Cancer Biomarkers - Volume 15, issue 2

Authors: Clancy, Cillian | Joyce, Myles R. | Kerin, Michael J.

Article Type: Review Article

Abstract: Background: Abnormal levels of microRNAs (miRNAs) have been found in the blood or its components in a number of different cancers including colorectal cancer. In addition to being abundant in circulation, miRNAs show remarkable stability in both plasma and serum making miRNAs ideal markers for early detection in colorectal cancer. Several miRNAs have been identified as potential circulating biomarkers although none have been incorporated into clinical practice. Objective: To identify the most consistently dysregulated circulating miRNAs in colorectal cancer patients according to current literature and postulate reasons for heterogeneity in results. Methods: A literature review was …performed using the electronic databases PubMed, Embase and the Cochrane Library. Results: The 6 circulating miRNAs most frequently found to be dysregulated in colorectal cancer are miR-18a-5p, miR-21-5p, miR-29a-5p, miR-92a-5p, miR-143-5p and miR-378-5p. There are, however, multiple studies with conflicting findings. Studies vary significantly in ethnicity of populations, use of endogenous controls, source of miRNAs (whole blood, serum and plasma) and methods of detection. Conclusions: Circulating miRNAs are promising diagnostic biomarkers in colorectal cancer. Further studies identifying the source of tumour derived miRNAs in circulation, including identification of exosomal miRNA content, are required. Identifying pre-profiling factors affecting miRNA expression and determining stable endogenous controls will expedite the incorporation of miRNAs into clinical practice. Show more

Keywords: Colorectal, microRNA, circulating

DOI: 10.3233/CBM-140456

Citation: Cancer Biomarkers, vol. 15, no. 2, pp. 103-113, 2015

Authors: Jiao, Shiping | Liu, Wenjie | Wu, Minqing | Peng, Cheng | Tang, Hailin | Xie, Xiaoming

Article Type: Research Article

Abstract: Background: Existing reports showed loss of Nrdp1, an E3 ubiquitin ligase, promoted breast cancer malignancy because of failure to deregulate ErbB3. However, the correlation between Nrdp1 expression with clinical data is still unknown. Objective: We explored the predictive value of Nrdp1 regarding the clinical outcome of patients and the benefit of adjuvant anthracycline-based chemotherapy. Methods: 113 primary breast cancer samples were obtained during surgery and the patients received average 10-year follow-up. We obtained Nrdp1 and ErbB3 expressions by immunohistochemstry. Results: Nrdp1 expression correlates with overall survival and disease-free survival of patients, with a hazard …ratio of 0.237 (p=0.001) and 0.280 (p< 0.001) respectively. Additionally Nrdp1 correlates inversely with ErbB3 expression in tumor tissue (p=0.009). However the prognosis of Nrdp1 was not solely dependent on its regulation of ErbB3 degradation since there was also a significant correlation between Nrdp1 and overall survival (p=0.005) in ErbB3-negative patients. In patients who received anthracycline-based chemotherapy, low Nrdp1 expression indicated decreased disease-free survival (p=0.006) and high rates of metastasis and/or recurrence (p<0.001). Conclusion: Nrdp1 may serve as a useful biomarker for the clinical outcome and efficacy of adjuvant anthracyclines-based chemotherapy in breast cancer.The prognosis of Nrdp1 was not solely dependent on its deregulation of ErbB3. Show more

Keywords: Nrdp1, ErbB3, breast cancer, biomarker, prognosis, anthracyclines-based chemotherapy

DOI: 10.3233/CBM-140443

Citation: Cancer Biomarkers, vol. 15, no. 2, pp. 115-123, 2015

Authors: Singh, Prithvi Kumar | Bogra, Jaishri | Chandra, Girish | Ahmad, Mohammad Kaleem | Gupta, Rajni | Kumar, Vijay | Jain, Amita | Ali Mahdi, Abbas

Article Type: Research Article

Abstract: Background: The pro-inflammatory cytokines play an essential role in immune response and are involved in a variety of inflammatory and infectious disease. Tumor necrosis factor alpha (TNF-α) gene polymorphism has been a potential determinant of susceptibility to various types of cancer. Objective: To evaluate the association of TNF-α gene promoter (-238) G/A and (-308) G/A polymorphisms with the susceptibility of OSCC patients in North Indian population. Methods: A total 272 patients with OSCC and 185 healthy volunteers were genotypes for the TNF-α (-238) G/A and (-308) G/A gene polymorphism. Genotypes were identified by polymerase chain reaction …(PCR) restriction fragment length polymorphism (RFLP). Genotype frequencies were evaluated by Chi-square test and Odds ratio (OR) relative risk. Results: TNF-α (-238) G/A polymorphism was significantly associated with OSCC patients as compared to healthy volunteers (GG vs. GA: OR=0.3500, 95% CI=0.1289–09502; p=0.036; G vs. A: OR=0.3589 1.477, 95% CI=0.1335–0.9652; p=0.0386). No significant association was found in TNF-α (-308) G/A gene polymorphism with OSCC patients and controls. Conclusions: We conclude that the TNF-α (-238) G/A polymorphism was significantly associated with OSCC however TNF-α (-308) G/A polymorphism was not associated in OSCC patients. Show more

