Cancer Biomarkers - Volume 20, issue 4

Authors: Fang, Enhao | Zhang, Xiuqing | Wang, Qi | Wang, Daoming

Article Type: Research Article

Abstract: BACKGROUND: Prostate cancer (PCa) is the most common and the second leading cause of cancer-related death among men in America. As the molecular mechanism of PCa has not yet been completely discovered, identification of hub genes and potential drug of this disease is an important area of research that could provide new insights into exploring the mechanisms underlying PCa. OBJECTIVE: The aim of this study was to identify potential biomarkers and novel drug for prostate cancer treatment. METHODS: The differentially expressed genes (DEGs) between prostate cancer and normal cells were screened using microarray …data obtained from the Gene Expression Omnibus database. Gene ontology (GO) and pathway enrichment analyses were performed in order to investigate the functions of DEGs, and the protein-protein interaction (PPI) network of the DEGs was constructed using the Cytoscape software. DEGs were then mapped to the connectivity map database to identify molecular agents associated with the underlying mechanisms of PCa. RESULTS: Totally, 359 genes (155 upregulated and 204 downregulated genes) were found to be differentially expressed between prostate cancer and normal cells. The GO terms significantly enriched by DEGs included cell adhesion, protein binding involved in cell-cell adhesion, response to BMP, extracellular region and extracellular region part. KEGG pathway analysis showed that the most significant pathways included cell adhesion molecules (CAMs) and TGF-beta signaling pathway. The PPI network of up-regulated DEGs and down-regulated DEGs were established, respectively. While CDH1 , BMP2 , NKX3-1 , PPARG and PRKAR2B were identified as the hub genes in the PPI network. CONCLUSIONS: The BMP2 , PPARG and PRKAR2B genes may therefore be potential biomarkers in the treatment of PCa. Additionally, the small molecular agent phenoxybenzamine may be a potential drug for PCa. Show more

Keywords: Prostate cancer, bioinformatics analysis, differently expressed genes, hub genes, therapeutic agent

DOI: 10.3233/CBM-170362

Citation: Cancer Biomarkers, vol. 20, no. 4, pp. 553-561, 2017

Authors: Kalantari, Elham | Asadi Lari, Mohammad Hossein | Roudi, Raheleh | Korourian, Alireza | Madjd, Zahra

Article Type: Research Article

Abstract: BACKGROUND: Gastric carcinoma is the third most common malignancy and is one of the main causes of cancer deaths worldwide. Cancer stem cells (CSCs) are a subpopulation of tumour cells capable of self-renewal and differentiation, likely responsible for the initiation, recurrence, metastasis and chemo/radio-resistance. OBJECTIVE: This study was conducted to evaluate the expression patterns and clinicopathologic significance of putative CSC markers, Lgr5 and DCLK1, in gastric carcinoma. METHOD: The expression levels of Lgr5 and DCLK1 were examined in a well-defined series of gastric carcinoma tissues, including 75 (80%) from intestinal and 19 (20%) from …diffuse subtypes, using tissue microarray (TMA). In addition, the correlation of the expression of these markers with clinicopathological factors was explored. RESULTS: Higher expressions of Lgr5 and DCLK1 were mainly detected in intestinal subtypes of gastric carcinomas compared to diffuse subtypes (P = 0.005 and P = 0.050, respectively). We also found a higher expression of Lgr5 and DCLK1 more frequently in well-differentiated gastric carcinoma cases (P < 0.001 and P = 0.007). The combined analysis demonstrated that the co-expression of Lgr5 and DCLK1 (Lgr5 High /DCLK1 High ) was more common in intestinal subtypes (P = 0.025) and well-differentiated gastric carcinoma samples (P < 0.001). Interestingly, there was a significant correlation between Lgr5 High /DCLK1 High phenotype and early-stage gastric carcinoma specimens (P = 0.045). CONCLUSION: Our findings indicated that the Lgr5 High /DCLK1 High expression pattern may be considered as a signature phenotype for intestinal subtypes of gastric carcinoma. Show more

