMs on LRG functions via their impact on the LRG structure. …RESULTS: While the results showed that the total LRG plasma concentration is not a suitable MDS marker, alterations within two LRG sites correlated with MDS diagnosis (p = 0.0011). Sequence analysis and the homology model suggest the influence of PTMs within the two LRG sites on the function of this protein. CONCLUSIONS: We report the presence of LRG proteoforms that correlate with diagnosis in the plasma of MDS patients. The combination of mass spectrometry, re-analysis of publicly available data, and homology modelling, represents an approach that can be used for any protein to predict clinically relevant protein sites for biomarker research despite the character of the PTMs being unknown. Show more

Keywords: Myelodysplastic syndrome, MDS, leucine-rich alpha-2-glycoprotein, LRG, proteomics

DOI: 10.3233/CBM-210033

Citation: Cancer Biomarkers, vol. 34, no. 3, pp. 485-492, 2022

Authors: Winter, Jean M. | Sheehan-Hennessy, Lorraine | Yao, Beibei | Pedersen, Susanne K. | Wassie, Molla M. | Eaton, Michael | Chong, Michael | Young, Graeme P. | Symonds, Erin L.

Article Type: Research Article

Abstract: BACKGROUND: Detection of circulating cell-free DNA (ccfDNA) methylated in BCAT1 and IKZF1 is sensitive for detection of colorectal cancer (CRC), but it is not known if these biomarkers are present in other common adenocarcinomas. OBJECTIVE: Compare methylation levels of BCAT1 and IKZF1 in tissue and plasma from breast, prostate, and colorectal cancer patients. METHODS: Blood was collected from 290 CRC, 32 breast and 101 prostate cancer patients, and 606 cancer-free controls. Tumor and matched normal tissues were collected at surgery: 26 breast, 9 prostate and 15 CRC. DNA methylation …in BCAT1 and IKZF1 was measured in blood and tissues. RESULTS: Either biomarker was detected in blood from 175/290 (60.3%) of CRC patients. The detection rate was higher than that measured in controls (48/606 (8.1%), OR = 18.2, 95%CI: 11.1–29.0). The test positivity rates in breast and prostate cancer patients were 9.4% (3/32) and 6.9% (7/101), respectively, and not significantly different to that measured in gender-matched controls (8.0% (33/382) females (OR = 0.84, 95%CI: 0.23–3.1) and 7.6% (26/318) males (OR = 0.86, 95%CI: 0.65–2.1). In tumor and non-neoplastic tissues, 93.5% (14/15) of CRC tumors were methylated in BCAT1 and/or IKZF1 (p < 0.004). Only 11.5% (3/26) and 44.4% (4/9) (p = 0.083) of breast and prostate tumors were hypermethylated in these two genes. CONCLUSIONS: Detection of circulating DNA methylated in BCAT1 and IKZF1 is sensitive and specific for CRC but not breast or prostate cancer. Show more

Keywords: ctDNA, biomarker, DNA methylation, bowel cancer, sensitivity, specificity, diagnostic accuracy

DOI: 10.3233/CBM-210399

Citation: Cancer Biomarkers, vol. 34, no. 3, pp. 493-503, 2022

Authors: Mehraj, Umar | Sofi, Shazia | Alshehri, Bader | Mir, Manzoor A.

Article Type: Research Article

Abstract: BACKGROUND: Globally, breast cancer (BC) has become one of the most prevalent malignancies and the leading cause of tumor-related deaths among women. Dysregulation of the cell cycle is a well-known hallmark of cancer development and metastasis. CDKs are essential components of the cell-cycle regulatory system with aberrant expression in a variety of cancers, including BC. In the development of targeted cancer treatment, reestablishing the regulation of the cell cycle by modulation of CDKs has emerged as a promising approach. METHODS: Herein, we used a bioinformatic approach to assess the expression pattern, prognostic and diagnostic importance, and …clinical relevance of CDKs in BC. Additionally, we conducted a functional enrichment analysis of deregulated CDKs using the STRING and KEGG databases to delineate the role of CDKs in breast tumorigenesis. RESULTS: Gene expression analysis revealed substantial deregulation of CDKs in BC, with CDK1, CDK11A, and CDK18 showing a fold change of > ± 1.5. Also, metastatic tumors showed high expression of CDK1 in the single cell RNA sequencing analysis of primary and metastatic breast tumors. Additionally, it was found that dysregulated CDK expression affects overall survival (OS) and relapse-free survival (RFS) of BC patients. CONCLUSION: The study’s multimodal analytical methodologies imply that modulating CDKs for BC treatment is a promising approach. Show more

Keywords: Breast cancer, CDKs, gene expression, prognostic factor, bioinformatics, cell cycle

DOI: 10.3233/CBM-210186

Citation: Cancer Biomarkers, vol. 34, no. 3, pp. 505-519, 2022