Cancer Biomarkers - Volume 16, issue 1

Authors: Wang, Qi | Wang, Shuai | Sun, Si-Qiao | Cheng, Zhi-Hua | Zhang, Yang | Chen, Guang | Gu, Meng | Yao, Hai-Jun | Wang, Zhong | Zhou, Juan | Peng, Yu-Bing | Xu, Ming-Xi | Zhang, Ke | Sun, Xi-Wei

Article Type: Research Article

Abstract: OBJECTIVE: This study was to explore the effects of RNA interference mediated vascular endothelial growth factor (VEGF ) gene silencing on biological behavior of renal cell carcinoma (RCC), transplanted renal tumor and angiogenesis in nude mice. METHODS: The specific siRNA sequence targeting VEGF were designed and synthesized to construct hVEGF-siRNA plasmid which was transfected into RCC 786-O cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used for the detection of VEGF gene expression and western blot was adopted for the examination of VEGF protein expression. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect cell …growth as well as cell migration and invasion. The transplanted renal tumor models in nude mice were established, and the growth condition of nude mice, and VEGF protein expression in transplanted tumor slices and the microvessel density (MVD) were detected. RESULTS: The expression level of VEGF mRNA in VEGF-siRNA group was significant lower than that in the control group and negative group, suggesting that establishment of plasmid specifically inhibited the expression of VEGF gene The expression level of VEGF protein in VEGF-siRNA group was significant lower than that in the control group and negative group. VEGF gene silencing has the significant inhibition effects on proliferation, migration and invasion of RCC 786-O cells. The tumor weight, VEGF protein positive rate and MVD in VEGF-siRNA group were significant lower than those in negative group and blank group. CONCLUSION: The VEGF gene silencing could inhibit the cell proliferation, migration and invasion of RCC 786-O cells; inhibition of VEGF protein expression could prevent transplanted RCC growth and tumor angiogenesis. Show more

Keywords: Vascular endothelial growth factor, renal cell carcinoma, transplanted tumor, nude mice, gene silencing, biological behavior, angiogenesis, gene therapy

DOI: 10.3233/CBM-150535

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 1-9, 2016

Authors: Li, Xiao | Gao, Yang | Zhou, Hai | Xu, Weizhang | Li, Pu | Zhou, Jin | Xu, Ting | Yu, Bin | Xu, Zicheng | Zou, Qing | Yin, Changjun | Cai, Hongzhou | Shen, Wenyi

Article Type: Research Article

Abstract: OBJECTIVE: A functional -94 insertion/deletion polymorphism (rs28362491) in the promoter of the NF-κ B1 gene was reported to influence NF-κ B1 expression and confer susceptibility to different types of cancer. This study aims to determine whether the polymorphism is associated with the risk of urinary cancer, including renal cancer, bladder cancer and prostate cancer. METHODS: TaqMan method was applied to genotype the NF-κ B1 -94 ins/del ATTG promoter polymorphism in three case-control studies: renal cell carcinoma group (1216 cases and 1588 controls), bladder cancer group (730 cases and 780 controls), and prostate cancer group (820 cases …and 945 controls). Logistic regression was used to assess the association between the polymorphism and urinary cancer risk. RESULTS: The del/del genotype was detected to be associated with a statistically significant increased risk of bladder cancer when taking the ins/ins genotypes as reference (P < 0.001, adjusted odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.14-1.52). Furthermore, in bladder cancer, the same results were observed in the del/del genotype compared with the ins/ins + ins/del genotypes (P < 0.001, OR = 1.82, 95% CI = 1.41-2.35), and the del allele compared with the ins allele (P < 0.001, OR = 1.29, 95% CI = 1.12-1.49). However, no significant difference was observed in the associations between the NF-κ B1 polymorphism and the risk of renal cell carcinoma or prostate cancer in all kinds of models. CONCLUSIONS: In the Chinese population, the -94 ins/del ATTG polymorphism in NF-κ B1 promoter may contribute to the etiology of bladder cancer instead of renal cell carcinoma or prostate cancer. Show more

Keywords: NF-κ B1 gene, polymorphism, renal cell carcinoma, bladder cancer, prostate cancer

DOI: 10.3233/CBM-150536

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 11-17, 2016

Authors: Luo, Yung-Hung | Tseng, Pei-Chun | Lee, Yu-Chin | Perng, Reury-Perng | Whang-Peng, Jacqueline | Chen, Yuh-Min

