Cancer Biomarkers - Volume Pre-press, issue Pre-press

Authors: Zhou, Chunhuan | Zhao, Juanjuan | Liu, Juanjuan | Wei, Sixi | Xia, Ying | Xia, Wansong | Bi, Ying | Yan, Zhiqiang | Huang, Hai

Article Type: Research Article

Abstract: Recent studies have shown that long noncoding RNAs (lncRNAs) have profound impacts on cancer development. In our previous study, we have confirmed that lncRNA small nucleolar RNA host gene 16 (SNHG16) is associated with poor prognosis and malignant phenotype of gastric cancer (GC). However, the biological function of lncRNA SNHG16 is still unclear. Here, we aimed to investigate the mechanisms underlying the roles of SNHG16 in GC. In this work, SNHG16 knockdown could inhibit epithelial-mesenchymal transition (EMT) and invasion of GC cells. Moreover, our results revealed that SNHG16 could promote EMT via down-regulation of Dickkopf WNT signaling pathway inhibitor 3 …(DKK3) in GC cells. In addition, SNHG16 was found to be upregulated whereas DKK3 was downregulated in tumor tissues compared with adjacent normal tissues. It showed that the expressions of SNHG16 and DKK3 were negatively correlated in clinical GC tissues. All these results suggested that SNHG16 promotes GC progression via regulation of DKK3 directly or indirectly. SNHG16 might be used as a putative biomarker for metastatic prediction in GC patients. Show more

Keywords: lncRNA SNHG16, epithelial-mesenchymal transition, DKK3, GC

DOI: 10.3233/CBM-190497

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Huang, Kaibin | Qu, Hongyue | Zhang, Xiaoni | Huang, Tanxiao | Sun, Xiao | He, Wan | Li, Mingwei | Lin, Liewen | Xu, Mingyan | Chen, Shifu | Xia, Ligang

Article Type: Research Article

Abstract: BACKGROUND: Circulating tumor DNA (ctDNA) has been recognized as a promising biomarker for colorectal cancer (CRC) early diagnosis and postoperative monitoring. However, we hypothesize that the clinical value of ctDNA sequencing may differ for colon cancer (CC) and rectal cancer (RC). METHODS: Forty-three patients with primary CRC were prospectively enrolled. Tumor tissue samples, paired preoperative plasma samples and a series of postoperative plasma samples were obtained. Mutations in each sample were identified and compared. RESULTS: For 73.0% patients, at least one concordant mutation was detected in both tumor tissue DNA and paired preoperative …ctDNA. The mutation concordance rate were higher in CC patients compared to RC patients (92.3% vs 45.5%; p = 0.004). For early stage patients, the mutation concordance rate was 72.7%. The recurrence rate was 33.3% for patients with postoperative ctDNA positive mutations, and 3.4% for patients with negative ctDNA (HR 10.767; 95% CI 1.1–103.8; p = 0.040). CONCLUSION: Liquid biopsy via ctDNA sequencing has great potential for the early detection and postoperative monitoring of CRC. The DNA of CC tissues is more likely to be released into blood than the DNA of RC tissues. This should be considered when diagnosing CRC patients with ctDNA sequencing technology. Show more

Keywords: Circulating tumor DNA, colorectal cancer, early diagnosis, predicting recurrence, next generation sequencing

DOI: 10.3233/CBM-190257

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Mitchell, Andrew | Hasanali, Sarrah L. | Morera, Daley S. | Baskar, Rohitha | Wang, Xin | Khan, Rahil | Talukder, Asif | Li, Charles S. | Manoharan, Meenakkshy | Jordan, Andre R. | Wang, Jiaojiao | Bollag, Roni J. | Singh, Nagendra | Albo, Daniel | Ghosh, Santu | Lokeshwar, Vinata B.

