Cancer Biomarkers - Volume 29, issue 3

Authors: Strzałka, Alicja | Hogendorf, Piotr | Skulimowski, Aleksander | Spychalski, Michał | Strzelczyk, Janusz | Durczynski, Adam

Article Type: Research Article

Abstract: BACKGROUND: The prognostic value of D-dimers concentration in portal blood in patients with pancreatic cancer has been established in several studies. Thyroid hormones and their receptors, especially T3 also seems to have a specific role in process of neoplasia and metastatic spread. OBJECTIVE: The aim of the study was to look for changes of thyroid hormones concentration between portal and peripheral blood. METHODS: We included prospectively 8 patients with pancreatic cancer, without liver dysfunction, qualified to surgical treatment. D-dimers, THS, fT3, fT4 concentration was determined in blood samples from portal and peripheral vein …taken intraoperatively. RESULTS: The difference and quotient of portal and peripheral concentration of D-dimers, THS, fT3 and fT4 was calculated (D-dimer-; THS-; fT3-; fT4-d and -q). The level of D-dimers measured in portal blood was > 2700 ng/mL in 3 patients. The peripheral fT3 level was significantly higher In high portal D-dimers group. FT3 change coefficients showed strong statistically significant negative correlation with portal D-dimer concentration level. CONCLUSIONS: We suggest that fT3 or its receptors can influence progression of pancreatic malignancies. The results of this study are also a new evidence that both fT3 and portal D-dimers are biologically linked to intensity of local neoplastic process. Nevertheless, deeper knowledge about portal circulation probably constitute missing part in understanding nature of pancreatic neoplasia. Investigations both on larger group and in the field of basic sciences are needed. Show more

Keywords: Pancreatic cancer, low T3 syndrome, portal blood, portal D-dimer level, deiodinase type 3

DOI: 10.3233/CBM-201595

Citation: Cancer Biomarkers, vol. 29, no. 3, pp. 301-306, 2020

Authors: Wang, Xiao-Jun | Li, Fei-Fei | Zhang, Yi-Jing | Jiang, Man | Ren, Wan-Hua

Article Type: Research Article

Abstract: BACKGROUND: Tribbles pseudokinase 3 (TRIB3) is a member of the tribbles-related family, which is involved a lot of cellular processes and multiple cancers, such as breast cancer, colorectal cancer, renal cell carcinomas, and lung cancer. However, the expression pattern and biological function of TRIB3 in hepatocellular carcinoma (HCC) has not yet been completely elucidated. METHODS: The expression of TRIB3 and clinicopathological characteristics were evaluated by HCC tissue microarray and qPCR analysis. Lentivirus packaging and transfection were employed to establish cell lines with TRIB3 overexpression or knockdown. The biological functions of TRIB3 in the growth of HCC …were determined using MTT and crystal violet assays. Tumor growth was monitored in a xenograft model in vivo . RESULTS: The expression of TRIB3 was upregulated in HCC tissue samples compared to paired normal tissues in 45 patients examined by qPCR assay. TRIB3 expression was significantly correlated with HCC tumor size and prognosis in postoperative patients by analysis of the TRIB3 expression data and HCC clinical features. Forced expression of TRIB3 significantly promoted HCC growth in vitro . In contrast, downregulation of TRIB3 inhibited cell growth in vitro . Moreover, knockdown of TRIB3 suppressed tumorigenesis of HCC cells in vivo . CONCLUSION: TRIB3 promotes growth abilities of HCC cells both in vitro and in vivo and predicts poor prognosis of HCC patients, which serves as a prognostic marker and might provide a potential therapeutic candidate for patients with HCC. Show more

Keywords: TRIB3, growth, hepatocellular carcinoma, prognosis

DOI: 10.3233/CBM-201577

Citation: Cancer Biomarkers, vol. 29, no. 3, pp. 307-315, 2020

Authors: Hao, Fengyun | Bi, Ya-Nan | Wang, Lei | Wang, Yubing | Ma, Jilei | Cui, Ping | Li, Xuhua | Sun, Shukai | Ning, Liang | Huang, Yichuan | Jiao, Xuelong | Chen, Dong

Article Type: Research Article

Abstract: This article has been retracted, and the online PDF has been watermarked ``RETRACTION''. The retraction notice is available at http://doi.org/10.3233/CBM219902.