Keywords: Oral squamous cell carcinoma, cytokines, tumor necrosis factor-α, inflammation, genotype

DOI: 10.3233/CBM-140444

Citation: Cancer Biomarkers, vol. 15, no. 2, pp. 125-131, 2015

Authors: Bobrowska-Korczak, Barbara | Skrajnowska, Dorota | Tokarz, Andrzej | Bialek, Slawomir | Jezierska, Ewelina

Article Type: Research Article

Abstract: The aim of the present study was to assess the effect of dietary supplementation (with zinc or zinc and polyphenolic compounds – resveratrol or genistein) on antioxidant enzymes (glutathione peroxidase – GPx, catalase – CAT and superoxide dismutase – SOD) and the frequency of microsatellite instability (MSI) in a widely used model of mammary carcinogenesis induced in the rat by treatment with 7,12-dimethyl-1,2-benz[a]anthracene (DMBA). The impact of selected compounds on the intensity of DMBA-induced carcinogenesis was also assessed. Sixty four Sprague-Dawley female rats were divided into study groups which, apart from the standard diet and DMBA, were treated …with zinc, zinc and resveratrol or zinc and genistein via gavage for a period ranging from 40 days to 20 weeks of age. On the basis of the obtained results it can be said that synergistic reaction between Zn(II) and genistein causes a delay in cancer development as compared with the animals treated with DMBA but with no food supplementation. Supplementation with Zn(II) and polyphenolic compounds resulted in the occurrence of microsatellite instabilities in tumors. LOH (loss of heterozygosity) was found in tumor samples at microsatellite D1Mgh6 and D3Mgh9. DMBA treatment increased significantly the glutathione peroxidase activity whereas it had no effect on the SOD and CAT activities, as compared with control rats. Diet supplementation has an effect on the activity of selected antioxidant enzymes. Diet supplementation has an effect on the occurrence of microsatellite instabilities as well as on the intensity of the neoplastic process. The intensity of occurrence of microsatellite instabilities does not depend on the activity of selected antioxidant enzymes. Show more

Keywords: Glutathione peroxidase, catalase, superoxide dismutase, microsatellite instability, DMBA, supplementation

DOI: 10.3233/CBM-140445

Citation: Cancer Biomarkers, vol. 15, no. 2, pp. 133-142, 2015

Authors: Kaigorodova, Evgeniya V. | Zavyalova, Marina V. | Bogatyuk, Maria V. | Tarabanovskaya, Natalia A. | Slonimskaya, Elena M. | Perelmuter, Vladimir M.

Article Type: Research Article

Abstract: Background: Heat shock protein beta-1 (HspB1) is a chaperone of the sHsp (small heat shock protein). The common functions of sHsps are chaperone activity, inhibition of apoptosis, regulation of cell development, and cell differentiation, take part in signal transduction. Objective: To study the intracellular localization of phosphorylated features and non-phosphorylated forms of HspB1 in primary breast cancer cells and to evaluate their relationship with regional lymphatic metastasis. Material and Methods: Tumor biopsies of breast tissue were collected from 100 patients with a confirmed diagnosis of invasive carcinoma, nonspecific type, between the ages of 31–80 years. Immunohistochemistry was used …to determine the intracellular localization of phosphorylated and non-phosphorylated forms of HspB1. Results: The result of this study showed that biopsies from patients with lymph node metastasis exhibited significantly higher levels of phosphorylated forms of HspB1 in the nucleus and cytoplasm compared with the group without lymph node metastasis. Analysis showed that the expression of phosphorylated forms of the chaperone HspB1 correlates with the amount and percentage of lymph node metastases affected. Conclusion: The nuclear expression of phosphorylated and non-phosphorylated forms of the chaperone HspB1 is a marker of tumor cells associated with lymphatic metastasis of breast cancer. Show more

Keywords: Breast cancer, lymph node metastases, heat shock protein beta-1 (HspB1), prognostic markers, immunohistochemistry

