Cancer Biomarkers - Volume 23, issue 1

Authors: Yuan, Jianfen | Xiao, Chunhong | Lu, Huijun | Yu, Haizhong | Hong, Hong | Guo, Chunyan | Wu, Zhimei

Article Type: Research Article

Abstract: Breast cancer is one common female specific malignant tumor and has gradually increased incidence. Matrix metalloproteinase-9 (MMMP-9) and its inhibitor TIMP-1 participate in tumor invasion and metastasis. This study analyzed the effect of various treatment approaches on TIMP-1 and MMP-9 levels in terminal stage breast cancer. Post-op breast cancer patients including chemo-radio therapy group, radio-chemo therapy group and simultaneously chemo- and radio-therapy group were compared for efficacy, along with assays for TIMP-1 and MMP-9 levels for analyzing their correlation with clinical-pathological features of breast cancer. Chemo + radio-therapy group had lower focal recurrence and distal metastasis than …the other two groups, plus higher 5-year survival rates (p < 0.05). After treatment, all patients showed lower serum MMP-9 level, activity and higher TIMP-1 levels than those before treatment (p < 0.05). Concurrent radio + chemo-therapy group showed lower serum MMP-9 level, activity and higher TIMP-1 levels (p < 0.05 compared to the other two groups). Serum MMP-9 and TIMP-1 levels after treatment are correlated with patient age, pathological grade, tumor size and lymph node metastasis (p < 0.05). Simultaneous chemo- and radio-therapy on breast cancer patients after surgery could reduce focal recurrent rate or distal metastasis rate, thus improving 5-year survival rate. MMP-9 and TIMP-1 levels are correlated with age, pathological grade, tumor size and lymph node metastasis of breast cancer patients. Show more

Keywords: Breast cancer, treatment efficacy, TIMP-1, MMP-9

DOI: 10.3233/CBM-170901

Citation: Cancer Biomarkers, vol. 23, no. 1, pp. 1-7, 2018

Authors: Ni, Wei | Luo, Lin | Zuo, Ping | Li, Ren-Ping | Xu, Xiao-Bing | Wen, Fan | Hu, Dong

Article Type: Research Article

Abstract: This article has been retracted, and the online PDF replaced with this retraction notice.

Keywords: lncRNAs, numb, GHET1, biological activities, vitro study, vivo study

DOI: 10.3233/CBM-171002

Citation: Cancer Biomarkers, vol. 23, no. 1, pp. 9-22, 2018

Authors: Li, Xin | Ma, Wenyi | Wang, Xiaojie | Ci, Yunzhe | Zhao, Yina

Article Type: Research Article

Abstract: BACKGROUND: Annexin A5 (ANXA5) is a kind of Ca 2 + -dependent phospholipid binding protein which is involved in cell membrane dynamics and organization. Recent data showed that ANXA5 might involve in tumorigenesis. OBJECTIVE: To explore what role ANXA5 play in human uterine cervical carcinoma. MATERIALS AND METHODS: In this study, a recombined ANXA5 plasmid was constructed and uterine cervical carcinoma cell lines HeLa and SiHa were transfected with it. After ANXA5 overexpression was determined by Western Blot, cell proliferation test was detected by MTT assay and colony formation …assay respectively. FACS assay and Hochest33258 staining methods were employed to detect cell apoptosis. To further investigate whether ANXA5 influence cell migration and invasion, wound healing assay and transwell assay were applied. At the same time, the relative mechanism was investigated. RESULTS: When ANXA5 expression increased, cell proliferation was inhibited by regulating the expression of bcl-2 and bax while cell metastasis was suppressed by regulating E-cadherin and MMP-9 expression. CONCLUSION: ANXA5 overexpression in the uterine cervical carcinoma might play important roles in cell proliferation and metastasis of uterine cervical cancer cells and act as an anti-cancer gene in uterine cervical cancer. Show more

Keywords: ANXA5, uterine cervical carcinoma cell, proliferation, apoptosis, invasion, migration