Article Type: Research Article

Abstract: BACKGROUND: Differential expression of chemokines/chemokine receptors in colorectal cancer (CRC) may enable molecular characterization of patients’ tumors for predicting clinical outcome. OBJECTIVE: To evaluate the prognostic ability of these molecules in a CRC cohort and the CRC TCGA-dataset. METHODS: Chemokine (CXCL-12α , CXCL-12β , IL-17A, CXCL-8, GM-CSF) and chemokine receptor (CXCR-4, CXCR-7) transcripts were analyzed by RT-qPCR in 76 CRC specimens (normal: 27, tumor: 49; clinical cohort). RNA-Seq data was analyzed from the TCGA-dataset (n = 375). Transcript levels were correlated with outcome; analyses: …univariate, multivariable, Kaplan-Meier. RESULTS: In the clinical cohort, chemokine/chemokine receptor levels were elevated 3-10-fold in CRC specimens (P ⩽ 0.004) and were higher in patients who developed metastasis (P = 0.03 ⩽ 0.0001). CXCR-4, CXCR-7, CXCL-12α , CXCL-8, IL-17 and GM-CSF levels predicted metastasis (P ⩽ 0.0421) and/or overall survival (OS; P ⩽ 0.0373). The CXCR-4+ CXCR-7+ CXCL-12 marker (CXCR-4/7+ CXCL-12 (α /b) signature) stratified patients into risk for metastasis (P = 0.0014; OR, 2.72) and OS (P = 0.0442; OR, 2.7); sensitivity: 86.67%, specificity: 97.06%. In the TCGA-dataset, the CXCR-4/7+ CXCL-12 signature predicted metastasis (P = 0.011; OR, 2.72) and OS (P = 0.0006; OR: 4.04). In both datasets, the signature was an independent predictor of clinical outcome. CONCLUSIONS: Results of 451 specimens from both cohorts reveal that the CXCR-4/7+ CXCL-12 signature potentially predicts outcome in CRC patients and may allow earlier intervention. Show more

Keywords: CXCL-12, CXCR-7, CXCR-4, CXCL-8, colorectal cancer

DOI: 10.3233/CBM-190210

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Li, Juncheng | Zou, Xiaoming

Article Type: Research Article

Abstract: PURPOSE: MicroRNAs (miRNAs) have been reported to be involved in tumorigenesis. The aim of this study was to investigate the functional role and prognostic value of miR-652 in gastric cancer (GC). METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the expression levels of miR-652 in human GC tissue samples and GC cell lines. The Kaplan-Meier survival curves and Cox regression analysis were performed to measure the prognostic value of miR-652 in GC. The tumor cell proliferation capacity was estimated by MTT assay, and cell migration and invasion were assessed by Transwell assays. The …luciferase reporter assay was performed to confirm the target gene of miR-652. RESULTS: MiR-652 was significantly elevated in GC tissues and cell lines (all P < 0.001). And the expression level of miR-652 was significantly associated with TNM stage and lymph node metastasis (all P < 0.05). GC patients with high expression of miR-652 had a shorter overall survival rate than those with low miR-652 expression (log-rank P < 0.001). The miR-652 and TNM stage were proven to be independent prognostic predictors for the GC patients. Overexpressing miR-652 could enhance cell proliferation, migration and invasion (all P < 0.01). RORA was proved to be the target gene of miR-652. CONCLUSION: MiR-652 functions as an oncogene in GC and promotes tumor progression via targeting RORA. MiR-652 might be a novel predictive marker for the poor prognosis of GC patients. Show more

Keywords: MicroRNA-652, prognosis, progression, gastric cancer

DOI: 10.3233/CBM-190361

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Huang, Ge | Huang, Qing | Xie, Zilu | Zhou, Huihui | Cao, Jiangbo | Shi, Long | Yang, Mingwei

