Cancer Biomarkers - Volume 23, issue 4

Authors: Li, Ying | Zhang, Xi-Yuan | Han, Jie | Wang, Ling

Article Type: Research Article

Abstract: OBJECTIVE: This study aims to analyze Chinese patients who developed acute leukemia after being diagnosed and treated for Philadelphia chromosome (Ph)-negative chronic myeloproliferative neoplasms (MPNs), and compare the findings of this series with similar studies from literature. METHODS: Nine patients who progressed to leukemia after being diagnosed with MPN were included into the present study. Clinical data including age, treatment modalities and duration of use in the myeloproliferative phase, latency to leukemic transformation (LT), characteristics of leukemia, chemotherapy administration, and survival after LT were examined. Furthermore, factors associated with leukemia transformation were analyzed. RESULTS: …Over a 13-year period, nine patients had LT in 192 Ph-negative MPNs. Among these patients, two patients had polycythemia vera (PV), three patients had essential thrombocythemia (ET), and four patients had myelofibrosis (MF). The median age at MPN diagnosis was 51 years old (range: 42–69 years old), and the median age upon reaching LT was 57 years old (range: 46–72 years old). Furthermore, the median latency to LT was 72.8 months (range: 7–144 months). Five patients had cytogenetic abnormalities (62.5%), with abnormalities in chromosomes - 5, + 8 and - 7 being common. Eight patients underwent the JAK2 V617F gene test when diagnosed with MPN. The prognosis of patients with LT was poor, and the average survival time was 6.7 months. This was not correlated with the treatment. CONCLUSION: LT in Ph-negative MPNs is rare, and has poor prognosis, which has been consistently reported in a number of studies, However, this needs to be further confirmed through larger studies. Show more

Keywords: Myeloproliferative neoplasms, acute myeloid leukemia

DOI: 10.3233/CBM-171145

Citation: Cancer Biomarkers, vol. 23, no. 4, pp. 469-472, 2018

Authors: Qin, Xiantao | Chang, Fangyuan | Wang, Zhenfeng | Jiang, Wenying

Article Type: Research Article

Abstract: OBJECTIVE: This study aimed to evaluate predictive value of 14 pro-angiogenic miRNAs for cardiotoxicity induced by epirubicin/cyclophosphamide follow by docetaxel (EC-D) in breast cancer (BC) patients. METHODS: Three hundred and sixty-three BC patients receiving EC-D neoadjuvant chemotherapy were consecutively enrolled in this prospective cohort study. Peripheral blood sample was obtained from each patient, and plasma was separated. The expressions of 14 pro-angiogenic miRNAs, cardiac troponin I (cTnI) and N-terminal pro brain natriuretic peptide (NT-proBNP) were evaluated. Left ventricular ejection fraction (LVEF) level at C0, the end of 4 cycles of EC chemotherapy (C4), the end of …4 cycles of docetaxel treatment (C8), 3rd months (M3), 6th months (M6), 9th months (M9) and 12th months (M12) after surgery were assessed. RESULTS: LVEF decreased at C4, C8, M3, M6, M9 and M12 compared with C0, and the total cardiotoxicity incidence was 5.2%. Additionally, the levels of let-7f, miR-17-5p, miR-20a, miR-126, miR-210 and miR-378 were reduced in cardiotoxicity patients. Multivariate logistic regression revealed that miR-17-5p and miR-20a were independently predictive factors for less cardiotoxicity. Receiver operating characteristics (ROC) curve displayed a satisfactory predictive value for lower cardiotoxicity risk with area under curve (AUC) of 0.842 of the combination of the miR-17-5p and miR-20a expressions. In addition, let-7f,miR-126, miR-210 and miR-378 levels negatively correlated with cTnI expression, and let-7f and miR-130a expressions reversely correlated with NT-proBNP level. CONLUSIONS: miR-17-5p and miR-20a could be served as biomarkers for lower cardiotoxicity induced by EC-D neoadjuvant chemotherapy in BC patients. Show more

Keywords: Pro-angiogenic, miRNAs, cardiotoxicity, EC-D neoadjuvant chemotherapy, breast cancer

