Cancer Biomarkers - Volume 19, issue 1

Authors: Mei, Li-Li | Qiu, Yun-Tan | Zhang, Bing | Shi, Zhi-Zhou

Article Type: Other

Abstract: Esophageal cancer is a common cause of cancer-related deaths worldwide. Squamous cell carcinoma (SCC) is the major histological type of esophageal cancer in developing countries including China, and the prognosis is very poor. Many microRNAs are involved in several important biological and pathologic processes, and promote tumorigenesis. To better understand the prognostic and therapeutic roles of microRNAs in ESCC, we reviewed the diagnosis and prognosis associated oncogenic microRNAs (e.g. miR-21 and miR-17-92 cluster) and tumor suppressor microRNAs (e.g. miR-375, miR-133a and miR-133b), and diagnosis and prognosis associated oncogenic target genes (e.g. PDCD4 and CCND1) and tumor suppressor target genes (e.g. …EZH2 and PDK1). We also summarized the prognostic microRNA and target gene pairs (e.g. miR-296 and CCND1, miR214 and EZH2). Taken together, our review highlights the opportunities and challenges for microRNAs in the molecular diagnosis and target therapy of ESCC. Show more

Keywords: MicroRNA, target gene, biomarker, therapeutic target, esophageal squamous cell carcinoma

DOI: 10.3233/CBM-160240

Citation: Cancer Biomarkers, vol. 19, no. 1, pp. 1-9, 2017

Authors: Gao, Peng | Wang, Shijie | Jing, Fuchun | Zhan, Jiang | Wang, Yunhui

Article Type: Research Article

Abstract: BACKGROUND AND AIMS: Growing evidence suggests that microRNA plays an essential role in the development and metastasis of many tumors, including gastric cancer (GC). Expression of microRNA-203 (miR-203) has been reported to decrease in GC. In addition, overexpression of miR-203 inhibits grow of GC cells in vitro and in vivo. However, whether miR-203 affects cell migration and invasion of GC remains unclear. This study aimed to reveal the role of miR-203 on migration and invasion of GC, and its potential mechanisms. METHODS: Synthetic pre-miR-203 (miR-203), anti-miR-203 and scrambled negative control RNAs was transfected into the …gastric cancer SGC7901 cells to generate miR-203 or anti-miR-203-transfected stable clones. The roles of miR-203 on cell invasion and motility were then analyzed by Transwell migration assay and Wound healing assay in vitro. Using siRNA to targeting ERK1/2, Slug, and E-cadherin or Slug cDNA transfection (to increase Slug expression) to examine the miR-203 signaling pathway. We also examined the efficacies of miR-203 or anti-miR-203 on peritoneal metastasis of SGC7901 cells in the nude mouse model. RESULTS: Overexpression of miR-203 inhibits SGC7901 cell invasion and motility, followed by decreased phospho-ERK1/2 (pERK1/2) and Slug expression, as well as increased E-cadherin expression. Re-expression of Slug in miR-203/SGC7901cells decreased E-cadherin expression and restored the invasive phenotypes. Targeting E-cadherin in miR-203/SGC7901cells also restored the invasive phenotypes. Inhibition of miR-203 promotes SGC7901 cell invasion and motility, followed by increased phospho-ERK1/2 (pERK1/2) and Slug expression, as well as decreased E-cadherin expression. Targeting ERK1/2 or Slug in anti-miR-203/SGC7901cells increased E-cadherin expression and reversed the invasive phenotypes. In addition, targeting ERK1/2 decreased Slug and increased the E-cadherin expression. Significantly, we found that miR-203 could exert marked inhibition of the peritoneal metastasis of SGC7901 in nude mice in vivo . Targeting miR-203 could exert marked promotion of the peritoneal metastasis of SGC7901 in nude mice in vivo . CONCLUSIONS: miR-203/ERK1/2/Slug/E-cadherin signaling pathway plays an essential role on SGC7901 cell invasion and motility. miR-203 can be novel modalities to prevent peritoneal metastasis of invasive cancers such as gastric cancer. Show more

Keywords: Gastric cancer, invasion, microRNA-203, extracellular signal-regulated kinase (ERK), slug