Article Type: Research Article

Abstract: BACKGROUND: The use of liquid tissue, such as circulating cells, to predict treatment response is attracting more attention. OBJECTIVE: The aim of this study was to evaluate association between circulating markers and treatment response. METHODS: One hundred and twelve advanced pulmonary adenocarcinoma patients who were going to receive epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were included. Tumor tissue and plasma specimens were collected before treatment and analyzed for EGFR mutation and plasma IL-6 and IL-8. Pre-treatment peripheral blood CD146+/CD3- cells (as circulating endothelial cells, CECs), CD34+/CD45- cells (as endothelial progenitor cells, …EPCs), and CD133+ cells (as cancer stem cells, CSCs) were measured with flow cytometry. RESULTS: The progression-free survival (PFS) was significantly longer in patients with low CEC, low EPC, and low CSC counts than in those with high cell counts (p < 0.001, 0.041, and 0.001, respectively). Multivariate analysis showed that mutant plasma EGFR (pEGFR) was a poor prognostic factor in EGFR -mutated patients (p = 0.048), and there was a tendency for EGFR mutation-negative patients with high IL-6 level to have worse overall survival (p = 0.051). CONCLUSIONS: CECs, EPCs, CSCs, and mutant pEGFR are useful predictive biomarkers of EGFR-TKI treatment efficacy. IL-6 may predict prognosis in advanced lung cancer. Show more

Keywords: Adenocarcinoma, cancer stem cells, circulating endothelial cells, endothelial progenitor cells, epidermal growth factor receptor (EGFR), cytokines

DOI: 10.3233/CBM-150537

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 19-29, 2016

Authors: Najafi, Ali | Tavallaei, Mahmood | Hosseini, Sayed Mostafa

Article Type: Research Article

Abstract: Non-small cell lung cancers (NSCLCs) is a prevalent and heterogeneous subtype of lung cancer accounting for 85 percent of patients. MicroRNAs (miRNAs), a class of small endogenous non-coding RNAs, incorporate into regulation of gene expression post-transcriptionally. Therefore, deregulation of miRNAs' expression has provided further layers of complexity to the molecular etiology and pathogenesis of different diseases and malignancies. Although, until now considerable number of studies has been carried out to illuminate this complexity in NSCLC, they have remained less effective in their goal due to lack of a holistic and integrative systems biology approach which considers all natural elaborations of …miRNAs' function. It is able to reliably nominate most affected signaling pathways and therapeutic target genes by deregulated miRNAs during a particular pathological condition. Herein, we utilized a holistic systems biology approach, based on appropriate re-analyses of microarray datasets followed by reliable data filtering, to analyze integrative and combinatorial deregulated miRNA-mRNA interaction network in NSCLC, aiming to ascertain miRNA-dysregulated signaling pathway and potential therapeutic miRNAs and mRNAs which represent a lion' share during various aspects of NSCLC's pathogenesis. Our systems biology approach introduced and nominated 1) important deregulated miRNAs in NSCLCs compared with normal tissue 2) significant and confident deregulated mRNAs which were anti-correlatively targeted by deregulated miRNA in NSCLCs and 3) dysregulated signaling pathways in association with deregulated miRNA-mRNAs interactions in NSCLCs. These results introduce possible mechanism of function of deregulated miRNAs and mRNAs in NSCLC that could be used as potential therapeutic targets. Show more

Keywords: Lung cancer, microRNAs, signaling pathway, systems biology

DOI: 10.3233/CBM-150538

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 31-45, 2016

Authors: Araújo, Amanda Souza | Nogueira, Ingrid Correia | Neto, Antero Gomes | de Medeiros, Israel Lopes | Morano, Maria Tereza Aguiar Pessoa | da Silva, Guilherme Pinheiro Ferreira | Santos, Flávia Almeida | Filho, Manoel Odorico De Moraes | Pereira, Eanes Delgado Barros

Article Type: Research Article

Abstract: BACKGROUND: Major thoracic surgery is characterized by release of inflammatory markers.The objective of this study was to assess the preoperative and postoperative systemic inflammatory markers of patients undergoing lung cancer resection. METHODS: This is a prospective follow up study conducted with 48 patients submitted to lung cancer resection.All patients were assessed before and 1 month after surgery through measurement of fibrinogen and C-reative protein(CRP), pulmonary function tests, 6- minute Walk Test (6MWT), maximal inspiratory pressure (PImax) and maximal expiratory preasure (PEmax), anxiety and depression scale and karnofsky performance status scale. RESULTS: Both fibrinogen …and CRP were higher 1 month after surgery, although only the change in CRP was statistically significant (p= 0.03). The following functional parameters: 6MWT, PImax, PEmax, FEV1(%) and FVC(%) decreased after surgery with p≤ 0.001 for all the parameters. Anxiety and depression improved and Karnofsky decrease after surgery (p= 0.03, p= 0.01 and p= 0.02; respectively). Change in CRP score following lung resection correlated significantly with changes in fibrinogen (r= 0.40; p= 0.003), change in Karnofsky scale (r= -0.50; p< 0.001) and a borderline significant trend with the 6MWT (r= -0.28; p= 0.05). With the exception of video-assisted thoracoscopic surgery (VATS), who had a significantly lower fibrinogen level 1 month after surgery compared with thoracotomy (p= 0.01), no significant differences in fibrinogen or CRP were noted in other subgroups of patients considered at increased risk for higher levels of inflammation compared with lower risk counterparts. CONCLUSION: Lung cancer resection surgery was associated with increased level of CRP, 1 month after surgery, and correlated directly with change in fibrinogen and inversely with measurement of performance status. VATS provided lower level of fibrinogen after surgery. Show more