Article Type: Research Article

Abstract: BACKGROUND: Lung squamous cell carcinoma (LUSC) is malignant disease with poor therapeutic response and unfavourable prognosis. OBJECTIVE: This study aims to develop a long non-coding RNA (lncRNA) signature for survival prediction in patients with LUSC. METHODS: We obtained lncRNA expression profiles of 493 LUSC cases from The Cancer Genome Atlas, and randomly divided the samples into a training set (n = 296) and a testing set (n = 197). Univariate Cox regression and random survival forest algorithm were performed to select optimum survival-related …lncRNAs. RESULTS: A lncRNA-focused risk score model was then constructed for prognosis prediction in the training set and further validated in the testing set and the entire set. Finally, bioinformatics analysis was carried out to explore the potential signaling pathways associated with the prognostic lncRNAs. A set of 9 lncRNAs were found to be strongly correlated with overall survival of LUSC patients. These 9 lncRNAs were integrated into a prognostic signature, which could separate patients into high- and low-risk groups with significantly different survival times in the training set (median: 30.5 vs. 80.5 months, log-rank P < 0.001). This signature was also confirmed in the testing set and the entire set. Besides, the prognostic value of the 9-lncRNA signature was independent of clinical features and maintained stable in stratified analyses. Functional enrichment study suggested that the 9 lncRNAs may be mainly involved in metabolism-related pathways, phosphatidylinositol signaling system, p53 signaling pathway, and notch signaling pathway. CONCLUSIONS: Our study demonstrated the potential clinical implication of the 9-lncRNA signature for survival prediction of LUSC patients. Show more

Keywords: Biomarker, long non-coding RNA, lung squamous cell carcinoma, prognosis

DOI: 10.3233/CBM-182275

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Paganelli, Alessia | Garbarino, Federico | Toto, Paola | Martino, Giuseppe Di | D’Urbano, Marika | Auriemma, Matteo | Giovanni, Pamela Di | Panarese, Fabrizio | Staniscia, Tommaso | Amerio, Paolo | Paganelli, Roberto

Article Type: Research Article

Abstract: BACKGROUND: To date, serological markers to monitor melanoma progression and response to therapy are lacking. In this context cytokines appear to be promising biomarkers of the disease. OBJECTIVE: To compare cytokine and chemokine levels in melanoma patients and in healthy controls and to assess possible variations according to melanoma stage. METHODS: Serum chemokine and cytokine levels were determined by ELISA in 34 patients diagnosed histologically of malignant melanoma. Seven healthy volunteers were used as controls. RESULTS: We found a subset of cytokines (CCL3, CCL4, IFN-γ and IL-10) …to be significantly higher in melanoma patients than in control group, thus confirming the importance of the inflammation in cancer. While CCL3 increased with tumor progression, IFN-γ and IL-10 showed higher levels in stage I patients. Moreover, we noticed a direct correlation between CCL3 level and the presence of ulceration in the primary tumor; on the contrary, CCL4, IL-10 and IFN-γ were lowered down in patients with ulcerated melanoma. CONCLUSIONS: These results expand and confirm observations made in other studies focusing on a more limited number of molecules. This extended panel of cytokines examines the potential roles of type2 cytokines (such as IL-4) and many chemokines (mainly CCL3) as biomarkers in melanoma progression. Show more

Keywords: Cytokines, chemokines, melanoma, biomarkers, cancer immunology

DOI: 10.3233/CBM-190370

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Huang, Ying | Xiao, Wenfeng | Jiang, Xiuli | Li, Honglei

Article Type: Research Article

Abstract: Colorectal cancer (CRC) is a common cause of cancer-related deaths worldwide. MicroRNA-935 (miR-935) has been reported to be involved in several cancers. In the present study, we aimed to investigate the role of miR-935 in the progression of CRC. The expression levels of miR-935 in CRC tissues and cells were detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The prognostic significance of miR-935 was identified using Kaplan-Meier survival analysis and Cox regression assay. Cell proliferation capacity was detected by Cell Counting Kit-8 (CCK-8) assay. Cell migration and invasion capacity were determined by Transwell assay in CRC cells. Bioinformatics analysis and …luciferase reporter assays were used to confirm the direct target of miR-935. The expression of miR-935 was increased in CRC tissues and cells. Overexpression of miR-935 was significantly associated with lymph node metastasis and TNM stage. Overexpression of miR-935 in patients predicted shorter overall survival compared to low miR-935 expression. The expression of miR-935 was indicated to be an independent prognostic factor for CRC patients. In addition, overexpression of miR-935 in CRC cells promoted cell proliferation, migration, and invasion, whereas inhibition of miR-935 suppressed cell proliferation, migration, and invasion. Bioinformatics and luciferase assays revealed that INPP4A is a direct target of miR-935. Our findings suggest that miR-935 functions as an oncogene and promotes CRC progression. INPP4A is a potential target of miR-935. And miR-935 may represent a prognostic biomarker and potential therapeutic strategy for CRC treatment. Show more