DOI: 10.3233/CBM-171040

Citation: Cancer Biomarkers, vol. 23, no. 1, pp. 23-32, 2018

Authors: Zhang, Meng-Hui | Niu, Hu | Li, Zheng | Huo, Ren-Tao | Wang, Jun-Mei | Liu, Jun

Article Type: Research Article

Abstract: OBJECTIVE: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy that has a poor prognosis. Through the literatures, TINAG significantly participated in the processes of the renal-associated diseases, but there were no studies about the roles of TINAG in the HCC development. Hence, we attempted to use the HCC samples collected by ourselves to reveal the clinical significance and prognostic impact of TINAG in HCC. METHODS: We first measured the expression level of TINAG in HCC on the basis of TCGA database. Then, real time quantitative reverse transcription PCR (RT-qPCR) was used to examine the expression level …of TINAG in 100 pairs of HCC tissues and corresponding adjacent non-tumor tissues, as well as HCC cell lines (HepG2, HB611, HHCC, and Hep3B). Moreover, Kaplan-Meier method and COX’s proportional hazards model were utilized to perform the survival and prognosis analyses using the clinical data collected by ourselves. After knockdown of TINAG, the cell proliferation, invasion and migration capacities of HepG2 and Hep3B cells were evaluate by counting kit-8 (CCK-8) assay (24 h, 48 h, 72 h, and 96 h post-cultivation), clone formation experiment, would-healing, and invasion as well as migration assays. To further explore whether the dys-regulated TINAG expression regulates the HCC progression and prognosis, protein biomarkers of PI3K signaling pathway, including AKT, p-AKT, PI3K, p-PI3K, p70S6K, and p-p70S6K were measured based on western blotting analysis. RESULTS: According to the data of TCGA database, clinical patients, and HCC cell lines, TINAG was highly expressed in HCC compared with normal. Relationship of TINAG expression level with the clinicopathological factors implicated that the high expression of TINAG was significantly associated with pathologic stage, pathologic-node, and pathologic-metastasis. Univariate as well as multivariate COX analysis indicated that TINAG expression and pathologic metastasis can serve as the independent prognostic factor for overall survival of HCC. After TINAG knockdown in HepG2 and Hep3B cells, cell proliferation rate, the colony numbers, and the invasive and migratory capacity were found to be suppressed. Remarkably, western blot results showed that reduction of TINAG remarkably decreased p-AKT, p-PI3K, and p-p70S6K expression level in HepG2 and Hep3B cells. CONCLUSION: Collectively, our results underscore the significance of TINAG in HCC progression and prognosis, and TINAG might be a novel candidate oncogene in HCC. These results propose that targeting TINAG might offer future clinical utility in HCC. Show more

