Cancer Biomarkers - Volume 22, issue 3

Authors: Chen, Bing | Li, Ya | He, Yuting | Xue, Chen | Xu, Feng

Article Type: Research Article

Abstract: Accumulating evidence suggests that long non-coding RNAs (lncRNAs) have important regulatory functions in gallbladder cancer (GBC) tumorigenesis and can serve as potential novel markers and/or targets for GBC. In this review, we critically discuss the emerging alteration of lncRNAs in GBC, the lncRNAs induced epigenetic regulation, the interaction of lncRNAs with microRNAs and lncRNAs effects on tumor-related signaling pathways. Additionally, contributions of lncRNAs in epithelial-mesenchymal transition process and energy metabolism reprogramming in GBC are also addressed. This may pave new ways towards the determination of GBC pathogenesis and lead to the development of new preventive and therapeutic strategies for GBC.

Keywords: Long non-coding RNAs, gallbladder cancer, epigenetic regulation, microRNAs, tumor-related signaling pathways

DOI: 10.3233/CBM-170979

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 359-366, 2018

Authors: Hong, Lan | Chen, Wangsheng | Wu, Dongcai | Wang, Yifeng

Article Type: Research Article

Abstract: BACKGROUND: Aberrant expression of long non-coding RNAs is involved in the progression of ovarian cancer. However, the clinical significance and biological functions of SNHG3 expression was little known in ovarian cancer (OC). METHODS: The SNHG3 expression in ovarian cancer tissues and paired adjacent normal tissues was detected using quantitative real time polymerase chain reaction (qRT-PCR). Gain-of function and loss-of function assays were performed in ovarian cancer cells to demonstrate the effects of SNHG3 expression on cell proliferation and invasion. The relative protein expression levels were determined using western blot analyses. RESULTS: The expression …of SNHG3 was significantly up-regulated in ovarian cancer tissues compared with adjacent normal tissues. Higher SNHG3 expression levels positively associated with FIGO stage, lymph node metastasis, and poor prognosis of ovarian cancer patients. Univariate and multivariate Cox regression analysis implied that FIGO stage, lymph node metastasis, higher SNHG3 expression were independent prognostic factors for overall survival (OS) rate in ovarian cancer patients. Gain-of function and loss-of function assays demonstrated that SNHG3 knockdown inhibited ovarian cancer cell proliferation and invasion abilities. However, SNHG3 overexpression promoted ovarian cancer cell proliferation and invasion abilities. Furthermore, cell proliferation and invasion related protein CyclinD1, CDK1, MMP9 and MMP3 were significantly downregulated after SNHG3 knockdown in ovarian cancer cells, while SNHG3 overexpression had reverse effects. In addition, SNHG3 functioned as an oncogene by regulating GSK3β /β -catenin signaling activity in ovarian cancer. CONCLUSIONS: Taken together, our data provide that SNHG3 has potential clinical value of and may serve as target of ovarian cancer treatment. Show more

Keywords: Ovarian cancer, long non-coding RNA, SNHG3, cell proliferation

DOI: 10.3233/CBM-170710

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 367-374, 2018

Authors: Zhao, Jingjing | Mai, Cong | Weng, Desheng | Chen, Changlong | Zhou, Ziqi | Liu, Yuan | Zhou, Zhiwei | Wang, Peng

Article Type: Research Article

Abstract: BACKGROUND: Rap1GAP, a member of the family of GTPase-activating proteins, is reported to be involved in cancer development and progression. OBJECTIVE: The study aimed to investigate the expression and prognostic value of Rap1GAP in gastric cancer patients. METHODS: Real-time quantitative polymerase chain reaction and western blotting were performed to examine Rap1GAP expression in tumorous and matched adjacent non-tumorous gastric tissues. Immunohistochemical staining was used to analyze Rap1GAP expression in 456 gastric cancer tissues. The correlation between Rap1GAP expression level and clinicopathological features as well as gastric cancer prognosis was analyzed. RESULTS: …Rap1GAP expression was remarkably decreased in tumor tissues at mRNA (p = 0.012) and protein (p = 0.034) level. Clinicopathological analysis revealed that low Rap1GAP expression was significantly correlated with tumor size (p = 0.033), histological grade (p = 0.034), T classification (p = 0.012), N classification (p = 0.006) and clinical stage (p = 0.005). Kaplan-Meier survival analysis revealed the association between low Rap1GAP expression and poor survival in gastric cancer patients. Furthermore, multivariate Cox regression analysis showed that Rap1GAP expression was an independent prognostic factor (p = 0.02). CONCLUSION: Rap1GAP may play a significant role in gastric cancer progression and act as a valuable prognostic marker for gastric cancer. Show more