Keywords: Colorectal cancer, microRNA-935, prognosis, proliferation, migration, invasion

DOI: 10.3233/CBM-190183

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Wu, Junxue | Zhang, Chao | Chen, Lu

Article Type: Research Article

Abstract: Osteosarcoma, a highly aggressive cancer, can rapidly metastasize to distant organs such as lung, liver, brain. Despite much progress in the therapeutic regime has been made, the prognosis of osteosarcoma remains poor. In present study, microRNA-511 (miR-511) is lowly expressed in osteosarcoma cells, including MG63, U-2 OS, Saos-2 cells, while mitogen activated protein kinase1 (MAPK1) is highly expressed in osteosarcoma cells. Interestingly, MAPK1 might be a target of miR-511. We found that overexpression of miR-511 by miR-511 mimic transfection may result to low expression of MAPK1. Further study showed that miR-511 mimic inhibits the development of osteosarcoma MG63 cell, including …proliferation and invasion. Moreover, miR-511 mimic transfection reduces metastatic osteosarcoma tumor burden in nude mice. These activities are mediated by targeting MAPK1. Our study provides a new sight for the molecular pathogenesis of osteosarcoma. Show more

DOI: 10.3233/CBM-190534

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Li, Zhichun | Guo, Qingbo | Lu, Yugang | Tian, Tian

Article Type: Research Article

Abstract: Aberrant expression of miR-181d has been noted in multiple human cancers, but its role in gastric cancer (GC) remains unclear. The aim of this study was to investigate the expression, clinical significance and functional role of miR-181d in GC. We applied quantitative real-time polymerase chain reaction (qRT-PCR) to quantify the expression of miR-181d in 131 GC tissues, as well as in GC cell lines. The correlation of miR-181d expression with overall survival of GC patients was analyzed using the Kaplan-Meier survival method. Cox regression analysis was conducted to further determine the prognostic value of miR-181d in GC. Cellular functional experiments …were carried out to calculated the effect that miR-181d had on GC behaviors. MiR-181d expression was significantly up-regulated in both GC tissues and cells (all P < 0.001), and correlated with TNM stage and lymph node metastasis (all P < 0.05). GC patients in the high miR-181d expression group had shorter survival time than those in the low miR-181d expression group (log-rank P < 0.001). Multivariate Cox regression analysis demonstrated that miR-181d expression and TNM stage were two independent prognostic markers for GC. Overexpression of miR-181d significantly promoted the NCI-N87 and MGC-803 cells proliferation, migration and invasion (all P < 0.05). MiR-181d serves a role as an oncogene in GC by promoting tumor progression. And miR-181d might be a novel predictive marker for the prognosis of GC patients. Show more

Keywords: MicroRNA-181d, prognosis, progression, gastric cancer

DOI: 10.3233/CBM-190091

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Salvianti, Francesca | Massi, Daniela | De Giorgi, Vincenzo | Gori, Alessia | Pazzagli, Mario | Pinzani, Pamela

Article Type: Research Article

Abstract: BACKGROUND: Circulating tumor cells (CTCs) and circulating cell free DNA (ccfDNA) represent a liquid biopsy of a tumor allowing real time disease monitoring especially in advanced stages of cancer, but their analysis is technically challenging. OBJECTIVE: We aimed to demonstrate the feasibility of two different technical approaches to detect the BRAFV600E mutation in the liquid biopsy of 20 metastatic melanoma patients by using both the enriched CTC fraction and circulating ccfDNA from the same blood sample. METHODS: We detected CTCs by a filtration method in 20 metastatic melanoma patients and detected BRAFV600E variant …on CTCs and ccfDNA by an allele-specific qPCR assay; the mutated samples were confirmed by ICE-COLD PCR followed by Sanger sequencing. RESULTS: We found CTCs in 70% of the samples, and identified the BRAFV600E variant on CTCs. We correlated the results with those obtained on ccfDNA from the same blood draw. We found some discordant results between CTCs and ccfDNA. CONCLUSIONS: Our results underline the importance of investigating both CTCs and ccfDNA in a liquid biopsy approach to melanoma patients. Show more