Keywords: TINAG, hepatocellular carcinoma, proliferation, invasion, migration

DOI: 10.3233/CBM-181277

Citation: Cancer Biomarkers, vol. 23, no. 1, pp. 33-43, 2018

Authors: Li, Jian | Ma, Rui | Cao, Zhenbin | Zhang, Dongmei

Article Type: Research Article

Abstract: OBJECTIVE: To investigate the correlations of magnetic resonance imaging (MRI) manifestations with survivin gene expression in primary hepatocellular carcinoma (HCC). METHODS: A total of 84 HCC patients receiving partial hepatectomy in the Surgery Department and Oncology Department in our hospital from April 2011 to May 2014 were recruited. At 1 week before operation, MRI was used to examine the imaging features of liver, a certain size of area was defined and the signal value of each sequence was recorded. HCC and para-carcinoma tissues were collected after operation, and the expression levels of survivin were detected via immunohistochemistry (IHC). …All patients were followed up for 30 months after operation, and the Kaplan-Meier survival curve was drawn. The correlations of survivin expression with MRI features and signal parameters of each sequence were analyzed. RESULTS: There was no expression of survivin in normal liver tissues. In HCC and para-carcinoma tissues, the nuclei of positive cells showed brown yellow. The positive expression rate of survivin in HCC tissues was 76.19% (64/84), which was significantly higher than that in para-carcinoma tissues (20.81%, 20/84) (p < 0.05). The overall survival (OS) of patients with high expression of survivin was 12.5 months, which was significantly shorter than that of patients with low expression of survivin (17.6 months) (p < 0.05). Results of chi-square test showed that the survivin level had no correlations with the MRI scan shape and edge in the tumor area (p > 0.05), but it was significantly correlated with tumor diameter, MRI enhancement features and lymphatic metastasis (p < 0.05). Pearson correlation analyses revealed that the survivin IHC score was not correlated with in-phase T1-weighted gradient-recalled echo (GRE), hepatic arterial-phase T1-weighted GRE, portal venous-phase T1-weighted GRE and equilibrium-phase T1-weighted GRE signals (p > 0.05). Besides, the survivin IHC score was negatively correlated with opposed-phase T1-weighted GRE (r = - 0.46, p = 0.038), but positively correlated with T2-weighted fast spin echo signal (r = - 0.49, p = 0.025). CONCLUSION: Survivin is significantly up-regulated in HCC tissues and associated with tumor growth and lymph node metastasis. Clinical detection of survivin level combined with MRI examination might be beneficial for clinical diagnosis and treatment of HCC. Show more

Keywords: Primary hepatic carcinoma, magnetic resonance imaging (MRI), survivin, prognosis

DOI: 10.3233/CBM-181285

Citation: Cancer Biomarkers, vol. 23, no. 1, pp. 45-51, 2018

Authors: Pang, Lan | Wang, Jing | Fan, Yong | Xu, Rui | Bai, Yuping | Bai, Liangcai

Article Type: Research Article

Abstract: OBJECTIVE: To investigate the correlations of expression of vascular endothelial growth factor (VEGF) in gastric cancer tissues of patients and magnetic resonance imaging (MRI) features with clinical tumor-node-metastasis (TNM) staging and lymph node metastasis, and to analyze the diagnostic value of MRI features for preoperative TNM staging and lymph node metastasis of patients with gastric cancer, and the roles of VEGF in tumor development and metastasis. METHODS: A total of 120 gastric cancer patients treated in our hospital from May 2015 to July 2017 were selected as objects of study. The VEGF protein expressions in gastric cancer …tissues of patients with different TNM staging and lymph node metastasis degrees were detected using immunohistochemical method, and the correlations of VEGF protein expression with TNM staging and lymph node metastasis were analyzed. Before operation, MRI was used to predict TNM staging and lymph node metastasis of all patients, and prediction results were compared with postoperative pathological diagnosis results. At the same time, the differences in lymph node apparent diffusion coefficient (ADC), long diameter and short diameter, relative ADC of primary lesion (rADCp) and relative ADC of muscle (rADCm) were compared and analyzed between lymph node metastasis group and non-lymph node metastasis group. RESULTS: The VEGF expression in patients with stage-N3 gastric cancer was about 7 times that in patients with stage-N0 gastric cancer, and it was increased with the increased degree of lymph node metastasis (p < 0.01). The VEGF expression in patients with distant metastasis of tumor cells was significantly higher than that in patients without distant metastasis (p < 0.01). The expression of VEGF in stage-T4 gastric cancer was about 10 times that in stage-Tis cancer, and the larger the infiltration depth of tumor cells was, the higher the expression level of VEGF would be (p < 0.01). The VEGF expression in gastric cancer tissues was positively correlated with the infiltration depth, lymph node metastasis and distant metastasis of tumor cells. Moreover, the prediction results of MRI for TNM staging and lymph node metastasis before operation were compared with postoperative pathological results, and it was found that there was better consistency (Kappa = 0.739). ADC, rADCp and rADCm in gastric cancer patients without lymph node metastasis were significantly higher than those in patients with lymph node metastasis, but the short diameter and long diameter were obviously shorter than those in patients with lymph node metastasis, and the differences were statistically significant (p < 0.05). CONCLUSION: The VEGF protein expression in gastric cancer tissues is positively correlated with TNM staging and lymph node metastasis in patients. The preoperative prediction results of MRI are well consistent with postoperative pathological results, and MRI features are correlated with lymph node metastasis in patients, which has an important guiding significance for the diagnosis and treatment of gastric cancer. Show more