Keywords: Lung cancer, surgery, inflammatory mediators

DOI: 10.3233/CBM-150539

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 47-53, 2016

Authors: Lamperska, Katarzyna M. | Kozlowski, Piotr | Kolenda, Tomasz | Teresiak, Anna | Blizniak, Renata | Przybyla, Weronika | Masternak, Michal M. | Golusinski, Pawel | Golusinski, Wojciech

Article Type: Research Article

Abstract: BACKGROUND: The necessity of prediction and treatment outcome improvement of HNSCC needs to find new biomarkers. miRNAs seem to be good candidate for that. OBJECTIVE: Analysis of selected 5 miRNAs (let-7d, miR-18a, miR-21, miR-205 and miR-375) as potential biomarkers that allows to distinguish tumor and healthy tissue taken from HNSCC patients. METHODS: Tumor and normal epithelial tissues were obtained from 75 HNSCC patients to analyze selected miRNAs. RESULTS: Analysis indicated significant increase of miR-21 and miR-205 in tumor when compared with healthy tissue (p= 0.0069 and p= 0.0029, respectively). There …was a significant correlation between let-7d and miR-18a. let-7d was down-regulated in 34.67% cases, miR-18a in 29.33%, miR-21 in 20%, miR-205 in 30.67% and miR-375 in 52% cases. At the same time over-expression of let-7d was detected in 18.67% cases, miR-18a in 22.67%, miR-21 in 48%, miR-205 in 41.33% and miR-375 in 52% cases. There was no correlation between miRNA expression and clinical data and the course of illness. CONCLUSION: Our study indicated that miR-21 and miR-205 can be used to analyze the clarity of surgical margins and that concomitant changes in the expression of let-7 and miR-18a in tumor tissues might represent important future markers indicating the biology of HNSCC. These observations will help with developing personalization for HNSCC patients' treatment. Show more

Keywords: Cancer, HNSCC, miRNA profile, qRT-PCR, biomarker

DOI: 10.3233/CBM-150540

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 55-64, 2016

Authors: Gao, Zhuo-Wei | Huang, Jing-Bin | Lin, Qing | Qin, Qiang | Liang, Yao-Jun | Zhou, Lu | Luo, Min

Article Type: Research Article

Abstract: Meningioma is one of the common brain tumors in adults. It had been shown that the allopregnanolone biosynthesis was associated with tumorigenesis and PK11195, the translocator protein 18 KDa (TSPO) antagonist, had the effects of the allopregnanolone biosynthesis. However, little is known about the association between the effects of PK11195 on meningioma and the allopregnanolone biosynthesis. To evaluate this, the meningioma cell line IOMM-LEE was applied. Cell viability and proliferation were determined by CCK-8 assay. The IC50 of PK11195 on the IOMM-LEE was 1.505 ± 0.08 nM. The cell viability and proliferation of AC-5216 (TSPO selective ligand, 2 and 4 …nM) was blocked by PK11195 (1.5 nM). Further, we evaluated the role of allopregnanolone biosynthesis in the effects of TSPO on meningioma. Enzyme-Linked ImmunoSorbent Assay (ELISA) was used in the measurement of the allopregnanolone level. It showed that the allopregnanolone level was increased by AC-5216 (2 and 4 nM) and the increase was reversed by PK11195 (1.5 nM). Collectedly, it firstly indicated that the effects of PK11195 on meningioma were relevant to the decrease of allopregnanolone biosynthesis, which was mediated by TSPO. Show more