Keywords: Liquid biopsy, BRAFV600E mutation, melanoma, circulating tumor cells (CTCs), circulating cell-free DNA (ccfDNA)

DOI: 10.3233/CBM-181647

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Gupta, Chhavi | Su, Jian | Zhan, Min | Stass, Sanford A. | Jiang, Feng

Article Type: Research Article

Abstract: BACKGROUND: Analysis of molecular changes in sputum may help diagnose lung cancer. Long non-coding RNAs (lncRNAs) play vital roles in various biological processes, and their dysregulations contribute to the development and progression of lung tumorigenesis. Herein, we determine whether aberrant lncRNAs could be used as potential sputum biomarkers for lung cancer. METHODS: Using reverse transcription PCR, we measure expressions of lung cancer-associated lncRNAs in sputum of a discovery cohort of 67 lung cancer patients and 65 cancer-free smokers with benign diseases and a validation cohort of 59 lung cancer patients and 60 cancer-free smokers with …benign diseases . RESULTS: In the discovery cohort, four of the lncRNAs displayed a significantly different level in sputum of lung cancer patients vs. cancer-free smokers with benign diseases (all P < 0.001). From the four lncRNAs, three lncRNAs (SNHG1, H19, and HOTAIR) are identified as a biomarker panel, producing 82.09% sensitivity and 89.23% specificity for diagnosis of lung cancer. Furthermore, the biomarker panel has a higher sensitivity (82.09% vs. 52.24%, P = 0.02) and a similar specificity compared with sputum cytology (89.23% vs. 90.77%, P = 0.45). In addition, the lncRNA biomarker panel had a higher sensitivity (87.50% vs. 70.07%, p = 0.03) for diagnosis of squamous cell carcinoma compared with adenocarcinoma of the lung, while maintaining the same specificity (89.23%). The potential of the sputum lncRNA biomarkers for lung cancer detection is confirmed in the validation cohort. CONCLUSION: We have for the first time shown that the analysis of lncRNAs in sputum might be a noninvasive approach for diagnosis of lung cancer. Show more

Keywords: Diagnosis, lung cancer, sputum, lncRNA, biomarkers

DOI: 10.3233/CBM-190161

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Gong, Zhitao | Hu, Guohua

Article Type: Research Article

Abstract: BACKGROUND: Downregulation of PCDH20 is frequently involved in tumorigenesis of many cancers, but the role of PCDH20 protein in hypopharyngeal squamous cell carcinoma (HSCC) is still unknown. OBJECTIVE: The aim of this study was to investigate the role of PCDH20 in hypopharyngeal squamous cell carcinoma (HSCC). METHODS: Immunohistochemistry (IHC) and qRT-PCR was carried out to estimate the expressions of PCDH20 protein and mRNA in HSCC tissues and adjacent non-tumor tissues. Correlation between the PCDH20 expression and clinicopathological characteristics was evaluated using chi-square test. Meanwhile, Kaplan-Meier method and log-rank test were applied to analyze …the overall survival. After transfection of PCDH20, the CCK8 assay, Cell migration assay and invasion assay were used to investigate the changes in the viability, migration and invasion of Fuda cells. The mechanisms by which reduced PCDH20 promote migration and invasion of Fuda cells were examined using western blotting. RESULTS: PCDH20 protein showed in tumor tissue low expression rates of 67.5% (54/80). The mRNA of PCDH20 indicated the consistent trend (80%, 8/10). Reduced PCDH20 expression was positively related to T stage and lymph node metastasis (P < 0.05). Patients with low levels of PCDH20 had worse overall survival compared with those with high PCDH20 levels (P < 0.001). The univariate Cox regression analysis described that lymph node metastasis (P = 0.043) and down-regulated PCDH20 expression (P = 0.045) were significantly prognostic factors.Multivariate analysis suggested that low PCDH20 expression (P = 0.015) were significantly independent prognostic factors for overall survival. PCDH20 in Fadu cells significantly inhibited cell viability, migration and invasion. Meanwhile, PCDH20 was involved in the disruption of HSCC progression through antagonizing its downstream Wnt/β -catenin signalling pathway. CONCLUSION: Our data highlight that the downregulated PCDH20 may serve as reliable diagnostic biomarker in HSCC. Show more