Keywords: Anaplastic thyroid carcinoma, MicroRNAs, miR-199a-5p, epithelial-mesenchymal transition

DOI: 10.3233/CBM-201518

Citation: Cancer Biomarkers, vol. 29, no. 3, pp. 317-326, 2020

Authors: Wan, Quan | Yan, Wangxiang | Liu, Yonghong | Lin, Yanzhu | Lu, Zhiyuan

Article Type: Research Article

Abstract: OBJECTIVE: In this study, we determined the prognostic values of magnetic resonance imaging (MRI)-based primary tumor regression and serum squamous cell carcinoma antigen (SSCC-Ag) levels 4 weeks after definitive radiotherapy (RT) in cervical squamous cell carcinoma (CSCC) patients. METHODS: This was a retrospective study involving 218 patients with histologically confirmed CSCC (stages IB-IVA). All the patients received definitive RT. Pre- and post-RT pelvic MRI and SSCC-Ag levels were measured. Locoregional control (LRC), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were evaluated, and possible OS prognostic factors were analyzed. RESULTS: …The median follow-up time was 25.57 (1.73–58.93) months. Thirty-six and 68 patients died and experienced recurrence, respectively, and the primary tumors of 130 (59.6%) and 88 (40.4%) patients exhibited complete response (CR) and non-CR, respectively. The 3-year OS, DFS, LRC, and DMFS rates were significantly higher in the CR than in the non-CR patients (85.2% vs. 67.9%, 78.9% vs. 39.0%, 93.4% vs. 63.8%, and 83.4% vs. 54.5%, respectively; p < 0.05). The 3-year OS, DFS, LRC, and DMFS rates were significantly lower in the patients with high post-RT SSCC-Ag levels than in those with low post-RT SSCC-Ag levels (38.0% vs. 83.9%, 21.2% vs. 66.3%, 73.0% vs. 84.9%, and 26.5% vs. 79.0%, respectively; p < 0.05). Multivariate analyses indicated that SSCC-Ag levels were an independent OS predictor (HR: 5.749, 95% CI: 2.598–12.723, p < 0.001). CONCLUSION: Post-RT SSCC-Ag levels are OS independent prognostic factors in CSCC patients receiving RT. Timely and optimized treatment plans for CSCC patients after 4 weeks of RT are necessary when patients with persistent tumor and/or positive SSCC-Ag. Show more

Keywords: Cervix uteri, squamous cell carcinoma, survival, radiation, magnetic resonance imaging

DOI: 10.3233/CBM-190934

Citation: Cancer Biomarkers, vol. 29, no. 3, pp. 327-335, 2020

Authors: Dobrescu, Ruxandra | Picu, Catalina | Caragheorgheopol, Andra | Manda, Dana | Ioachim, Dumitru | Goldstein, Andrei | Badiu, Corin

Article Type: Research Article

Abstract: BACKGROUND: Matrix metalloproteinase-9 (MMP-9) is an important mediator of invasion and metastasis in neoplasia. In thyroid cancer expression levels correlate with aggressiveness but data on peripheral MMP-9 levels are less definitive. OBJECTIVE: Prospective study evaluating serum MMP-9 in the diagnosis and prognosis of papillary thyroid cancer. METHODS: Serum samples of MMP-9 were drawn before surgery in 185 consecutively enrolled patients with nodular thyroid disease, stratified on pathology as benign disease (N = 88) and papillary thyroid cancer (N = 97). Serum MMP-9 was …measured by an immunometric assay. RESULTS: MMP-9 levels were not different between benign vs malignant pathology (p = 0.3). In papillary thyroid cancer there was no significant difference in MMP-9 levels between histologies, TNM stage and invasive/non-invasive cancers. High-risk patients with multiple features of aggressiveness had significantly higher MMP-9 levels compared to low-intermediate risk patients (767.5 ± 269.2 ng/ml vs 563.7 ± 228.4 ng/ml, p = 0.019). A cut-off of 806 ng/ml distinguished high from low-intermediate risk patients with a sensitivity of 60% and a specificity of 87.36%, p = 0.018. In patients with available follow-up data (N = 78), MMP-9 was higher in patients who required ⩾ 2 doses of 131 I therapy (p = 0.009) and in those with biochemical evidence of persistent disease/who required additional therapy to achieve disease-free status (p = 0.017). CONCLUSION: Serum MMP-9 is not useful in the diagnosis of PTC, but preliminary data shows that high pre-surgical serum MMP-9 levels may identify patients at higher risk of persistent disease who require intensive treatment. Large volume prospective studies are required to confirm this observation. Show more