Keywords: Rap1GAP, gastric cancer, prognosis, survival

DOI: 10.3233/CBM-170832

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 375-384, 2018

Authors: Wang, Dan | Wen, Gui-Min | Hou, Wei | Xia, Pu

Article Type: Research Article

Abstract: BACKGROUND: This study was carried out to investigate the correlation between CD133 and non-small cell lung cancer (NSCLC) clinicopathological features and its impact on survival of the patients with NSCLC. METHODS: In the first, we detected the level and localization of CD133 protein in NSCLC specimens and confirmed that CD133 expression was closely linked to poor prognosis of NSCLC. Secondly, TCGA genomic data for LUNG (Provisional) was retrieved and analyzed for genetic alterations of CD133 in different lung cancer subtypes. In the last, a comprehensive literature search for relevant studies published up to December 2015 was …performed using Medline, EMBASE Classic + EMBASE, and The Cochrane Central Register of Controlled Trials. RESULTS AND CONCLUSION: Both our experimental results and pooled results of previous studies indicated that CD133 may be used as a prognostic marker for the patients with NSCLC. However, more studies are required to evaluate CD133 potential use in predicting patients’ outcome. Show more

Keywords: Non-small-cell lung cancer, histology, differentiation, hazard ratio, survival

DOI: 10.3233/CBM-170835

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 385-394, 2018

Authors: Ge, Liyuan | Chen, Wei | Cao, Wenmin | Liu, Guangxiang | Zhang, Qing | Zhuang, Junlong | Zhang, Mingxin | Yang, Jun | Guo, Suhan | Zhao, Xiaozhi | Guo, Hongqian

Article Type: Research Article

Abstract: Postoperative recurrence for papillary renal cell carcinoma (PRCC) remains a tough problem in clinic. Previous studies have shown that general control nonderepressible kinase 2 (GCN2) was critically involved in tumour development. However, its function and clinical significance in renal cancer remain unknown. In this study, we investigated the role of GCN2 in PRCC. GCN2 silencing suppressed the viability and proliferation, promoted apoptosis of renal cancer cells. We found that the protein level of GCN2 was increased in PRCC tissues. Immunohistochemistry was performed in 84 patients with PRCC to explore the association of GCN2 level with clinical significance. High GCN2 protein …level was observed to be significantly correlated with adverse clinicopathological parameters, such as larger tumor size, higher TNM stage, higher Fuhurman Grade, and lymph node metastasis. We evaluated patient outcomes according to various clinical parameters as well as GCN2 expression by Kaplan-Meier curves. Multivariate analysis revealed that GCN2 overexpression can be a predictive factor correlated with reduced OS and PFS of postoperative PRCC patients. Collectively, GCN2 is potentially to play crucial roles in PRCC progression, and its overexpression may be used to predict poor prognosis and promising therapeutic strategy for PRCC patients. Show more

Keywords: GCN2, PRCC, prognosis, overall survival, progression free survival

DOI: 10.3233/CBM-170922

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 395-403, 2018

Authors: Ma, Ge | Huang, Huaxing | Li, Minghui | Li, Li | Kong, Peng | Zhu, Yichao | Xia, Tiansong | Wang, Shui