DOI: 10.3233/CBM-181301

Citation: Cancer Biomarkers, vol. 23, no. 4, pp. 473-484, 2018

Authors: Luo, Wenfeng | Yu, Huilan | Zou, Xingli | Ni, Xun | Wei, Jin

Article Type: Research Article

Abstract: OBJECTIVE: This study aimed to explore the correlation of long non-coding RNA taurine-upregulated gene 1 (lncRNA TUG1) expression with clinicopathological features and its predictive value for treatment response and survival profiles in refractory or relapsed acute myeloid leukemia (R/R AML) patients. METHODS: Seventy three R/R AML patients who received cladribine combined with cytarabine and granulocyte colony-stimulating factor (G-CSF) (CLAG) or fludarabine combined with cytarabine and G-CSF (FLAG) based chemotherapy and 37 non-malignant controls were recruited. LncRNA TUG1 expression was detected in bone marrow sample obtained before treatment. Complete response (CR), partial response (PR), overall response rate (ORR) …and overall survival (OS) were evaluated. RESULTS: LncRNA TUG1 expression was upregulated in R/R AML patients compared to controls. It was also elevated in R/R AML patients with age ⩾ 60 years (vs. age < 60 years, P = 0.030) and in patients with secondary AML (vs. primary AML, P = 0.035). R/R AML patients with lncRNA TUG1 high expression achieved numerically lower CR (P = 0.053), decreased ORR (P = 0.028) and shorter OS (P < 0.001) than patients with lncRNA TUG1 low expression. Univariate logistic regression and COX’s regression disclosed that lncRNA TUG1 high expression correlated with declined ORR, numerically decreased CR, and reduced OS. Furthermore, multivariate analyses verified that lncRNA TUG1 high expression was an independent predictive factor for decreased ORR and worse OS. CONCLUSIONS: In conclusion, lncRNA TUG1 expression was elevated in R/R AML patients, and it might serve as a potential biomarker for poor prognosis in R/R AML patients treated with CLAG or FLAG based chemotherapy. Show more

Keywords: LncRNA TUG1, refractory or relapsed acute myeloid leukemia (R/R AML), CLAG, FLAG, prognosis

DOI: 10.3233/CBM-181405

Citation: Cancer Biomarkers, vol. 23, no. 4, pp. 485-494, 2018

Authors: Huang, Yi | Huang, Yu | Zhang, Liang | Chang, Aoshuang | Zhao, Peng | Chai, Xiao | Wang, Jishi

Article Type: Research Article

Abstract: BACKGROUND: Multidrug resistance of Hodgkin’s lymphoma (HL) often results in recurrence. Thus, we aimed to explore the underlying molecular mechanisms of multidrug resistance using bioinformatics strategies. METHODS: The gene expression profile was obtained from GEO database. Then, the differentially expressed genes were screened out, and their functional annotations were carried out. Then, gene-signal interaction network was constructed and Connectivity Map (CMAP) analysis was performed. RESULTS: A total of 1425 dysregulated genes were screened out, which were mainly enriched in biological items, such as small molecule metabolic, signal transduction, and cell apoptosis. Some survival-related …pathways, such as MAPK pathways, apoptosis, and P53 pathway, and several hub genes, such as PRKCA, ACTN1, PIP5K1B, PRKACB, and JAK2, might play key roles in the development of multidrug resistance. Interestingly, felodipine was predicted to be a potential agent overcoming the multidrug resistance. CONCLUSIONS: The present study offered new insights into the molecular mechanisms of multidrug resistance and identified a series of important hub genes and small agents that might be critical for treatment of multidrug-resistant HL. Show more

Keywords: Multidrug resistance, differentially expressed genes, dysfunctional pathway, function enrichment analysis, Hodgkin’s lymphoma