Keywords: Matrix metalloproteinase-9, MMP-9, papillary thyroid cancer, prognostic marker, neoplasia marker

DOI: 10.3233/CBM-190609

Citation: Cancer Biomarkers, vol. 29, no. 3, pp. 337-346, 2020

Authors: Zhu, Lin | Chen, Yinan | Liu, Jing | Nie, Kai | Xiao, Yongxin | Yu, Hong

Article Type: Research Article

Abstract: OBJECTIVE: MicroRNA-629 (miR-629) has been found to play an important role in the pathogenesis of human cancers. However, the function of miR-629 is still unknown in non-small-cell lung cancer (NSCLC). The purpose of this study is to preliminarily elucidate the regulatory mechanism of miR-629 in NSCLC. MATERIALS AND METHODS: The mRNA and protein expression was measured by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The function of miR-629 was investigated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) and Transwell assays. The relationship between miR-629 and FOXO1 was confirmed by dual luciferase assay. RESULTS: …MiR-629 was upregulated in NSCLC tissues and cells. High expression of miR-629 predicted poor prognosis in patients with NSCLC. Moreover, miR-629 promoted cell proliferation, migration and invasion in NSCLC cells. In addition, FOXO1 was confirmed as a direct target of miR-629 in NSCLC. Furthermore, knockdown of FOXO1 also promoted proliferation, migration and invasion of NSCLC cells. More importantly, overexpression of FOXO1 weakened the carcinogenesis of miR-629 in NSCLC. Besides that, miR-629 promoted EMT and activated the PI3K/AKT pathway in NSCLC. CONCLUSIONS: MiR-629 promotes the progression of NSCLC by targeting FOXO1 and regulating EMT/PI3K/AKT pathway. Show more

Keywords: miR-629, non-small-cell lung cancer, FOXO1, PI3K/AKT pathway

DOI: 10.3233/CBM-201685

Citation: Cancer Biomarkers, vol. 29, no. 3, pp. 347-357, 2020

Authors: Rhone, Piotr | Zarychta, Elżbieta | Bielawski, Kornel | Ruszkowska-Ciastek, Barbara

Article Type: Research Article

Abstract: BACKGROUND: Endothelial and platelet activation as well as a disruption of haemostatic balance are crucial in cancer-dependent venous thromboembolism development. OBJECTIVE: The aim of this study was to investigate the influence of von Willebrand factor (VWF), sE-selectin, sP-selectin as well as VWF/sE-selectin and sP-selectin/sE-selectin ratios on the probability of disease relapse in invasive breast carcinoma (IBrC) cases. METHODS: Eighty-four patients with IA-IIB stage of IBrC who passed a comprehensive clinicopathologic evaluation were included in the study. Follow-up was completed in all patients with a 15.48 % recurrence rate. An immunoassay of VWF antigen, …sE-selectin, sP-selectin, as well as an immunohistochemistry of oestrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2) and Ki67 was performed in all cases. RESULTS: The VWF/sE-selectin ratio was significantly higher in patients with poorly differentiated tumours than in those with high-differentiated tumours. A positive correlation between VWF concentration and tumour grade was noted. Eleven of 13 events happened in patients with VWF value below 600 mU/mL with recurrence rate of 25%, but only two events occurred in subject with VWF values above the 600 mU/mL (5%; P = 0.0028). CONCLUSIONS: Our study show that VWF could be considered as a suitable biomarker of breast cancer relapse. Show more

Keywords: Invasive breast cancer, tumour progression, von Willebrand factor, soluble form of E-selectin, soluble form of P-selectin

DOI: 10.3233/CBM-191096

Citation: Cancer Biomarkers, vol. 29, no. 3, pp. 359-372, 2020

Authors: Peng, Cheng | Wang, Jizhuang | Bao, Qiyuan | Wang, Jun | Liu, Zhuochao | Wen, Junxiang | Zhang, Weibin | Shen, Yuhui