Article Type: Research Article

Abstract: Neoadjuvant chemotherapy (NCT) is the standard treatment for locally advanced breast cancer (LABC). Pathological complete response (pCR) is commonly used as a valid predictor of NCT long-term outcomes. Blood-based tumor biomarkers have the potential to predict response to NCT at early stage non-invasively. We believed plasma CCL5 could be a potential marker to predict NCT of LABC. Its efficiency and possible mechanism was studied in this work. Human Cytokine Antibody Microarray was applied to screen different cytokine concentration in plasma between low histological regression (Low-R) and high histological regression (High-R) patients. LABC patients were divided into two groups according to …pathological reactivity. The concentration of plasma CCL5 in different groups was determined by ELISA analysis. CCK8 assay was performed to analyze epirubicin susceptibility of breast cancer cells. Transwell assay was performed to determine the effect of CCL5 on breast cancer cells’ migration and invasion. qRT-PCR and western blot were used to verify the EMT (epithelial-mesenchymal transition) markers in CCL5-treated and epirubicin-treated breast cancer cells. The concentration of plasma CCL5 of Low-R group was higher than High-R group before NCT. The plasma levels of CCL5 were significantly reduced after NCT in the group of high histological regression (High-R). Epirubicin susceptibility decreased in the breast cancer cells treated by recombinant CCL5. Migration and invasion were significantly enhanced in breast cancer cells treated by recombinant CCL5. E-cadherin expression was decreased whereas vimentin increased significantly in CCL5-treated breast cancer cells. The phosphorylation of ezrin in Y-567 and its downstream protein cortactin increased significantly in CCL5-treated breast cancer cells. Plasma CCL5 level could be a promised candidate to predict chemotherapy response of breast cancer. Plasma CCL5 plays an important role in EMT process of breast cancer. Show more

Keywords: Neoadjuvant chemotherapy, breast cancer, CCL5, predictive marker

DOI: 10.3233/CBM-170986

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 405-415, 2018

Authors: Liu, De-Gang | Xue, Lei | Li, Jun | Yang, Qiang | Peng, Jiang-Zhou

Article Type: Research Article

Abstract: BACKGROUND: Circulating tumor cells (CTCs) is a promising biomarker for cancer prognosis and monitoring. Molecular characterizing of CTCs could provide beneficial information on the basis of CTCs counting. OBJECTIVE: To investigate the epithelial-mesenchymal transition (EMT) phenotypes and GALC mRNA expression of CTCs in non-small cell lung cancer (NSCLC) patients. METHODS: We analyzed the baseline number, EMT classification, and GALC expression of CTCs in 47 NSCLC patients using CanPatrol platform and RNA in situ hybridization technique. RESULTS: CTCs were detected in 91.5% patients ranging 0–47/5 mL blood. Increased CTCs were …associated with advanced tumor stages (6/5 mL) compared with early stages (3.5/5 mL). Patients with effective treatment response presented lower CTCs (3.5/5 mL) than patients with insufficient response (7/5 mL). Epithelial, hybrid and mesenchymal CTCs were detected in 55.4%, 78.7% and 61.7% patients, respectively. Patients with distant metastasis and poor curative outcomes presented higher level of EMT-CTCs. GALC expression was positive in CTCs of 80.6% patients and closely correlated with tumor number and distant metastasis and treatment outcomes. CONCLUSIONS: EMT phenotypes and GALC expression of CTCs are correlated with cancer metastasis and therapeutic outcomes, suggesting them to be potential markers for the prognosis of NSCLC. Show more

Keywords: CTCs detection, cancer metastasis, circulating biomarkers, therapeutic monitoring and prognosis

DOI: 10.3233/CBM-170995

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 417-426, 2018

Authors: Ding, Wei | Tan, Hongbo | Li, Xuemei | Zhang, Yue | Fang, Fang | Tian, Yuanyuan | Li, Jin | Pan, Xinghua

Article Type: Research Article

Abstract: BACKGROUNDS: MicroRNAs (miRNAs) are some RNA molecules that negatively regulate gene expression by binding to the 3’-untranslated region (3’-UTR) of target mRNA molecules. The aim of the study is to investigate the clinical role and functional effects of microRNA-493 (miR-493) in human hepatocellular carcinoma (HCC). METHODS: Expression of miR-493 in 58 cases of HCC tissues and adjacent normal tissues was determined by using quantitative real-time PCR (qRT-PCR) analyses. In vitro , cell proliferation and invasion capacity was evaluated by CCK8 assay and trans-well invasion assay. Luciferase reporter assay, western blot and qRT-PCR were used to detect …the association between miR-493 expression and zinc finger protein X-linked (ZFX) in HCC. RESULTS: Expression of miR-493 was significantly downregulated in HCC tissues compared to adjacent normal tissues. Lower miR-493 expression associated with tumor size, vascular invasion and poor overall survival (OS) and disease free survival (DFS) time of HCC patients. In vitro , transfection of miR-493 mimic in HCC cells inhibited cell proliferation and invasion abilities. However, transfection of miR-493 inhibitor in HCC cells had promoting effects. Luciferase reporter assay, qRT-PCR and western blot analysis demonstrated that miR-493 targeting 3’-untranslated region (3’-UTR) of ZFX and overexpression of miR-493 inhibited its expression. Moreover, enforced ZFX expression rescued the effects of miR-493 mimic on cell proliferation and invasion. CONCLUSION: MiR-493 functioned as tumor suppressor in HCC cells by regulating ZFX expression. Thus, miR-493 may provide potential value for HCC treatment. Show more