Keywords: AC-5216, allopregnanolone, meningioma, PK11195, TSPO

DOI: 10.3233/CBM-150541

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 65-69, 2016

Authors: Wang, Yihan | Peng, Qian | Jia, Hongyuan | Du, Xiao

Article Type: Research Article

Abstract: BACKGROUND: The Hedgehog (Hh) signaling pathway has recently been reported to be associated with the prognosis of digestive system cancers. However, the results are inconsistent. OBJECTIVE: This study aimed to investigate the association between Hh pathway components and survival outcomes in patients with digestive system cancers. METHODS: We conducted a comprehensive retrieval in PubMed, EMBASE and Cochrane library for relevant literatures until May 1st, 2015. The pooled hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) with 95% confidence intervals (CIs) were calculated to clarify the prognostic value of Hh pathway …components, including Shh, Gli1, Gli2, Smo and Ptch1. RESULTS: A total of 16 eligible articles with 3222 patients were included in the meta-analysis. Pooled HR suggested that over-expression of Shh and Gli1 were both associated with poor OS (HR = 1.87, 95% CI: 1.14-3.07 and HR = 1.96, 95% CI: 1.66-2.32, respectively) and DFS (HR = 2.37, 95% CI: 1.19-4.72 and HR = 2.18, 95% CI: 1.61-2.96, respectively). In addition, over-expression of Smo was associated with poor DFS (HR = 1.38, 95% CI: 1.08-1.75). CONCLUSIONS: This study reveals that over-expressed Hh pathway components, including Shh, Gli1 and Smo, are associated with poor prognosis in digestive system cancer patients. Hh signaling pathway may become a potential therapeutic target in digestive system cancers. Show more

Keywords: Hedgehog signaling pathway, digestive system cancers, meta-analysis, prognosis

DOI: 10.3233/CBM-150542

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 71-79, 2016

Authors: Yang, Jingke | Xiao, Xiang | Li, Ruijuan | Li, Zijian | Deng, Mingyang | Zhang, Guangsen

Article Type: Research Article

Abstract: BACKGROUND: Aberrant DNA methylation status of some genes has been shown to be involved in chemoresistance of acute myeloid leukemia (AML). We have recently found that down-regulation of the β subunit of mitochondrial ATP synthase (ATPsyn-β) leads to adriamycin resistance in acute and chronic myeloid leukemia cells, and hypermethylation of the ATPsyn-β gene promoter is associated with chemoresistance in chronic myeloid leukemia. OBJECTIVE: To further investigate the relationship between methylation of ATPsyn-β gene, mRNA expression as well as chemoresistance in AML. METHODS: Quantitative RT-PCR and methylation specific PCR were performed …to assess mRNA expression and methylation status of ATPsyn-β gene on primary bone marrow nuclear cells (BMMCs), and cell proliferation assay was used to determine the sensitivity of BMMCs to adriamycin. RESULTS: Hypermethylation status of ATPsyn-β gene promoter existed in those relapsed/refractory AML patients, and this hypermethylation of the gene was associated with a suppressed mRNA expression levels. Four patients at diagnosis and relapse underwent gene methylation status shift from hypermethylation to hypomethylation, which was accompanied by reduced mRNA expression of the gene. 5-azacitidine(5-Aza)- a demethylating agent, could restore ATPsyn-β mRNA expression and increase the adriamycin sensitivity of primary leukemic cells from seven relapsed/ refractory AML patients. CONCLUSIONS: Hypermethylation of ATPsyn-β gene promoter is associated with a down-regulated mRNA expression and chemoresistance in AML patients. Show more

Keywords: Methylation, mitochondrial ATP synthase, chemoresistance, acute myeloid leukemia

DOI: 10.3233/CBM-150543

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 81-88, 2016

Authors: Lv, Yang | Ding, Xuan-Sheng | Li, Yan | An, Xiang | Miao, Li-Yun

Article Type: Research Article

Abstract: BACKGROUND: Chemotherapy-related hepatic dysfunction affected the prognosis of non-small cell lung cancer (NSCLC). However, predictive factors of chemotherapy-related hepatic dysfunction remained undefined. OBJECTIVE: To identify the predictive factors for hepatic dysfunction during cytotoxic chemotherapy in Chinese patients with advanced NSCLC. METHODS: We retrospectively reviewed the medical records of patients with advanced NSCLC who received cytotoxic chemotherapy at Division of Respiratory Medicine, the affiliated Drum Tower Hospital of Nanjing University, from July 2012 to January 2015. We investigated the incidence of hepatic dysfunction during chemotherapy and evaluated several clinical factors that are associated with …hepatic dysfunction, including body mass index (BMI) and high density lipoprotein cholesterol (HDL-C). RESULTS: A total of 116 patients were enrolled in study, 54 patients (46.57%) experienced hepatic dysfunction after receiving chemotherapy. Multivariate analysis for hepatic dysfunction in patients with advanced NSCLC showed that hepatic dysfunction was associated with higher BMI (odds ratio = 4.742, P = 0.001) and lower HDL-C (odds ratio = 3.018, P = 0.019). Pearson's rank correlation analysis revealed that HDL-C and BMI presented a negative correlation in patients with hepatic dysfunction (r = -0.487, P < 0.001). CONCLUSIONS: Higher BMI and lower HDL-C levels seem to be good independent predictive factors for chemotherapy-related hepatic dysfunction in advanced NSCLC. In addition, a negative correlation was presented between BMI and HDL-C. Show more

Keywords: NSCLC, chemotherapy, hepatic dysfunction, BMI, HDL-C

DOI: 10.3233/CBM-150544

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 89-97, 2016