DOI: 10.3233/CBM-160167

Citation: Cancer Biomarkers, vol. 19, no. 1, pp. 11-20, 2017

Authors: Al Ahmed, Hala Abdel | Nada, Ola

Article Type: Research Article

Abstract: BACKGROUND: Many researches aiming to explore the pathogenesis of lung cancer have extensively studied the molecular alteration in such disease. OBJECTIVE: In the present study we measured the blood E2F3 mRNA using real-time RT-PCR technique in order to evaluate its clinical significance in early diagnosis and monitoring of lung cancer. METHODS: This case-control study included 50 lung cancer patients, 20 patients with benign lung diseases and 20 healthy controls. Relative quantification of blood E2F3 mRNA was done by real-time RT-PCR. RESULTS: Blood E2F3 mRNA levels were significantly higher in lung …cancer patients when compared to either patients with benign lung diseases or healthy subjects. This elevation was significant in those with metastatic lung cancer as compared to those with localized lung cancer. At a cutoff^{(2-Δ Δ CT)} 1.5, blood E2F3 mRNA was able to distinguish malignant from benign lung conditions with a diagnostic sensitivity of 100%; while at a cutoff^{(2-Δ Δ CT)} 5.3, blood E2F3 mRNA discriminated localized from metastatic lung cancer with a sensitivity of 93.6%. CONCLUSIONS: Blood E2F3 mRNA is a sensitive diagnostic marker in lung cancer; moreover, it is a promising prognostic marker capable of efficiently discriminating early from late stages of the disease. Show more

Keywords: E2F3, cyclin dependent kinase, lung cancer, RT-PCR, Rb protein

DOI: 10.3233/CBM-160196

Citation: Cancer Biomarkers, vol. 19, no. 1, pp. 21-26, 2017

Authors: Zhang, Shiying | Li, Jianye | Zhou, Gaobiao | Mu, Dawei | Yan, Jingmin | Xing, Jizhang | Yao, Zhiyong | Sheng, Haibo | Li, Di | Lv, Chao | Sun, Bin | Hong, Quan | Guo, Heqing

Article Type: Research Article

Abstract: BACKGROUND: Aurora A kinase is frequently overexpressed in a variety of tumor types, including the prostate. However, the function of Aurora A in autophagy in prostate cancer has not been investigated. Here, we aimed to study the functioning mechanism and autophagy associated signaling pathways of Aurora A in prostate cancer. METHODS: To investigate the biological function of Aurora A, down-regulation of Aurora A was performed followed by functional testing assays. Immunohistochemistry was used to detect the expression of Aurora A in human prostate cancer specimens. CCK8, Transwell, flow cytometric analysis and measurement of tumor formation in …nude mice were performed to test the effects of Aurora A down-regulation in vivo and in vitro . Signaling pathway analysis was performed by using Western blot. Autophagy activity was measured by monitoring the expression levels of LC3-II. RESULTS: Aurora A overexpression was significantly higher in human prostate cancer specimens than in BPH. Furthermore, Aurora A knockdown inhibited the proliferation of prostate cancer cells by suppressing the Akt pathway, indicating that Akt is a novel Aurora A substrate in prostate cancer. Additionally, Aurora A down-regulation prompts autophagy in prostate cancer cells. Most importantly, Aurora A ablation almost fully abrogates tumorigenesis in nude mice, suggesting that Aurora A is a key oncogenic effector in prostate cancer. CONCLUSIONS: Taken together, our data suggest that Aurora-A plays an important role in the suppression of autophagy by inhibiting the phosphorylation of Akt, which in turn prevents autophagy-induced apoptosis in prostate cancer. Show more

Keywords: Aurora A, autophagy, prostate cancer, chromosome instability gene

DOI: 10.3233/CBM-160238

Citation: Cancer Biomarkers, vol. 19, no. 1, pp. 27-34, 2017

Authors: Rong, Biaoxue | Nan, Yandong | Liu, Hua | Gao, Wenlong

Article Type: Research Article

Abstract: BACKGROUND: Previous studies show that overexpression of stathmin involved in the malignant biological behavior of lung cancer. This investigation is to disclose the expression status of stathmin in non-small cell lung cancer (NSCLC) and its clinical value for the diagnosis and prognosis to lung cancer. METHODS: The expression of stathmin in cells and tissues of NSCLC was examined using immunohistochemistry (IHC), in-situ hybridization (ISH), and Western blot. The correlation between stathmin expression and survival of lung cancer patients was evaluated by a Kaplan-Meier method and the multiple regression analysis. RESULTS: NSCLC tissues …and cells showed an overexpression of stathmin compared with normal lung tissues and cells (p< 0.05). And the expression level of stathmin was significantly associated with lung adenocarcinoma (LAC) (p< 0.05), lymphatic invasion (p< 0.05) and advanced stages of NSCLC (p< 0.05). Moreover, overexpression of stathmin predicted a reduced survival (p<0.05). CONCLUSION: Increased stathmin correlated with pathologic grade, lymphatic invasion, advanced stage and poor survival of NSCLC, which indicated that stathmin could serve as a potential biomarker of NSCLC. Show more

Keywords: Stathmin, expression, survival, biomarker, non-small cell lung cancer, NSCLC

DOI: 10.3233/CBM-160239

Citation: Cancer Biomarkers, vol. 19, no. 1, pp. 35-43, 2017

Authors: Sun, Jian | Liu, Ning-Bo | Zhuang, Hong-Qing | Zhao, Lun-Jun | Yuan, Zhi-Yong | Wang, Ping