Keywords: MicroRNAs, miR-493, ZFX, cell proliferation, cell invasion

DOI: 10.3233/CBM-171036

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 427-434, 2018

Authors: Wang, Ning | Che, Yanci | Yin, Fufen | Yu, Fengsheng | Bi, Xiaoning | Wang, Yankui

Article Type: Research Article

Abstract: BACKGROUND: Cervical cancer is one of the malignant tumors which seriously threaten the women health worldwide. SPINT2 is an endogenous inhibitor of hepatocyte growth factor activator and down regulated or even silenced in many human malignant tumors. OBJECTIVE: This study was performed to explore the promoter methylation status of SPINT2 gene and the effect on its expression in cervical carcinoma. METHODS: HPV-positive and -negative cervical cancer cell lines, 50 cases of cervical carcinoma tissues, and 20 cases of normal cervical tissues were used for this study. The methylation status of promoter and the …first exon of SPINT2 gene were analyzed. The expression of SPINT2 was analyzed by qRT-PCR. RESULTS: HPV E6/E7 infection affects SPINT2 methylation rate in cell lines. SPINT2 methylation rate of HT-3E6/E7 was 8.8%, while the methylation rate of SPINT2 in HT-3 was 0%. In cervical tissues, the methylation rate of SPINT2 in cervical cancers was 54%, while the methylation rate of SPINT2 in normal cervical samples was 25%. As for cervical cancers, the methylation rate of SPINT2 gene was higher in grade 3 than those of grade 2. CONCLUSIONS: The expression of SPINT2 gene is regulated by its methylation status, and the methylation status of SPINT2 is altered by HPV infection. The aberrant methylation status of SPINT2 gene may play an important role in the development of cervical cancer. Show more

Keywords: SPINT2, cervical carcinoma, HPV, methylation, 5-Aza-CdR

DOI: 10.3233/CBM-171050

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 435-442, 2018

Authors: Ma, Shuyun | Rong, Xuan | Gao, Fei | Yang, Yang | Wei, Lin

Article Type: Research Article

Abstract: BACKGROUND: Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated proteinrequired for mitosis and spindle assembly. It has been revealed that TPX2 is overexpressedin various human cancers and promotes cancer progression. METHODS: The expression of TPX2 was examined in ovarian cancer (OC) tissues and by Western blotting, quantitative real-time reverse transcription PCR (qRT-PCR) and immunohistochemistry. The effects of TPX2 on proliferation and migration of two OC cell lines SKOV3and RMG1 were analyzed using the methylthiazol tetrazolium (MTT) assay, flow cytometry and transwell assay. The mechanisms underlying the effects of TPX2 on OC cells were …explored by qRT-PCR and Western blot. RESULTS: In this study, we found that TPX2 was upregulated in OC tissues. We observed knockdown of TPX2 inhibited the expression of Polo-like kinase 1 (PLK1), which has an important role in the regulation of M phase of the cell cycle, and the activity of Cdc2, induced cell arrested at the G2/M phase and decreased proliferation. Moreover, our data revealed that the levels of PLK1, β -catenin, MMP7 and MMP9 were inhibited following TPX2 knockdown, leading to decrease of cell migration. Finally, we showed that the restoration of PLK1 expression attenuated the anti-proliferation and anti-migration effects of TPX2 knockdown in OC cells. CONCLUSIONS: TPX2 promotes the proliferation and migration of human OC cells by regulating PLK1 expression. Show more

Keywords: Ovarian cancer, TPX2, OC cell line, proliferation, migration

DOI: 10.3233/CBM-171056

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 443-451, 2018