Article Type: Research Article

Abstract: BACKGROUND: Extracellular vesicles(EVs) is an emerging approach of cancer liquid biopsy. Although the precipitation-based method with commercial kits has gained popularity as the second most commonly used technique, these protocols vary tremendously with many included reagents still unknown to the community. METHODS: In this study, we assigned each of the 3 clinical plasma samples into 6 aliquots to assess five commercial EV isolation kits, in comparison with ultracentrifugation(UC). We implemented a standardized EV preparation and transcriptome analysis workflow except the EV isolation methods used. The metrics of EVs and its RNA cargo (evRNA) were compared to …assess the technical variations versus the biological variations in the clinical setting. RESULTS: Although the size range of the isolated EVs demonstrated a similar distribution, we found significant technical variability among these methods, in terms of EV amount, purity, subpopulations and RNA integrity. Such variabilities were further relayed to a drastic divergence of evRNA expression on a transcriptome-wide fashion. CONCLUSIONS: Our study demonstrated a highly variable result from polymeric precipitation-based EV isolation methods, making EVs based biomarker analysis difficult to interpret and reproduce. We highlighted the importance of benchmarking and transparent reporting of the precipitation-based protocols in the liquid biopsy research. Show more

Keywords: Extracellular vesicles, commercial kits, ultracentrifugation, the extracellular RNA, osteosarcoma

DOI: 10.3233/CBM-201651

Citation: Cancer Biomarkers, vol. 29, no. 3, pp. 373-385, 2020

Authors: Zhao, Yangli | Zhang, Tingjuan | Zhao, Yangjing | Zhou, Jingdong

Article Type: Research Article

Abstract: BACKGROUND: The runt-related transcription factor family (RUNXs ) including RUNX1 , RUNX2 , and RUNX3 are key transcriptional regulators in normal hematopoiesis. RUNXs dysregulations caused by aberrant expression or mutation are frequently seen in various human cancers especially in acute myeloid leukemia (AML). OBJECTIVE: We systemically analyzed the expression of RUNXs and their relationship with clinic-pathological features and prognosis in AML patients. METHODS: Expression of RUNXs was analyzed between AML patients and normal controls from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) projects. Correlations between RUNXs …expression and clinical features together with survival were further analyzed. RESULTS: All RUNXs expression in AML patients was significantly increased as compared with controls. RUNXs expression was found to be significantly associated with genetic abnormalities such as RUNX1 mutation, t(8;21) and inv(16)/t(16;16). By Kaplan-Meier analysis, only RUNX3 overexpression was associated with shorter overall survival (OS) and disease-free survival (DFS) among non-M3 AML patients. Notably, in high RUNX3 expression groups, patients received hematopoietic stem cell transplantation (HSCT) had markedly better OS and DFS than patients without HSCT among both all AML and non-M3 AML. In low RUNX3 expression groups, there were no significant differences in OS and DFS between HSCT and non-HSCT groups among both all AML and non-M3 AML. In addition, a total of 835 differentially expressed genes and 69 differentially expressed microRNAs were identified to be correlated with RUNX3 expression in AML. CONCLUSION: RUNXs overexpression was a frequent event in AML, and was closely associated with diverse genetic alterations. Moreover, RUNX3 expression may be associated with clinical outcome, and helpful for guiding treatment choice between HSCT and chemotherapy in AML. Show more

Keywords: RUNX, expression, prognosis, biomarker, acute myeloid leukemia

DOI: 10.3233/CBM-200016

Citation: Cancer Biomarkers, vol. 29, no. 3, pp. 387-397, 2020

Authors: Yang, Dan | He, Yang | Wu, Bo | Liu, Ruxi | Wang, Nan | Wang, Tieting | Luo, Yannan | Li, Yunda | Liu, Yang