Article Type: Research Article

Abstract: BACKGROUND: Radiosensitivity by blocking the epidermal growth factor receptor and cyclooxygenase-2 pathways with erlotinib and celecoxib in A549 human lung cancer cell was investigated. METHODS: MTT assays were used to detect the antitumor effects of erlotinib and celecoxib in A549 cells. Colony formation assays were used to evaluate the antitumor effects. Flow cytometry analysis was used to assess the cell cycle and cell apoptosis, and western blotting analysis was performed to evaluate the expression of AKT and phosphorylated AKT. RESULTS: Either erlotinib or celecoxib inhibited the A549 cell proliferation in a dose-dependent manner. …Combining Erlotinib or celecoxib with radiation can suppress the cell colony formation and the Dq, D0 , SF2 of the combining erlotinib or celecoxib with radiation was lower than in the combinations either erlotinib or celecoxib with radiation (t= 6.62, P< 0.05). The SER of radiation with celecoxib or erlotinib and celecoxib and erlotinib were 1.299, 1.503 and 2.217, respectively. The Flow cytometry analysis results showed that either celecoxib or erlotinib could induce G0 /G1 arrest, and reduction of S phase cell proportion, especially when combinations erlotinib-celecoxib with radiation. Either celecoxib or erlotinib could enhance radiation-induced apoptosis, especially significant when combinations erlotinib-celecoxib with radiation. Moreover, radiation can promote the expression of pAKT, and the pAKT was remarkably lowest in the combinations erlotinib-celecoxib with radiation group (t= 4.89, P< 0.05). CONCLUSIONS: Blocking both EGFR- and COX-2-related pathways could enhance the antitumor effect of radiation. The underlying mechanisms including the enhancement of apoptosis and radiation-induced G0 /G1 arrest, possibly via inhibiting the PI3K/AKT signaling pathway. Show more

Keywords: Celecoxib, erlotinib, lung adenocarcinoma, radiosensitizing

DOI: 10.3233/CBM-160323

Citation: Cancer Biomarkers, vol. 19, no. 1, pp. 45-50, 2017

Authors: Motalebzadeh, Jamshid | Mahjoubi, Frouzandeh | Nafissi, Nahid | Hashemian, Maria | Taheri, Mohsen | Hosseinpour, Younes

Article Type: Research Article

Abstract: BACKGROUND: Fibulin-4 (FBLN-4) is an extracellular glycoprotein that is upregulated in some cancer and is khown as prognostic marker in ovarian and cervical cancer. Breast cancer resistance protein (BCRP ) is an ATP-binding cassette transporter that facilitates the efflux of various anticancer drugs from the cell and cause MDR phenotype in breast tumors. Many studies are available that indicat overexpression of BCRP gene in breast cancer. OBJECTIVE: In the present study we aimed to analyze the expression level of FBLN-4 and BCRP in Iranian breast cancer patients. METHODS: We collected …40 samples of breast cancer and normal tissue from Tehran Khatam-al-Anbia hospital. To analyze the gene expression by using Real Time RT-PCR FBLN-4 and BCRP gene expression level were measured and then the association of gene expression with breast cancer were determined. RESULTS: Surprisingly the expression level of FBLN-4 and BCRP genes were downregulated in tumor tissues compared to adjacent normal tissues. Comparison of the gene expression and clinico-pathology reports indicate FBLN-4 gene expression was associated with breast cancer histological grade. We found no correlation between the expressions of BCRP gene with any clinico-pathological characters. CONCLUSION: Interestingly and in contrast with our expectation, we found that the expression level of FBLN-4 and BCRP were downregulated in tumor compared to adjacent normal tissues. FBLN-4 was associated with grade histology and therefore can be considered as a potential prognostic biomarker. Show more

Keywords: Fibulin-4, BCRP, breast cancer, prognostic marker

DOI: 10.3233/CBM-160335

Citation: Cancer Biomarkers, vol. 19, no. 1, pp. 51-55, 2017

Authors: Deng, Jianliang | Chen, Wenjiao | Du, Yuan | Wang, Weiming | Zhang, Guoqiang | Tang, Yuehua | Qian, Zhangjun | Xu, Ping | Cao, Zhihong | Zhou, Yan

