Cancer Biomarkers - Volume 29, issue 1

Authors: Han, Lina | Wang, Yu | Sun, Shulun

Article Type: Research Article

Abstract: PTEN exerts tumor suppressor role through inhibiting PI3K/AKT signaling. DJ-1 plays an oncogenic role through negatively regulation of PTEN expression. Curcumin (Cur) is a phenolic compound extracted from a variety of plant roots, with multiple anti-tumor pharmacological effects. This study aims to investigate whether Cur plays a role in the regulation of DJ-1-PENT/PI3K/AKT signaling as well as the proliferation and apoptosis of hepatocellular carcinoma cells. Normal human hepatocyte HL-7702 and hepatocellular carcinoma cell lines SMMC-7721 and HepG2 were cultured followed by analysis of the expression of DJ-1 and PTEN. SMMC-7721 and HepG2 cells were treated with different concentrations of Cur …(0, 5, 10 μ M) followed by measuring cell proliferation by CCK-8, caspase-3 activity as well as DJ-1 expression by western blot. In addition, SMMC-7721 or HepG2 cells were divided into two groups: Cur+ pcDNA3.1-Blank and Cur+ pcDNA3.1-DJ-1 for analysis of the expression of DJ-1, PTEN and p-AKT, cell apoptosis and proliferation. Compared with HL-7702, SMMC-7721 and HepG2 cells displayed significantly higher DJ-1 expression and lower PTEN expression. Cur treatment significantly inhibited proliferation of SMMC-7721 and HepG2 cells, increased caspase-3 activity and downregulated DJ-1 expression. Transfection of pcDNA3.1-DJ-1 significantly increased DJ-1 and p-AKT expression, promoted cell proliferation, but decreased PTEN expression and cell apoptosis. In conclusion, Cur inhibits proliferation of hepatocellular carcinoma cells and PTEN/PI3K/AKT signaling pathway via the reduction of DJ-1 expression, which provides new insights to the anticancer effects of curcumin in hepatocellular carcinoma. Show more

Keywords: Curcumin, DJ-1, PTEN/PI3K/AKT, hepatocellular carcinoma

DOI: 10.3233/CBM-190427

Citation: Cancer Biomarkers, vol. 29, no. 1, pp. 1-8, 2020

Authors: Aref, Salah | Azmy, Emaad | El Ghannam, Doaa | Haroun, Marwa | Ibrahim, Lamiaa | Sabry, Mohamed

Article Type: Research Article

Abstract: BACKGROUND : This study aimed to assess the significance of combined expression of interleukin-2 receptor (CD25) and the interleukin-3 receptor (CD123) in acute myeloid leukemia (AML) patients. METHODS : The expression of CD25 and CD123 on blast cells in bone marrow samples were identified by flowcytometry in 94 patients (⩽ 60 years old) with de novo acute myeloid leukemia (AML) treated at the Mansoura University Oncology Center (MUOC). RESULTS : Of the 94 samples at diagnosis there were 17 (18.1%) CD25 + /CD123 + (double positive) …cases; 25 (26.6%) CD25 + /CD123 - (single positive); 32 (34.0%) CD25 - /CD123 + (single positive) cases; 20 (21.3%). CD25 - /CD123 - (double negative). Most of the AML patients have double CD25 + /CD123 + were significantly associated with poor and intermediate risk as compared to those associated with those in the good risk group (P = 0.005). The lowest induction of remission was recorded in AML patients have double CD25 + /CD123 + expression as compared to the remaining AML patient group. Study the effect of these biomarkers on the overall survival reveal that AML patients exhibited double CD25 + /CD123 + expression had significantly shorter overall survival as compared to negative ones. CONCLUSION: Double CD25 + /CD123 + co-expression in AML patients is a dismal prognostic marker and could be used as novel biomarker for risk stratification for AML patients. Show more

Keywords: CD25, CD123, AML, prognosis

DOI: 10.3233/CBM-201519

Citation: Cancer Biomarkers, vol. 29, no. 1, pp. 9-16, 2020

Authors: Lin, Jin-Ching | Wang, Chen-Chi | Jiang, Rong-San | Wang, Wen-Yi | Liu, Shih-An