Keywords: Gastric carcinoma, cancer stem cells, Lgr5, DCLK1

DOI: 10.3233/CBM-170383

Citation: Cancer Biomarkers, vol. 20, no. 4, pp. 563-573, 2017

Authors: Luan, Suxian | Mu, Meiling | Sun, Liangzhi

Article Type: Research Article

Abstract: OBJECTIVE: Selfheal has been used for many years in hyperprolactinemia induced galactorrhea, menstrual disorders, and dysgenesis with satisfactory curative effect. However, its mechanism is still unclear. This study intended to investigate the effect of selfheal extract on hyperprolactinemia in vivo and in vitro, in order to elucidate its mechanism of anti-hyperprolactinemia. PATIENTS AND METHODS: Hyperprolactinemia rat model was established. High dose (28.8 g/(kg⋅ d)), middle dose (14.4 g/ (kg⋅ d)), and low dose (7.2 g/(kg⋅ d)) of selfheal extract were used to treat the model to observe impact on serum estradiol (E2), …progesterone (P), prolactin (PRL), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels. Three cell lines MMQ, GH3, and PC12 were applied to investigate selfheal extract effect on PRL secretion, dopamine D2 receptor, and dopamine transporter (DAT). RESULTS: High and middle dose of selfheal extract significantly reduced PRL level in hyperprolactinemia rat compared with model group (P < 0.01). Compared with normal control, 5 mg/ml and 10 mg/ml selfheal extract obviously inhibited PRL secretion in MMQ cells that high expressed D2 receptor after 24 hours (P < 0.01), but did not affect PRL secretion in GH3 cells lack of D2 receptor. 8 mg/ml selfheal extract markedly suppressed D2 receptor and DAT expression in PC12 cells that strongly expressed D2 receptor and DAT (P < 0.01). CONCLUSIONS: Selfheal extract treated hyperprolactinemia through dopamine D2 receptor with significant effect. Show more

Keywords: Selfheal extract, hyperprolactinemia, PRL, dopamine D2 receptor, DAT

DOI: 10.3233/CBM-170454

Citation: Cancer Biomarkers, vol. 20, no. 4, pp. 575-580, 2017

Authors: Xu, Zhi-Hong | Liu, Cai-Hong | Hang, Jun-Biao | Gao, Bei-Li | Hu, Jia-An

Article Type: Research Article

Abstract: Tyrosine kinase inhibitors (TKIs), a novel group of target-specific anti lung cancer drugs, have recently been found to resistant to some NSCLC cells which have the T790M EGFR mutation. However, recent investigations on the therapies of resistance to EGFR-TKIs are very limited. Therefore, it is important to develop more effective therapies to reverse EGFR-TKIs resistance. In our present study, erlotinib was used as the TKIs drug and the effects of the erlotinib on cell growth were evaluated. Cell viability and concentration dependent studies were performed using HCI-H1975 and HCI-H1299 cells alone with erlotinib, respectively. Further combined with rituximab, the results …showed that erlotinib and rituximab were significantly inhibited the cell growth. Furthermore, the combination of erlotinib and rituximab greatly decreased the expression of p-mTOR and p-EGFR. Additional results from western blotting and immunofluorescence assays demonstrated that the accumulation of rictor was also decreased on MAM. Thus, all these results suggested that EGFR-TKIs combined with CD20 mono-antibody significantly decrease the cell growth of H1975 cells and H1299, with T790M EGFR mutation, and inhibit the localization of the key mTOR pathway proteins to MAM. So, it may be a promising strategy for overcoming EGFR TKI resistance in NSCLC patients. Show more

Keywords: Rituximab, tyrosine kinase inhibitors, ER-membrane, NSCLC cells

DOI: 10.3233/CBM-170575

Citation: Cancer Biomarkers, vol. 20, no. 4, pp. 581-588, 2017

Authors: Xia, Hong-Liang | Lv, Yao | Xu, Chun-Wei | Fu, Ming-Cui | Zhang, Ting | Yan, Xiang-Ming | Dai, Shu | Xiong, Qian-Wei | Zhou, Yun | Wang, Jian | Cao, Xu

Article Type: Research Article

Abstract: Neuroblastoma is a brain malignancy of childhood and accounts for 7–10% of childhood cancers, leading to approximately 15% of pediatric cancer deaths. MicroRNAs (miRNAs) are a family of short (about 18–25 nucleotides), noncoding and single stranded endogenous RNAs, which complementarily bind to the 3’ untranslated regions of their target genes. Recently, glutamine metabolism has been recognized as an important nutrition source for tumor cells, and hence targeting glutamine metabolism could benefit to development of anti-cancer agents. In this study, we investigate the roles of miR-513c in human neuroblastoma. We report miR-513c is significantly downregulated in human neuroblastoma tissues compared with …their adjacent normal tissues. Moreover, miR-513c is significantly downregulated in neuroblastoma cell lines compared with normal neuroblast cells. Overexpression of miR-513c suppresses neuroblastoma cells’ migration, invasion, and proliferation. We demonstrate the glutaminase (GLS) is a direct target of miR-513c in human neuroblastoma cells. In addition, we found restoration of GLS expression recovered the neuroblastoma cells’ migration, invasion, and proliferation. In summary, this study illustrates a miR-513c mediated neuroblastoma cells suppression, providing a new aspect on the miRNA-based therapeutic approach for the treatments of neuroblastoma. Show more