DOI: 10.3233/CBM-181496

Citation: Cancer Biomarkers, vol. 23, no. 4, pp. 495-503, 2018

Authors: Luo, Ling | Gao, Yuqiang | Sun, Xiaofeng

Article Type: Research Article

Abstract: OBJECTIVE: The aim of this study was to evaluate the correlation of circular RNA itchy E3 ubiquitin protein ligase (Circ-ITCH) expression with clinicopathological features and survival in patients with epithelial ovarian cancer (EOC), and to explore its effect on cells proliferation as well as apoptosis in EOC cells. METHODS: Seventy-seven EOC patients underwent surgery were retrospectively reviewed. Tumor tissues and paired adjacent tissues samples were collected, and Circ-ITCH expression was evaluated by quantitative polymerase chain reaction (qPCR). Blank mimic, Circ-ITCH mimic, blank inhibitor and Circ-ITCH inhibitor plasmids were transfected into SKOV3 cells and OVCAR-3 cells, and …Counting Kit-8 (CCK-8) was performed to assess cells proliferation and Annexin V (AV)/propidium iodide (PI) was conducted to detect cells apoptosis. RESULTS: Median value of Circ-ITCH relative expression was 0.697 (0.367–1.106) in tumor tissues, which was lower compared with paired adjacent tissues (1.690 (0.867–2.813)) (P < 0.001), and it negatively correlated with tumor size (P = 0.005) as well as International Federation of Gynecology and Obstetrics (FIGO) stage (P < 0.001) in EOC patients. Multivariate Cox’s analysis revealed that high Circ-ITCH expression was an independent predictive factor for favorable OS in EOC patients. Moreover, further in vitro experiments disclosed that Circ-ITCH expression was decreased in several EOC cell lines compared with normal ovarian epithelial cell line, and it inhibited cells proliferation while promoted cells apoptosis in SKOV3 and OVCAR-3 cells. CONCLUSIONS: Circ-ITCH correlates with small tumor size, decreased FIGO stage and prolonged OS, and it inhibits cells proliferation while promotes cells apoptosis in EOC. Show more

Keywords: Epithelial ovarian cancer, Circ-ITCH, overall survival, cells proliferation, cells apoptosis

DOI: 10.3233/CBM-181609

Citation: Cancer Biomarkers, vol. 23, no. 4, pp. 505-513, 2018

Authors: Zhuang, Qianfeng | Shen, Jie | Chen, Zhen | Zhang, Mingran | Fan, Min | Xue, Dong | Lu, Hao | Xu, Renfang | He, Xiaozhou | Hou, Jianquan

Article Type: Research Article

Abstract: OBJECTIVE: Renal cancer accounts for about 3% of human cancer, and clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Recently, microRNAs (miRNAs) are found to be the biomarkers for cancer diagnosis, prognosis and the targets for tumor management. This study aimed to examine the expression of miR-337-3p in ccRCC and to elucidate the molecular mechanisms underlying miR-337-3p-mediated ccRCC progression. METHODS: The miRNA and mRNA expression levels in ccRCC cells and tissues were measured by qRT-PCR. Cell proliferation, cell adhesion, colony growth and cell invasion were examined by CCK-8 assay, cell …adhesion assay, colony formation assay and Transwell invasion assay, respectively. The protein levels were detected by western blot assay. The effects of miR-337-3p on tumor growth in vivo was assessed in a nude mice xenograft model. RESULTS: MiR-337-3p was down-regulated in ccRCC cell lines, and miR-337-3p overexpression suppressed cell proliferation, colony growth and invasion, but enhanced cell adhesion in ccRCC; while knockdown of miR-337-3p exerted the opposite effects on ccRCC. Bioinformatics analysis and luciferase reporter assay showed that Calpain small subunit 1 (Capn4) was negatively regulated by miR-337-3p, and overexpression of miR-337-3p attenuated the miR-337-3p-mediated effects on ccRCC cellular functions. In addition, miR-337-3p also suppressed epithelial-mesenchymal transition in ccRCC. The in vivo tumor growth was markedly suppressed after miR-337-3p overexpression. Data from clinical data showed that down-regulation of miR-337-3p and up-regulation of Capn4 mRNA and protein were identified in the ccRCC tissues, and miR-337-3p expression level was inversely correlated with Capn4 mRNA expression level in ccRCC tissues. CONCLUSIONS: Collectively, these data suggested the tumor suppressive role of miR-337-3p in ccRCC. MiR-337-3p suppressed cell proliferation and metastasis in ccRCC partially via targeting Capn4. Show more