DOI: 10.3233/CBM-140446

Citation: Cancer Biomarkers, vol. 15, no. 2, pp. 143-150, 2015

Authors: Raphael, Jacques | Massard, Christophe | Gong, Inna Y. | Farace, Françoise | Margery, Jacques | Billiot, Fanny | Hollebecque, Antoine | Besse, Benjamin | Soria, Jean-Charles | Planchard, David

Article Type: Research Article

Abstract: Background: The independent prognostic value of Circulating Tumour Cells (CTC) level has been demonstrated in several solid tumours. There is currently few data on Malignant Pleural Mesothelioma (MPM) and CTC. We investigated whether the presence of CTC was correlated with prognosis factors and treatment efficacy. Methods/Objectives: MPM patients (pts) were enrolled in a prospective monocentric study. CTC detection was made using the “CellSearch” assay. The correlation between the presence of CTC and worse prognosis factors was assessed using the X2 test. Comparison of Overall Survival (OS) and Progression Free Survival (PFS) according to CTC detection was performed …using the log-rank test. Results: Twenty-seven MPM pts with a median follow-up of 4.2 months were included. CTC were detected in 44% of pts with a median level of 1.5. No significant correlation was observed between the presence of CTC and worse prognosis factors. Moreover, CTC detection was not a significant predictor of OS or PFS (p=0.155 and p=0.32 respectively). Conclusions: CTC were detected in a small cohort of MPM patients. We couldn’t demonstrate a significant prognostic value or a difference in OS/PFS between CTC levels. Further analyses, validation studies and detection techniques are needed to establish their real clinical value in MPM. Show more

Keywords: Malignant pleural mesothelioma, circulating tumour cells, prognosis factors, progression free survival, overall survival.

DOI: 10.3233/CBM-140448

Citation: Cancer Biomarkers, vol. 15, no. 2, pp. 151-156, 2015

Authors: Dikaiakos, Panagiotis | Gazouli, Maria | Rizos, Spyros | Zografos, George | Theodoropoulos, George E.

Article Type: Research Article

Abstract: Background: Aberrant expression and structural alteration of miRNAs are considered to participate in cancer development. It has been suggested that common single-nucleotide polymorphisms (SNPs) in miRNAs are associated with susceptibility to several human diseases including colorectal cancer (CRC). Methods: A case-control study at 157 CRC patients and 299 healthy controls of Greek origin was undertaken in order to investigate the association between the genotype and allelic frequencies of three common SNPs (rs2910164, rs11614913 and rs3746444) in pre-miRNAs, miR-146a, miR-196a2 and miR-499. Results: The risk for CRC was significantly higher at the carriers of miR-146a rs2910164 CC …genotype and C allele (p=0.02 and p< 0.001, respectively). None of the other performed analysis showed any statistically significant results. Conclusions: Our findings suggest that the rs2910164 polymorphism in pre-miRNA, miR-146a may be associated with the risk of CRC. Show more

Keywords: Colorectal cancer, miRNA, single nucleotide polymorphisms, SNPs

DOI: 10.3233/CBM-140449

Citation: Cancer Biomarkers, vol. 15, no. 2, pp. 157-162, 2015

Authors: Lu, Min | Zhou, Lei | Zheng, Xiaohui | Quan, Yi | Wang, Xiaoli | Zhou, Xinna | Ren, Jun

Article Type: Research Article

Abstract: Background: Breast cancer stem cells (CSCs) are thought to initiate mammary tumors and render them resistant to anti-cancer therapies. However, there are currently no ideal biomarkers to identify this minority population in breast cancer. Objective: To find out the oligonucleotides with high specificity and affinity for mammosphere cells using a high capacity ssDNA library. Methods: We used the cell-SELEX (systematic evolution of ligands by exponential enrichment process) method. MCF-7 cells were cultured in serum-free media to form mammosphere cells as enriched stem cells, and were used as the positive target cells. The normal breast epithelial MCF-10A …and MCF-7sal cells, which are MCF-7 cells treated with Salinomycin, were used as the negative target cells. We collected the ssDNA pools that were bound to positive target cells, and could not bind negative target cells. Results: After 13 rounds of selection, we isolated the MS03 aptamer with high specificity and affinity for mammosphere cells. When compared with CD44+ /CD24- / low cells, MS03+ cells did not show any significant difference in sphere formation ability in vitro. In addition, 63.3% of MS03 aptamer-selected cells exhibited the CD44+ /CD24- / low phenotype. Because the MS03 aptamer is synthesized easily and non-immunogenic, it is much more flexible than CD44/CD24 as a breast CSC biomarker. Conclusions: The MS03 aptamer may become a promising molecular probe during diagnostic and therapeutic applications in breast cancer. Show more