Article Type: Research Article

Abstract: BACKGROUND: Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer worldwide. Until now, the molecular mechanisms underlying LUAD progression have not been fully explained. This study aimed to construct a competing endogenous RNA (ceRNA) network to predict the progression in LUAD. METHODS: Differentially expressed lncRNAs (DELs), miRNAs (DEMs), and mRNAs (DEGs) were identified from The Cancer Genome Atlas (TCGA) database with a | log 2 FC| > 1.0 and a false discovery rate (FDR) < 0.05. Gene Ontology (GO), Kyoto …Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI) network, and survival analyses were performed to analyse these DEGs involved in the ceRNA network. Subsequently, the drug-gene interaction database (DGIdb) was utilized to select candidate LUAD drugs interacting with significant DEGs. Then, lasso-penalized Cox regression and multivariate Cox regression models were used to construct the risk score system. Finally, based on the correlations between DELs and DEGs involved in the risk score system, the final ceRNA network was identified. Meanwhile, the GEPIA2 database and immunohistochemical (IHC) results were utilized to validate the expression levels of selected DEGs. RESULTS: A total of 340 DELs, 29 DEMs, and 218 DEGs were selected to construct the initial ceRNA network. Functional enrichment analyses indicated that 218 DEGs were associated with the KEGG pathway terms “microRNAs in cancer”, “pathways in cancer”, “cell cycle”, “HTLV-1 infection”, and the “PI3K-Akt signalling pathway”. K-M survival analysis of all differentially expressed genes involved in the ceRNA network identified 24 DELs, 4 DEMs, and 29 DEGs, all of which were significantly correlated with LUAD progression (P < 0.05). Furthermore, 15 LUAD drugs interacting with 29 significant DEGs were selected. After lasso-penalized Cox regression and multivariate Cox regression modelling, PRKCE, DLC1, LATS2, and DPY19L1 were incorporated into the risk score system, and the results suggested that LUAD patients who had the high-risk score always suffered from a poorer overall survival. Additionally, the correlation coefficients between these 4 DEGs and their corresponding DELs involved in the ceRNA network suggested that there were 2 significant DEL-DEG pairs, NAV2-AS2 – PRKCE (r = 0.430, P < 0.001) and NAV2-AS2 – LATS2 (r = 0.338, P < 0.001). And NAV2-AS2 – mir-31 – PRKCE and NAV2-SA2 – mir-31 – LATS2 were finally identified as ceRNA network involved in the progression of LUAD. CONCLUSIONS: The lncRNA-miRNA-mRNA ceRNA network plays an essential role in predicting the progression of LUAD. These results may improve our understanding and provide novel mechanistic insights to explore prognosis and therapeutic drugs for LUAD patients. Show more

Keywords: ceRNA, lung adenocarcinoma, bioinformatics, lncRNA, miRNA, risk score

DOI: 10.3233/CBM-200133

Citation: Cancer Biomarkers, vol. 29, no. 3, pp. 399-416, 2020

Authors: Ji, Tao | Zhang, Yanan | Wang, Zheng | Hou, Zuoxu | Gao, Xuhui | Zhang, Xiaoming

Article Type: Research Article

Abstract: BACKGROUND: Long non-coding RNA (lncNRA) forkhead box D3 antisense RNA 1 (FOXD3-AS1) has been proved to promote or suppress the occurrence and development of multiple types of human tumors. However, the function and mechanism of FOXD3-AS1 in non-small cell lung cancer (NSCLC) are scarcely understood. METHODS: qRT-PCR was used for detecting FOXD3-AS1, miR-150 and SRC kinase signaling inhibitor 1 (SRCIN1) mRNA expression in NSCLC tissues, and the relationship between pathological characteristics of NSCLC patients and FOXD3-AS1 expression level was analyzed. With human NSCLC cell lines H1299 and A549 as cell models, CCK-8 and BrdU assays were …employed for detecting cancer cell proliferation, and Transwell assay was employed for detecting cell invasion ability. Dual luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay were used for the verification of the targeting relationshipe between FOXD3-AS1 and miR-150, and Western blot was employed for detecting SRCIN1 protein expression. RESULTS: FOXD3-AS1 expression was significantly reduced in NSCLC tissues and cell lines, and low expression of FOXD3-AS1 was closely related to positive lymph node metastasis and relatively high tumor grade. FOXD3-AS1 over-expression inhibited the proliferation and invasion of H1299 cell lines, while its knockdown promoted the proliferation and invasion of A549 cells. Additionally, it was confirmed that FOXD3-AS1 suppressed the expression of miR-150 by targeting it, and up-regulated the expression of SRCIN1. CONCLUSIONS: FOXD3-AS1 indirectly enhances the expression of SRCIN1 by targeting miR-150, thereby inhibiting NSCLC progression. Show more

Keywords: NSCLC, FOXD3-AS1, MiR-150, SRCIN1

DOI: 10.3233/CBM-200059

Citation: Cancer Biomarkers, vol. 29, no. 3, pp. 417-427, 2020