Article Type: Research Article

Abstract: BACKGROUND: Practical cancer biomarkers for oral cavity cancer are currently in limited use. OBJECTIVE: We aimed to investigate the differences in soluble E-cadherin between patients with oral cavity cancer and matched healthy participants via Proximity Ligation Assay (PLA). METHODS: Samples were taken from both patients diagnosed with oral cavity cancer, as well as non-cancerous participants. PLA was used to detect soluble E-cadherin and Cycle threshold (Ct) values derived from qPCR in order to calculate the number of starting amplicons. RESULTS: In total, 74 patients with oral cavity cancer and 55 …matched non-cancerous participants were included for final analysis. The Ct value of E-cadherin was found to be lower in oral cavity cancer patients when compared with that of the matched non-cancerous participants (20.72 ± 0.39 versus 21.27 ± 0.45, P < 0.001). Using a Ct value of 20.9 as a cut-off point, the sensitivity and specificity of discriminating patients with oral cavity cancer from the healthy controls was 63.5% and 87.3%, respectively. CONCLUSION: Plasma soluble E-cadherin levels were significantly higher in patients with oral cavity cancer when compared with those from the matched non-cancerous participants. Show more

Keywords: Oral cavity cancer, proximity ligation assay, biomarker, squamous cell carcinoma, E-cadherin

DOI: 10.3233/CBM-191195

Citation: Cancer Biomarkers, vol. 29, no. 1, pp. 17-23, 2020

Authors: Zhao, Wei-Xin | Tang, Yan-Lei | Wang, Wei-Hua | Bao, Min-Wei

Article Type: Research Article

Abstract: BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common malignant tumor worldwide. This work focuses on investigating the role of circ_0000353 in NSCLC and its potential mechanism of action. METHODS: The expression levels of circ_0000353 and miR-411-5p in NSCLC and their matched normal lung tissues were detected by real-time PCR (RT-PCR). The correlation between the circ_0000353 expression and the clinicopathological parameters of NSCLC patients was also analyzed. CCK-8, BrdU and colony formation assays were adopted to detect the role of circ_0000353 in the proliferation of NSCLC cells. The metastasis of NSCLC cells was measured by …Transwell assay. The dual-luciferase reporter gene assay was used to confirm the targeting relationship between circ_0000353 and miR-411-5p. The expression level of FOXO1 was detected by western blot. RESULTS: Circ_0000353 was significantly down-regulated in NSCLC tissues and cell lines, and the decreased expression was significantly linked to the increased clinical stage, larger tumor volume, and metastasis. The circ_0000353 over-expression restrained the proliferation, migration, and invasion of NSCLC cells in vitro . Additionally, up-regulation of miR-411-5p was observed in NSCLC tissues and cell lines, and luciferase assay and RT-PCR assay showed that circ_0000353 over-expression could target miR-411-5p and suppress its expression. Further studies confirmed that circ_0000353 and miR-411-5p modulated the FOXO1 expression. CONCLUSION: Circ_0000353 repressed the proliferation, migration, and invasion of NSCLC cells via inhibition of miR-411-5p and up-regulation of FOXO1. Show more

Keywords: NSCLC, circ_0000353, miR-411-5p, FOXO1

DOI: 10.3233/CBM-190812

Citation: Cancer Biomarkers, vol. 29, no. 1, pp. 25-37, 2020

Authors: Wu, Kerong | Hu, Linkun | Lv, Xiuyi | Chen, Junfeng | Yan, Zejun | Jiang, Junhui | Cheng, Yue | Hou, Jianquan

Article Type: Research Article

Abstract: BACKGROUND: Long non-coding RNAs (lncRNAs) play important roles in cancer development, yet their roles in renal carcinoma remain unclear. OBJECTIVE: We performed this study in order to investigate the expression and roles of lncRNAs in renal cell carcinoma. METHODS: In this study, we investigated the expression of lncRNAs in renal cell carcinoma through microarray analysis. Quantitative real-time PCR was performed to measure the expression of lncRNAs. Gain- or loss-of-function experiments were performed to investigate the roles of lncRNAs in cell proliferation and apoptosis. RNA pull-down and western blotting were performed to explore …the underlying mechanism. RESULTS: The microarray analysis identified an upregulated lncRNA MIR4435-1HG in renal carcinoma. The expression level of MIR4435-1HG was correlated with TNM stage, tumor size, and Fuhrman grade. High expression of MIR4435-1HG indicated poor prognosis. MIR4435-1HG knockdown inhibited cell proliferation, and suppressed the migrating and invasive capacity of renal carcinoma cells. RNA pull-down followed by mass spectrometry revealed an interaction between MIR4435-1HG and pyruvate carboxylase, which was later corroborated by western blotting. CONCLUSIONS: MIR4435-1HG plays a critical role in the oncogenesis of renal cell carcinoma and may serve as a potential biomarker for renal cell carcinoma. Show more

Keywords: Long non-coding RNA, MIR4435-1HG, pyruvate carboxylase, renal cell carcinoma, tumorigenesis

DOI: 10.3233/CBM-201451

Citation: Cancer Biomarkers, vol. 29, no. 1, pp. 39-50, 2020

Authors: Zhou, Yong-Mei | Yao, Yi-Lin | Liu, Wei | Shen, Xue-Min | Shi, Lin-Jun | Wu, Lan