Keywords: MiR-513c, neuroblastoma, glutaminase, migration, invasion, proliferation

DOI: 10.3233/CBM-170577

Citation: Cancer Biomarkers, vol. 20, no. 4, pp. 589-596, 2017

Authors: Sun, Yi | Li, Li | Xing, Shigang | Pan, Yinghua | Shi, Yunxiang | Zhang, Linghua | Shen, Qiang

Article Type: Research Article

Abstract: Studies have shown that microRNAs (miRNAs) can promote or suppress tumor growth and therefore act as targets for cancer therapy. Hsa-miR-503-5p, a mature miRNA derived from 5’ ends of pre-miR-503, has been proved to regulate cell proliferation, transformation, migration and invasion. However, the biological function of miR-503-3p derived from 3’ ends of pre-miR-503 has never been reported. In current study, we found that miR-503-3p inhibits lung cancer cell viability and induces cell apoptosis. To better understand the molecular mechanism underlying the miR-503-3p participating in this process, PCR array and RNA-sequencing (RNA-seq) were performed and some differential expression genes were discovered …between NC and miR-503-3p treated groups. Biological interaction network showed that p21 and CDK4 are the most important proteins involving miR-503-3p signal pathway. Dual-luciferase assay results shown miR-503-3p directly regulates the expression of p21 by targeting 3’-UTR of its mRNA. These results shed light on the potential roles of miR-503-3p, indicating that it may act as an anti-oncogene factor to inhibit lung cancer cell viability. Show more

Keywords: Lung cancer, miR-503-3p, apoptosis, p21

DOI: 10.3233/CBM-170585

Citation: Cancer Biomarkers, vol. 20, no. 4, pp. 597-608, 2017

Authors: Liu, Li-Wei | Yang, Ming-Ya | Zhou, Min | Li, Jia-Jia | Liu, Bo | Pan, Yue-Yin

Article Type: Research Article

Abstract: OBJECTIVE: To investigate the improvement of cytotoxicity of autologous CIKs from patients with breast cancer to MCF-7 cells by suppressed PD-1 expression. METHODS: The Lentiviral Vector/PD-1 carrying the gene that can suppressed PD-1 was transferred to CIK cells from patients with breast cancer to inhibit PD-1 expression. The PD-1 protein were detected by RT-PCR and Western blot. The positive PD-1 of CIKs and PD-L1 of MCF-7 cells were detected by FCM, and cytotoxicity of CIKs to MCF-7 was assayed by CCK-8. RESULTS: The PD-1 positive CIKs with Lentiviral Vector/PD-1 transferred from patients with breast …cancer were 16.02%, 14.36% and 14.64% at 14 th , 21 st and 28 th day, obviously inhibited as compared to 50.54%, 74.50% and 73.36% in CIKs without transinfection (P < 0.05); the Lentiviral Vector/PD-1 decreased the PD-1 mRNA levels in CIK cells, and Lentiviral Vector/PD-1-transferred CIKs had lower PD-1 expression; CCK-8 detection showed that at 14 th day, the cytotoxicity rates of CIKs with blank plasmids and those with PD-1 transfection to MCF-7 cells were 58.78% and 68.14%, respectively. CONCLUSION: MCF-7 cells have a strong PD-L1 expression at its surface, and inhibition of PD-1 expression can improve the cytotoxicity of CIK cells. Show more

Keywords: CIKs, MCF-7 cells, PD-1, PD-L1, cytotoxicity

DOI: 10.3233/CBM-170588

Citation: Cancer Biomarkers, vol. 20, no. 4, pp. 609-615, 2017

Authors: Liu, Guang-Wei | Qin, Zhao-Min | Shen, Qin-Hai

Article Type: Research Article

Abstract: OBJECTIVE: It is crucially important to discover the relationships between genes and microRNAs (miRNAs) in cancer. Thus, we proposed a combined bioinformatics method integrating Pearson’s correlation coefficient (PCC), Lasso, and causal inference method (IDA) to identify the potential miRNA targets for stomach adenocarcinoma (STAD) using Borda count election. MATERIALS AND METHODS: Firstly, the ensemble method integrating PCC, IDA, and Lasso was used to predict miRNA targets. Subsequently, to validate the performance ability of this ensemble method, comparisons between verified database and predicted miRNA targets were implemented. Pathway analysis for target genes in the top 1000 miRNA-mRNA interactions …was implemented to discover significant pathways. Finally, the top 10 target genes were identified based on predicted times > 3. RESULTS: The ensemble approach was confirmed to be a feasible method to predict miRNA targets The 527 target genes of the top 1000 miRNA-mRNA interactions were enriched in 21 pathways. Of note, cell adhesion molecules (CAMs) was the most significant one. The top 10 target genes were identified based on predicted times > 3, such as GABRA3, CSAG1 and PTPN7. These targets were all predicted by 4 times. Moreover, GABRA3 and CSAG1 were simultaneously targeted by miRNA-105-1, miRNA-105-2, and miRNA-767. Significantly, among these top 10 targets, PTPN7 and GABRA3-miRNA interactions owned the highest correlation with 691. CONCLUSION: The combined bioinformatics method integrating PCC, IDA, and Lasso might be a valuable method for miRNA target prediction, and dys-regulated expression of miRNAs and their potential targets might be prominently involved in the pathogenesis of STAD. Show more