Keywords: Gastric cancer, TNM staging, lymph node metastasis, VEGF, MRI

DOI: 10.3233/CBM-181287

Citation: Cancer Biomarkers, vol. 23, no. 1, pp. 53-59, 2018

Authors: Zare, Razieh | Malekzadeh, Mahyar | Hashemi, Mohamad | Khademi, Bijan | Andishe-Tadbir, Azadeh

Article Type: Research Article

Abstract: BACKGROUND: Interleukin-33 (IL-33) has been recently discovered as an influential factor in the process of tumor immunity, and is presented in cancer pathogenesis. OBJECTIVE: This study aimed to determine the serum levels of IL-33 in patients with benign and malignant Salivary gland tumors (SGTs). METHODS: This descriptive cross-sectional study was performed on 47 samples of malignant SGTs including 18 mucoepidermoid carcinoma (MEC), 8 adenoid cystic carcinoma (ADCC), 21 malignant mixed tumor (MMT), and 14 benign pleomorphic adenoma (PA). A control group was considered consisting of 28 healthy subjects. The serum level of IL-33 was measured by using sandwich ELISA …method. The data were statistically analyzed through Kruskal-Wallis and Mann-Whitney tests. RESULTS: The median concentration of IL-33 was 6.91 in malignant, 5.14 in benign, and 5.01 in healthy cases, with a statistically significant difference (P = 0.001). The median serum levels of IL-33 increased significantly in ADCC (7.15), MEC (7.03), and MMT (6.91) compared with the control group (5.01) (P < 0.05). The mean rank of MEC was significantly higher than PA (P = 0.01). IL-33 concentration was positively and significantly correlated with the tumor stage (P = 0.02) and tumor size (P = 0.03). CONCLUSIONS: IL-33 could be suggested as a novel biomarker to distinguish different types of SGTs. Show more

Keywords: Salivary gland tumor, IL-33, malignant, benign, biomarker

DOI: 10.3233/CBM-181309

Citation: Cancer Biomarkers, vol. 23, no. 1, pp. 61-65, 2018

Authors: Wang, Xiaohui | Qu, Huajun | Dong, Yinghe | Wang, Guozhi | Zhen, Yuchen | Zhang, Linxia

Article Type: Research Article

Abstract: Melanoma treatment with the BRAF V600E inhibitor vemurafenib provides therapeutic benefits but the common emergence of drug resistance remains a challenge. To define molecular mechanisms of vemurafenib resistance, we generated A375-R, WM35-R cell lines resistant to vemurafenib and show that the phosphorylated (p)-STAT3 was upregulated in these cells in vitro and in vivo . In particular, activation of the Signal-transducer-and-activator-of-transcription 3 (STAT3) pathway was associated with vemurafenib resistance. Inhibition of this pathway with STAT3-specific siRNA (shRNA) sensitized A375-R, WM35-R cells to vemurafenib and induced apoptosis in vitro and in vivo . Moreover, targeting STAT3 induced expression of miR-579-3p …and elicited resistance to vemurafenib. However, targeting microRNA (miR)-579-3p with anti-miR-579-3p reversed the resistance to vemurafenib. Together, these results indicated that STAT3-mediated downexpression of miR-579-3p caused resistance to vemurafenib. Our findings suggest novel approaches to overcome resistance to vemurafenib by combining vemurafenib with STAT3 sliencing or miR-579-3p overexpression. Show more

Keywords: Melanoma, BRAF V600E inhibitor, Signal-transducer-and-activator-of-transcription 3, miR-579-3p