Article Type: Research Article

Abstract: BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most common malignant neoplasm of the mouth. Some studies have found that multiple microRNAs (miRs) participate in OSCC physiological and pathological processes. METHODS: We explored the mechanism of action of miR-134 in OSCC involving the PI3K-Akt signaling pathway. Different bioinformatics methods were used to analyze the potential genes and their related miRs in OSCC. Tumor stem cells were separated from OSCCs through magnetic cell sorting. Regulatory pattern between miR-134 and LAMC2 in OSCC was evaluated by ectopic expression, knockdown and reporter assay experiments. The expression of miR-134, LAMC2, …genes in PI3K-Akt signaling pathway, and apoptosis-related genes was detected. Cell proliferation was assessed by MTT assay, cell invasion by scratch test, cell migration by Transwell assay, cell cycle and apoptosis by flow cytometry, and cell growth and migration by xenograft tumor in nude mice. LAMC2 was predicted as the crucial factor related to OSCC using different chip data, and miR-134 was predicted to specifically bind LAMC2 in all five databases. RESULTS: Overexpressed miR-134 or silenced LAMC2 was observed to inhibit cell proliferation, migration, invasion of OSCC cells, growth of subcutaneous xenograft in nude mice, as well as promote OSCC cell apoptosis. LAMC2, a target gene of miR-134, decreased following miR-134 promotion, while the PI3K-Akt signaling pathway was inactivated following LAMC2 knockdown. Furthermore, we also observed that the effect of overexpressed miR-134 was enhanced when LAMC2 was knocked down. CONCLUSIONS: Taken together, these findings suggest that miR-134-mediated direct downregulation of LAMC2 inhibits migration and invasion of tumor stem cells in OSCC by suppressing the PI3K-Akt signaling pathway. Show more

Keywords: MicroRNA-134, LAMC2, PI3K-Akt signaling pathway, oral squamous cell carcinoma, cell migration, cell invasion

DOI: 10.3233/CBM-191362

Citation: Cancer Biomarkers, vol. 29, no. 1, pp. 51-67, 2020

Authors: Cai, Changzhou | Song, Xin | Yu, Chaohui

Article Type: Research Article

Abstract: BACKGROUND: Hepatocellular carcinoma (HCC) is the leading cause of mortality worldwide. In recent years, the incidence of HCC induced by NAFLD is growing rapidly. OBJECTIVE: To screen for new pathogenic genes and related pathways both in NAFLD and HCC, and to explore the pathogenesis of progression from NAFLD to HCC. METHODS: Gene expression microarrays (GSE74656, GSE62232) were used for identifying differentially expressed genes (DEGs). Functional enrichment and pathway enrichment analyses indicated that these DEGs were related to cell cycle and extracellular exosome, which were closely related to NAFLD and HCC development. We then …used the Search Tool for the Retrieval of Interacting Genes (STRING) to establish the protein-protein interaction (PPI) network and visualized them in Cytoscape. And the overall survival (OS) analysis and gene expression validation in TCGA of hub genes was performed. RESULTS: Seven hub genes, including CDK1, HSP90AA1, MAD2L1, PRKCD, ITGB3BP, CEP192, and RHOB were identified. Finally, we verified the expression level of ITGB3BP and CEP192 by quantitative real-time PCR in vitro . CONCLUSIONS: The present study implied possible DEGs, especially the new gene CEP192, in the progression of NAFLD developing to HCC. Further rigorous experiments are required to verify the above results. Show more

Keywords: Expression, bioinformatics, hepatocellular carcinoma, non-alcoholic fatty liver disease, CEP192