Keywords: Stomach adenocarcinoma, ensemble method, miRNA targets

DOI: 10.3233/CBM-170595

Citation: Cancer Biomarkers, vol. 20, no. 4, pp. 617-625, 2017

Authors: Wei, Yi-Sheng | Zhou, Ya-Guang | Wang, Guo-Ying | Liang, Zhi-Hua | Luo, Min-Rui | Yang, Tian-Ai | Huang, Jun

Article Type: Research Article

Abstract: BACKGROUND AND OBJECTIVE: The association of chemotherapy-associated hemoglobin and survival of colorectal cancer (CRC) receiving adjuvant chemotherapy is uncertain. We sought to explore the prognostic value of chemotherapy-associated hemoglobin in CRC receiving adjuvant chemotherapy and the best cut point affecting prognosis. METHODS: Three hundred and twenty stage II and III CRC patients receiving adjuvant FOLFOX chemotherapy from March 2003 to March 2012 were enrolled. The associations between chemotherapy-associated hemoglobin (the absolute levels of post-chemotherapy) or chemotherapy-associated hemoglobin change (change between the pre- and post-chemotherapy hemoglobins) and disease free survival (DFS) or overall survival (OS) of CRC, …and the best cut point were investigated. RESULTS: Log rank test showed the best cut points for chemotherapy-associated hemoglobin and chemotherapy-associated hemoglobin change were respectively 90 g/L, 30 g/L. Cox regression model showed chemotherapy-associated hemoglobin < 90 g/L was the independent prognostic factor for DFS (HR, 2.221; 95% CI = 1.157–4.262), OS (HR, 2.058; 95% CI = 1.009–4.197), respectively, but no association of chemotherapy-associated hemoglobin change ⩾ 30g/L and DFS (HR, 2.063; 95% CI = 0.929–4.583), OS (HR, 1.386; 95% CI = 0.553–3.471) was found. CONCLUSIONS: Chemotherapy-associated hemoglobin < 90 g/L has a significant prognostic value in CRC receiving adjuvant chemotherapy, which is a significant biomarker in the individualized management and may suggest the simple indication for the treatment of anemia in adjuvant chemotherapy in CRC. Show more

Keywords: Adjuvant chemotherapy, colorectal cancer, hemoglobin, disease free survival, overall survival

DOI: 10.3233/CBM-170601

Citation: Cancer Biomarkers, vol. 20, no. 4, pp. 627-635, 2017

Authors: Majek, Pavel | Pecankova, Klara | Cermak, Jaroslav | Gasova, Zdenka | Prochazka, Bohumir | Dyr, Jan E.

Article Type: Research Article

Abstract: BACKGOUND: It has been indicated in plasma proteomic studies on different myelodysplastic syndrome (MDS) cohorts that alpha-2-HS-glycoprotein could be a promising MDS biomarker candidate. OBJECTIVE: The goal of this work was to estimate alpha-2-HS-glycoprotein (AHSG) plasma levels and its biomarker value in the low- and high-risk subgroups of MDS patients. METHODS: The level of AHSG was estimated for 115 plasma samples using ELISA. RESULTS: The AHSG plasma level was found to be decreased significantly (p = 2.59 × 10 - 7 …) in MDS patients (515 ± 58 μ g/ml) when compared to healthy controls (579 ± 64 μ g/ml). Pearson and Spearman correlation analyses showed that age is the principal factor affecting the AHSG plasma level, rather than risk/diagnosis in MDS. CONCLUSIONS: In this work we demonstrate that although the total plasma level of AHSG is decreased in myelodysplastic syndrome patients, in particular in advanced MDS, that decrease correlates more strongly with age than with diagnosis within our studied cohort. Thus, according to the AHSG data gathered so far, AHSG total plasma level does not seem to be a suitable MDS biomarker, but its particular proteoforms should be considered for the next steps in MDS research. Show more

Keywords: AHSG, alpha-2-HS-glycoprotein, MDS, myelodysplastic syndrome

DOI: 10.3233/CBM-170638

Citation: Cancer Biomarkers, vol. 20, no. 4, pp. 637-639, 2017