Keywords: Breast cancer, cancer stem cell, SELEX, cell-SELEX, aptamer, biomarker

DOI: 10.3233/CBM-140450

Citation: Cancer Biomarkers, vol. 15, no. 2, pp. 163-170, 2015

Authors: Wang, Yajie | Gao, Yingtang | Shi, Wenxia | Zhai, Daokuan | Rao, Quan | Jia, Xiaobo | Liu, Jiao | Jiao, Xiaolei | Du, Zhi

Article Type: Research Article

Abstract: Background: Abnormally expressed circulating microRNA (miRNA) may serve as a potential biomarker for the diagnosis of cancer patients. Objective: We sought to determine the differentially expressed circulating microRNAs in patients with hepatitis B virus (HBV)-positive small hepatocellular carcinoma (HCC) compared to other HBV-positive benign liver diseases. Methods: The miScript miRNA PCR Array was used to detect the levels of 84 miRNAs in plasma or serum samples of patients with HBV-related small HCC (23 cases), liver cirrhosis (LC) (20 cases), chronic hepatitis B (CHB) (20 cases) and healthy controls (16 cases). MiRNAs with fold-change values ≥ 2 …or ≤ 0.5 compared to healthy controls were considered to be deregulated miRNAs. Results: The results of duplicate plasma experiments were not reliable. Comprehensive analysis of the two serum experiments showed that the quality controls all met the requirements. We found 18 differentially expressed miRNAs. Relative to healthy controls, nine, three, and 11 miRNAs were up-regulated in the CHB group, LC group and small HCC group, respectively. In contrast, one, three, and three miRNAs were down-regulated in the same patient groups, respectively. Interestingly, miR-195, miR-25 and miR-16 were up-regulated, and miR-205 was down-regulated, in all three experimental groups. Moreover, only in the HCC group, miR-18a, miR-100, miR-145 and miR-223 were up-regulated 3.48-, 2.95-, 2.12- and 3.91-fold, respectively, and miR-200a and miR-222 were down-regulated 2.56- and 2.00-fold, respectively. Conclusions: Our study demonstrated the presence of six differentially expressed serum microRNAs in HBV-positive small HCC compared to other benign liver diseases associated with HBV. Show more

Keywords: Hepatocellular carcinoma, miRNA PCR Array, microRNA, HBV

DOI: 10.3233/CBM-140451

Citation: Cancer Biomarkers, vol. 15, no. 2, pp. 171-180, 2015

Authors: Dou, Xue | Wang, Renben | Meng, Xiangjiao | Yan, Hongjiang | Jiang, Shumei | Zhu, Kunli | Xu, Xiaoqing | Chen, Dong | Song, Xianrang | Mu, Dianbin

Article Type: Research Article

Abstract: Background: At present no useful factors to predict the sensitivity to neoadjuvant chemoradiotherapy (nCRT) have been established in patients with locally advanced rectal cancer (LARC). Objective: The objective of this study was to explore the prognostic role of T cell factor 4 (TCF4) expression in predicting tumor response to nCRT and tumor outcomes for patients with LARC. Methods: The study enrolled 96 patients who underwent nCRT followed by total mesorectal excision (TME). The TCF4 expression of all patients’ biopsies before nCRT was evaluated by Immunohistochemical staining method. Results: After completion of nCRT, 5 cases …(5.2%) achieved clinical complete response (cCR) thus the remaining 91 patients underwent a standardized total mesorectal excision (TME) procedure. There were 44 patients (45.8%) achieved good tumor response (including TRG 3-4 and 5 cCR patients) while poor response (TRG 0-2) was achieved in 52 patients (54.2%). Our results demonstrated that patients with low expression of TCF4 were more sensitive to nCRT than those with high TCF4 expression (P=0.031). Low TCF4 expression before nCRT and good response were significantly associated with improved 5-year disease-free survival and 5-year overall survival (P<0.05). Multivariate analysis confirmed that the pretreatment TCF4 expression was an independent prognostic factor. Conclusions: Our data revealed that low TCF4 protein expression was a useful predictive factor of good tumor response to nCRT and good outcomes in patients with LARC. Show more

Keywords: T cell factor 4 (TCF4), rectal cancer, neoadjuvant chemoradiotherapy, tumor regression grade

DOI: 10.3233/CBM-140452

Citation: Cancer Biomarkers, vol. 15, no. 2, pp. 181-188, 2015

Authors: Ghanbari, Reza | Mosakhani, Neda | Asadi, Jahanbakhsh | Nouraee, Nazila | Mowla, Seyed Javad | Poustchi, Hossein} | Malekzadeh, Reza | Knuutila, Sakari