Keywords: ccRCC, miR-337-3p, Capn4, epithelial-mesenchymal transition, proliferation, metastasis

DOI: 10.3233/CBM-181645

Citation: Cancer Biomarkers, vol. 23, no. 4, pp. 515-525, 2018

Authors: Zhao, Yina | Yang, Qiang | Wang, Xiaojie | Ma, Wenyi | Tian, Huanna | Liang, Xiujun | Li, Xin

Article Type: Research Article

Abstract: BACKGROUND: Hepatocellular carcinoma is one of the most fatal malignancies worldwide with high lethality. However, the exact mechanism of liver tumorigenesis is still unclear. AnnexinA7 (ANXA7) is a Ca 2+ -binding protein which is involved in membrane organization and dynamics and indicated a role of ANXA7 in cancer. However, the action of ANXA7 in hepatocellular carcinoma and the relative mechanism is still indistinct. OBJECTIVE: To gain more insight into the biological function of ANXA7 and assess its possible influence on proliferation and metastasis capacity of human hepatocellular carcinoma cells with the relative mechanism. …METHODS : ANXA7 was down-regulated by RNA interference in both HepG2 and smmc-7721 cells. The decreased cell proliferation was detected by MTT method and colony formation assay. To confirm the result of cell proliferation, Ki-67 and cyclinD1 expression was examined by Western Blot. The increased apoptosis capacity of the cells was detected with cell cytometry and PI staining respectively. Bcl-2 and Bax expression was further investigated by Western blot and the decreased ration of Bcl-2/Bax might explain the increased apoptosis. RESULTS: Cell metastasis showed significantly limited ability which was tested by wound healing assay and Transwell assay. Meanwhile, the key biomarkers of cell metastasis E-cadherin expression increased while MMP-9 decreased. Furthermore, we found that ANXA7 played its role via MAPK/ERK pathway. CONCLUSIONS: ANXA7 might involve in the development of hepatocellular carcinoma and act as an oncogene which might be a potential therapeutic target for treatment. Show more

Keywords: Annexin A7, hepatocellular carcinoma, proliferation, metastasis, MAPK/ERK pathway

DOI: 10.3233/CBM-181651

Citation: Cancer Biomarkers, vol. 23, no. 4, pp. 527-537, 2018

Authors: Gráf, László | Barabás, Lóránd | Madaras, Balázs | Garam, Nóra | Maláti, Éva | Horváth, Laura | Prohászka, Zoltán | Horváth, Zsolt | Kocsis, Judit

Article Type: Research Article

Abstract: BACKGROUND: Hsp70 plays important role in the development and progression of cancer. Previously we described the association between serum Hsp70 levels and mortality of colorectal cancer. OBJECTIVE: In this new prospective study we aimed to confirm and extend our previous findings in a larger cohort of patients, based on a longer follow-up period. METHODS: Two hundred and thirty-two patients diagnosed with colorectal cancer were enrolled in the study. Baseline serum Hsp70 level and classical biomarker levels were measured. Patients were treated according to stage of the tumor and follow-up lasted for a median …46.4 months. RESULTS: We found that serum Hsp70 concentrations increase significantly with stage of the disease (1.79; 2.23 and 3.21 ng/ml in stage I+ II, III and IV respectively, p = 0.012 and 0.002, Mann-Whitney test) and with other known biomarkers of the disease. We managed to confirm our previous findings that high baseline serum Hsp70 level (> 1.64 ng/ml) predicted poor 5-year survival (risk of death HR: 1.94 CI: 1.294–2.909; univariate; HR: 2.418 CI: 1.373–4.258; multivariate Cox regression analysis) in the whole patient population and also in subgroups of stage IV and stage III disease. The strongest association was observed in women under age of 70 (HR: 8.12, CI: 2.02–35.84; p = 0.004; multivariate Cox regression). The power of this colorectal cancer prognostic model could be amplified by combining Hsp70 levels and inflammatory markers. Patients with high Hsp70, CRP and high baseline WBC or platelet count had 5-times higher risk of death (HR: 5.07 CI: 2.74–9.39, p < 0.0001; and HR: 4.98 CI: 3.08–8.06, p < 0.0001 respectively). CONCLUSIONS: These results confirm and validate our previous findings that serum Hsp70 is a useful biomarker of colorectal cancer. Show more