DOI: 10.3233/CBM-190169

Citation: Cancer Biomarkers, vol. 29, no. 1, pp. 69-78, 2020

Authors: Bai, Zhile | Feng, Mengyu | Du, Yang | Cong, Lin | Cheng, Yong

Article Type: Research Article

Abstract: BACKGROUND: Pancreatic cancer is a malignant tumor and its incidence has increased in recent years. Carboxypeptidase E (CPE) is a prohormone/proneuropeptide processing enzyme that has been shown to be associated with tumor growth and invasion in various cancers including pancreatic cancer. OBJECTIVE: To understand the molecular mechanism underlying the proliferative effects of CPE in cancer cells. METHODS: We down-regulated CPE gene expression in PANC-1 cell, a pancreatic cell line, and investigated mRNA, miRNA, circRNA and lncRNA expression profiling in PANC-1 cells from control group and CPE knock-down group by microarray analysis. We further …validated the top 14 differentially expressed circRNAs by qRT-PCR. RESULTS: Our results showed that CPE down-regulation caused decreased cell proliferation. The microarray data showed 107, 15, 299 and 360 differentially expressed mRNAs, miRNAs, circRNAs, and lncRNAs, respectively between control group and CPE knock-down group. Of Which, 41 mRNAs, 12 miRNAs, 133 circRNAs, and 262 lncRNAs were down-regulated; 66 mRNAs, 3 miRNAs, 166 circRNAs, and 98 lncRNAs were up-regulated. Bioinformatics analysis showed that the top significantly enriched pathways for the differentially expressed RNAs were related to cancer onset and/or progression, these included p53 signaling pathway, ECM-receptor interaction, focal adhesion and Wnt signaling pathway. We further performed network analysis to assess the mRNA, miRNA, circRNA and lncRNA correlations, and showed that HUWE1, hsa-miR-6780b-5p, has_circ_0058208 and lnc-G3BP1-3:8 were in the core position of the network. CONCLUSIONS: Taken together, these results identified potential CPE regulated core genes and pathways for cell proliferation in pancreatic cancer cell, and therefore provide potential targets for the treatment of pancreatic cancer. Show more

Keywords: Pancreatic cancer, Carboxypeptidase E, ceRNA analysis

DOI: 10.3233/CBM-191163

Citation: Cancer Biomarkers, vol. 29, no. 1, pp. 79-88, 2020

Authors: Wu, Jun

Article Type: Research Article

Abstract: BACKGROUND: The CKLF-like MARVEL transmembrane domain-containing family (CMTM) is the protein product of at least one splice variant of each gene contained a Marvel (MAL and related proteins for vesicle trafficking and membrane link) domain, involved in a variety of cellular processes and the pathogenesis of diseases, including tumorigenesis. However, the diverse expression patterns and prognostic values of eight CMTMs have yet to be elucidated. OBJECTIVE: We analyzed the expressions and impacts on survival of different CMTM factors in BC patients to determine their potential diagnosis and prognosis values in BC. METHODS: In …the current study, we examined the transcriptional and survival data of CMTMs in patients with breast carcinoma (BC) from ONCOMINE, GEPIA, Kaplan-Meier Plotter, and cBioPortal databases. RESULTS: It was found that CMTM5/7 were down-regulated, whereas CMTM1/6 were up-regulated in BC patients compared with the normal tissues. In survival analyses through the Kaplan-Meier plotter database, increased mRNA expressions of CMTM5/6/7 and decreased mRNA expression of CMTM4 were associated with better relapse-free survival (RFS) of BC patients. CONCLUSIONS: These data provided CMTM5/7 as new biomarker and prognostic factors in BC. Show more

Keywords: CMTM, breast carcinoma, bioinformatics, prognosis

DOI: 10.3233/CBM-191226

Citation: Cancer Biomarkers, vol. 29, no. 1, pp. 89-99, 2020

Authors: Shee, Kevin | Seigne, John D. | Karagas, Margaret R. | Marsit, Carmen J. | Hinds, John W. | Schned, Alan R. | Pettus, Jason R. | Armstrong, David A. | Miller, Todd W. | Andrew, Angeline S.

Article Type: Research Article

Abstract: BACKGROUND: Among patients diagnosed with non-muscle invasive bladder cancer (NMIBC), 30% to 70% experience recurrences within 6 to 12 years of diagnosis. The need to screen for these events every 3 to 6 months and ultimately annually by cystoscopy makes bladder cancer one of the most expensive malignancies to manage. OBJECTIVE: The purpose of this study was to identify reproducible prognostic microRNAs in resected non-muscle invasive bladder tumor tissue that are predictive of the recurrent tumor phenotype as potential biomarkers and molecular therapeutic targets. METHODS: Two independent cohorts of NMIBC patients were analyzed …using a biomarker discovery and validation approach, respectively. RESULTS: miRNA Let-7f-5p showed the strongest association with recurrence across both cohorts. Let-7f-5p levels in urine and plasma were both found to be significantly correlated with levels in tumor tissue. We assessed the therapeutic potential of targeting Lin28, a negative regulator of Let-7f-5p, with small-molecule inhibitor C1632. Lin28 inhibition significantly increased levels of Let-7f-5p expression and led to significant inhibition of viability and migration of HTB-2 cells. CONCLUSIONS: We have identified Let-7f-5p as a miRNA biomarker of recurrence in NMIBC tumors. We further demonstrate that targeting Lin28, a negative regulator of Let-7f-5p, represents a novel potential therapeutic opportunity in NMIBC. Show more

Keywords: miR, miRNA, bladder cancer, urothelial carcinoma, recurrence

DOI: 10.3233/CBM-191322

Citation: Cancer Biomarkers, vol. 29, no. 1, pp. 101-110, 2020