Article Type: Research Article

Abstract: Background: Colorectal cancer (CRC) is a major cause of cancer-related deaths world-wide. Detection of molecular markers in stool samples is a promising strategy for CRC screening. MicroRNAs (miRNAs) are short, non-coding RNA molecules that are commonly dysregulated in neoplasia. Objective: The objective of this study was to evaluate the fecal miRNAs differentiation between early-stage CRC patients and healthy subjects. Methods: Stool samples were collected from 40 patients with early stage (I, II) CRC and 16 healthy controls. RNA was extracted from all samples using miRNAeasy Mini Kits. MiRNA microarray expression profiling was performed with Agilent’s miRNA …Microarray system on 12 CRC and 8 normal stool samples. The expression levels of miR-4478 and miR-1295b-3p were determined by the SYBR Green miScript PCR system. Results: In profiling study, we found 215 down-regulated miRNAs in CRC group. Furthermore, in validation study we found that the expression levels of fecal miR-4487 and miR-1295b-3p were significantly decreased in CRC patients compared to healthy controls. Conclusions: The expression of miR-4478 and miR-1295b-3p were significantly diminished in stool samples of CRC patients with early stage (I, II) in comparison with normal group. These miRNAs maybe use as potential non-invasive molecular markers for CRC diagnosis, but further studies are needed. Show more

Keywords: Profiling, microarray, diagnosis

DOI: 10.3233/CBM-140453

Citation: Cancer Biomarkers, vol. 15, no. 2, pp. 189-195, 2015

Authors: Mhaidat, Nizar M. | Alzoubi, Karem H. | Almomani, Nabeela | Khabour, Omar F.

Article Type: Research Article

Abstract: Background: Colorectal cancer (CRC) is an important health problem all over the world. A great improvement in the screening and early detection of CRC has been achieved. However, a new molecular prognostic marker is largely required. Glucose regulated protein 78-kDa (GRP78) is the central regulator of the endoplasmic reticulum (ER) and has an important role in the proliferation, differentiation and resistance to chemotherapy in cancer cells. Objective: The aim of the present study was to investigate the impact of elevated level of GRP78 on CRC prognosis and chemosensitivity. Methods: Sixty eight CRC tissue samples were collected …and protein expression of GRP78 was evaluated using immunohistochemistry. The clinicopathological factors of the patients were correlated with GRP78 level. Results: GRP78 expression increased with the progression from early to advanced CRC stages. In addition, GRP78 level was increased with the progression from early T1-2 to late T3-4 tumor localization (p< 0.05). Moreover, a significant association was found between GRP78 expression and response to chemotherapy (p< 0.05). Association between GRP78 expression and patient’s clinical characteristics including lymph node involvement and metastasis was not significant. Conclusions: Results suggest the possibility to use GRP78 as a biomarker for progression of CRC and its chemosensitivity to therapy. Show more

Keywords: Colorectal cancer, GRP78, Chemotherapy, Apoptosis

DOI: 10.3233/CBM-140454

Citation: Cancer Biomarkers, vol. 15, no. 2, pp. 197-203, 2015

Authors: Yang, Jie | Yang, Fan | Nie, Jiqin | Zou, Xiaohua | Tian, Huiqun | Qin, Yu'e | Liu, Chaoqi

Article Type: Research Article

Abstract: Annexin A2 (ANXA2) is a 36 kDa protein which orchestrates multiple biologic processes and clinical associations, especially in cancer progression. It is important to establish a specific and sensitive ANXA2 enzyme-linked immunosorbent assay (ELISA) for the study of ANXA2 functions and its clinical application. Therefore, we prepared a polyclonal antibody (PAb) in rabbits and a monoclonal antibody (MAb) in mices immunized with a recombinant ANXA2 protein. Based on our self-made MAb and PAb, highly specific and sensitive ELISA was developed. The detection limitation of ANXA2 was 10 ng/mL and the linear dynamic range was between 10 and 500 ng/mL. Using …the established ELISA, we detected ANXA2 protein in human serum. It was found that soluble ANXA2 concentration in serum samples from 42 lung cancer patients was significantly higher than that from 43 healthy individuals (p< 0.01). Our data provides a new approach for detecting soluble ANXA2, especially in large ongoing and future clinical studies. Show more

Keywords: Annexin A2, serum biomarker, lung cancer, ELISA

DOI: 10.3233/CBM-140455

Citation: Cancer Biomarkers, vol. 15, no. 2, pp. 205-211, 2015