Keywords: Hsp70, colorectal cancer, prognostic model, CRP, survival

DOI: 10.3233/CBM-181683

Citation: Cancer Biomarkers, vol. 23, no. 4, pp. 539-547, 2018

Authors: Wang, Xiang | Hu, Kai Bin | Zhang, You Qian | Yang, Chun Jian | Yao, Han Hui

Article Type: Research Article

Abstract: Cholangiocarcinoma (CCA) is a highly malignant and poorly differentiated bile duct cancer with an extremely poor prognosis, but the pathogenesis of CCA remains not well-known. Attention has been increasingly focused on long noncoding RNAs, which plays an important role in tumorigenesis. However, the roles of cancer specific lncRNA and its related competitive endogenous RNAs (ceRNA) network in CCA remain elusive. In this study, we comprehensively integrated expression profiles, including data on mRNAs, lncRNAs and miRNAs obtained from 36 CCA tissues and 9 normal tissues in The Cancer Genome Atlas. 1434 cancer specific lncRNAs, 68 miRNAs and 3538 mRNAs (| …logFC | > 1, p < 0.05) were identified. Based on bioinformatics generated from miRcode, starBase, miRTarBase, TargetScan and miRDB, we constructed an lncRNA-miRNA-mRNA network (ceRNA network) in CCA. We constructed the lncRNA-miRNA-mRNA ceRNA network consisting of 206 molecules and 454 interactions. In addition, we used Cytoscape software to visualize the ceRNA network in WGCNA, 22 mRNA network modules were identified, five of which were significantly related to tumor grade and survival time. Moreover, three lncRNAs COL18A1-AS1, SLC6A1-AS1 and HULC were found to be significantly associated with overall survival. The present study provides novel insight for better understanding of lncRNA-related ceRNA network in CCA and useful resource for identifcation of novel biomarkers of CCA. Show more

Keywords: Cholangiocarcinoma, lncRNA, ceRNA, miRNA, mRNA, TCGA

DOI: 10.3233/CBM-181684

Citation: Cancer Biomarkers, vol. 23, no. 4, pp. 549-559, 2018

Authors: Zhou, Lei | Ma, Xiao | Yue, Jian | Chen, Tong | Wang, Xin-yang | Wang, Zhi-wei | Pan, Jiang | Lin, Yuan

Article Type: Research Article

Abstract: BACKGROUND: The microRNA, miR-139-5p, plays an important role in the initiation and progression of various tumor types including osteosarcoma (OS). OBJECTIVE: This study aimed to detect the serum miR-139-5p expression in OS and analyze its association with clinical variables. METHODS: Blood samples were taken from 98 OS patients and 50 healthy individuals, and serum miR-139-5p levels were measured by quantitative reverse transcription-polymerase chain reaction. RESULTS: We found the expression of serum miR-139-5p in OS patients was significantly lower than that in healthy individuals, and miR-139-5p levels were dramatically decreased in patients …with distant metastasis or in higher clinical stage. Receiver-operating characteristic (ROC) analysis revealed that serum miR-139-5p could well discriminate OS patients from healthy controls with a high sensitivity and specificity. Moreover, low serum miR-139-5p expression was strongly associated with distant metastasis, tumor stage and shorter overall survival. Both univariate and multivariate analyses showed that serum miR-139-5p level could serve as an independent prognostic marker for OS. CONCLUSIONS: Taken together, data from this study demonstrates that serum miR-139-5p could be used as a tumor biomarker for OS diagnosis and prognosis. Show more

Keywords: Osteosarcoma, miR-139-5p, biomarker, diagnosis, prognosis

DOI: 10.3233/CBM-181744

Citation: Cancer Biomarkers, vol. 23, no. 4, pp. 561-567, 2018