Article Type: Research Article

Abstract: BACKGROUND: Cullin1 and MMP-2 have been identified as important markers in various cancers, but their roles in colorectal cancer (CRC) have remained to be discovered. The aim of this study was to investigate the expression pattern and significance of Cullin1 and MMP-2 in CRC. METHODS: A total of 470 CRC patients were enrolled. Archival paraffin-embedded CRC tissue samples were used to generate tissue microarray blocks, which were immunohistochemically stained for Cullin1 and MMP-2. Prognostic and predictive role of Cullin1 and MMP-2 expression was evaluated by univariate and multivariate analysis, respectively. Values of p < 0.05 were …considered statistically significant. RESULTS: Cullin1 and MMP-2 protein levels were significantly upregulated in CRC tissues compared with adjacent noncancerous tissues. High tumoral Cullin1 or MMP-2 expression significantly correlated with shorter overall survival (OS), as well as with clinicopathologic characteristics in patients. Multivariate regression analysis showed that high Cullin1 and MMP-2 expressions, separately and together, were independent negative markers of OS. CONCLUSION: Cullin1 and MMP-2 expressions could be novel diagnostic and prognostic markers for CRC patients. Show more

Keywords: Cullin1, MMP-2, colorectal cancer, diagnosis, prognosis

DOI: 10.3233/CBM-160341

Citation: Cancer Biomarkers, vol. 19, no. 1, pp. 57-64, 2017

Authors: Yang, Bo | Guo, Qing | Wang, Fei | Cai, Kemin | Bao, Xueli | Chu, Jiusheng

Article Type: Research Article

Abstract: OBJECTIVE: The present study was performed to identify a gene set for predicting the relapse in laryngeal carcinoma using large data analysis methods. METHODS: Two gene expression profile data of laryngeal carcinoma (GSE27020 and GSE25727) were downloaded from public database. Genes associated with tumor relapse, namely informative genes, were identified by Cox regression analysis. Then the protein-protein interaction (PPI) network consisting of informative genes was constructed. Afterwards, the optimized support vector machine (SVM) classifier was constructed to classify the relapsed laryngeal carcinoma samples based on genes in specific PPI network. Furthermore, the efficiency of the SVM …classifier was verified by other two independent datasets. RESULTS: A total of 331 informative genes were obtained from GSE27020 and GSE25757 datasets. A PPI network specific to laryngeal carcinoma relapse was constructed which contained informative genes and critical non-informative genes. The top 10 genes in specific PPI network were APP , NTRK 1, TP 53, PTEN , FN 1, ELAVL 1, HSP 90AA 1, XPO 1, LDHA and CDK 2 ranked by BC (betweenness centrality) value. The optimized SVM classifier including top 80 genes showed accuracy of 100% to classify the relapsed cases from laryngeal carcinoma samples. Next, the efficiency of the SVM classifier to predict relapse samples was verified in another independent datasets, which showed accuracy of 97.47%. The informative genes in the optimized SVM classifier were enriched in several pathways associated with tumor progression. CONCLUSION: A 80-gene set was identified as biomarker to predict the relapse of laryngeal carcinoma, which would be potentially applied in decision of different treatments for patients with different relapse risks. Show more

Keywords: Laryngeal carcinoma, prognosis factor, relapse, support vector machine

DOI: 10.3233/CBM-160375

Citation: Cancer Biomarkers, vol. 19, no. 1, pp. 65-73, 2017

Authors: Ning, Li | Li, Zhiguo | Wei, Dianjun | Chen, Haiyan | Yang, Chao

Article Type: Research Article

Abstract: BACKGROUND: The long non-coding RNAs (lncRNAs) are emerging as important regulators in cancer progression. Clear cell renal cell carcinoma (ccRCC) is one of the most common urological cancers with poor prognosis. In this study, we examined the functional role of the lncRNA, nuclear enriched abundant transcript 1 (NEAT1) in ccRCC progression. METHODS: We performed quantitative real time PCR and western blotting assays to measure mRNA and protein expression levels, respectively. CCK-8 assay, cell invasion and migration assays were used to determine the cell proliferative, cell invasive and migratory ability. Flow cytometric analysis was performed to examine …cell apoptosis. RESULTS: The expression levels of NEAT1 was up-regulated in ccRCC tissues and up-regulation of NETA1 was positively correlated with tumor size, higher Fuhrman grade, and lymph node metastasis, and also predicts worse 5-year survival rate of patients with ccRCC. NEAT1 knock-down by NEAT siRNAs transfection suppressed cell proliferation and induced cell apoptosis in ccRCC cell lines. In addition, NEAT1 knock-down suppressed cell invasion and migration and inhibited the mRNA and protein expression levels of epithelial-mesenchymal transition-related markers in ccRCC cell lines. CONCLUSIONS: In conclusion, NEAT1 may be an important mediator in the regulation of ccRCC progression and predicts the poor prognosis in patients with ccRCC. Show more

Keywords: lncRNA, ccRCC, NEAT1, epithelial-mesenchymal transition, progression, prognosis

DOI: 10.3233/CBM-160376

Citation: Cancer Biomarkers, vol. 19, no. 1, pp. 75-83, 2017