DOI: 10.3233/CBM-181365

Citation: Cancer Biomarkers, vol. 23, no. 1, pp. 67-77, 2018

Authors: Dou, Daoqin | Yang, Shaohua | Lin, Yunzheng | Zhang, Jiren

Article Type: Research Article

Abstract: PURPOSE: The purpose of this study was to establish a risk scoring system based on miRNAs to evaluate the prognosis in pancreatic adenocarcinoma. METHODS: Using a miRNA microarray dataset (179 pancreatic adenocarcinoma specimens and 4 normal control specimens) from TCGA, differentially expressed miRNAs were identified. Cox proportional hazards regression analysis was used to identify significant prognostic miRNAs, with which a risk scoring system was established and tested on a validation set. Cox regression analysis was performed to identify independent predictors of survival from clinical characteristics. Stratified Cox regression analyses were conducted to unravel the associations of clinical characteristics …with survival. Differentially expressed genes (DEGs) were screened followed by functional annotation of the DEGs. RESULTS: Eight miRNAs (miR-1301, miR-598, miR-1180, miR-155, miR-496, miR-203, miR-193b, miR-135b) were independent predictors for survival. A risk scoring system was established with the 8 signature miRNAs. Upon Cox multivariate regression analysis, risk score, new tumor and targeted molecular therapy were independent predictors of prognosis. Stratified Cox regression analyses found that targeted molecular therapy and new tumor are associated with survival of patients. Survival-related DEGs were significantly enriched with regulation of transforming growth factor beta receptor, potassium ion transport and MAPK signaling pathway. CONCLUSIONS: The study proposes 8-miRNA expression-based risk scoring system to predict prognosis in pancreatic adenocarcinoma. New tumor and targeted molecular therapy were independent predictors of prognosis. Transforming growth factor beta receptor, potassium ion transport and MAPK signaling pathway may be related to prognosis in pancreatic adenocarcinoma. Show more

Keywords: miRNA, prognosis, pathway, risk score, stratified analyses

DOI: 10.3233/CBM-181420

Citation: Cancer Biomarkers, vol. 23, no. 1, pp. 79-93, 2018

Authors: Mou, Yonghua | Wang, Dongguo | Xing, Renwei | Nie, Hanqiu | Mou, Yiping | Zhang, Yang | Zhou, Xianfei

Article Type: Research Article

Abstract: BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancer worldwide and chronic infection of hepatitis B virus (HBV) serve as one of leading causes of HCC. OBJECTIVE : This study aimed to identify the novel long noncoding RNAs (lncRNAs) biomarkers for HBV-associated HCC. METHODS: The lncRNA and mRNA expression profiles of HCC patients with HBV infection were downloaded from The Cancer Genome Atlas. The differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) between HCC and adjacent tissues were identified. The optimal diagnostic and prognostic lncRNA biomarkers for HCC were identified by …using feature selection procedure and classification model. Functional annotation of DEmRNAs co-expressed with these lncRNAs biomarkers were performed. Receiver operating characteristic (ROC) curve and survival analysis of these lncRNAs biomarkers were performed. qRT-PCR validation was performed. RESULTS: A total of 82 DElncRNAs and 805 DEmRNAs between HBV-associated HCC and normal tissues were identified. CAPN10-AS1, LINC01093, RP5-890E16.2, FENDRR and C17orf82 were selected as optimal diagnostic and prognostic lncRNA biomarkers for HBV-associated HCC that were co-expressed with 105, 86, 70, 30 and 1 DEmRNAs, respectively. Based on the DEmRNAs co-expressed with these five lncRNAs biomarkers, Jak-STAT signaling pathway and retinol metabolism were two significantly enriched pathways. The result in qRT-PCR validation were consistent with our analysis based on TCGA, generally. CONCLUSIONS: This study identified five potential lncRNAs biomarkers for HBV-associated HCC with great diagnostic and prognostic value and provided clues for their functions in HBV-associated HCC. Show more

Keywords: Hepatocellular carcinoma (HCC), hepatitis B virus (HBV), biomarker, long noncoding RNAs (lncRNAs)

DOI: 10.3233/CBM-181424

Citation: Cancer Biomarkers, vol. 23, no. 1, pp. 95-106, 2018