Keywords: PCDH20, hypopharyngeal squamous cell carcinoma, clinicopathological features, lymph node metastasis, prognostic

DOI: 10.3233/CBM-190442

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Wang, Xiaoqiong | Jin, Qiaozhi | Wang, Xue | Chen, Wubing | Cai, Zhiyi

Article Type: Research Article

Abstract: BACKGROUND: Increasing evidence shows that long non-coding RNAs (lncRNAs) play a key role in the development of various cancers. Zinc finger antisense 1 (ZFAS1 ) is a novel lncRNA with previously demonstrated associations with several types of cancer. Here we examined the expression and potential function of the ZFAS1 in nasopharyngeal carcinoma (NPC). METHODS: We detected ZFAS1 expression in GSE12452, a human microarray dataset, and NPC cell lines. Small interfering RNA against ZFAS1 was used to elucidate the cellular functions of ZFAS1 using MTT, colony formation, cell cycle, cell apoptosis, transwell …invasion and migration and western blot assays. An activator of the PI3K/AKT signaling pathway (740Y-P) was used to determine the contribution of PI3K/AKT. RESULTS: ZFAS1 was significantly upregulated in NPC tissues and cell lines. Silencing ZFAS1 significantly inhibited cell proliferation and invasion, arrested cell cycle progression and promoted cell apoptosis, as well as reduced epithelial–mesenchymal transition. Moreover, 740Y-P could rescue the effects of ZFAS1 knockdown on proliferation, apoptosis and invasion in 5-8F cells. CONCLUSIONS: ZFAS1 might play an oncogenic role in NPC and facilitate cell proliferation and invasion via the PI3K/AKT signaling pathway in NPC cells. Show more

Keywords: ZFAS1, nasopharyngeal carcinoma, EMT, apoptosis, p-AKT

DOI: 10.3233/CBM-182080

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Jin, Wei | Han, Haiming | Liu, Dandan

Article Type: Research Article

Abstract: BACKGROUND: miR-539 functions as a tumor suppressor in many types of cancer. However, the role of miR-539 in gastric cancer remains unclear. The aim of this study is to investigate the clinical significance and functional role of miR-539 in gastric cancer. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression levels of miR-539 in gastric cancer patients tissues and cells. We analyzed the association between miR-539 expression levels and clinicopathological features, as well as overall survival information with Kaplan-Meier survival curves and Cox regression analysis. The functional role of miR-935 on the …proliferation, migration, and invasion was also investigated by using miR-539 mimic or miR-539 inhibitor through CCK-8 assay, Transwell migration and invasion assays. The relationship between miR-539 and RUNX2 was verified by a dual luciferase assay. RESULTS: The expression of miR-539 was decreased in gastric cancer tissues and cell lines. Downregulation of miR-539 was closely associated with differentiation, lymph node metastasis, TNM stage, and poor survival outcome of gastric cancer patients. Furthermore, overexpression of miR-539 inhibited cell proliferation, migration, and invasion of gastric cancer cells. In addition, RUNX2 was a direct target of miR-539. CONCLUSION: Taken together, miR-539 may serve as a tumor suppressor for inhibiting cell proliferation, migration, and invasion by targeting RUNX2. Reduced expression of miR-539 is an independent prognostic factor in gastric cancer and may be a potential prognostic biomarker and miR-539/RUNX2 axis may serve as a potential therapeutic target for the treatment of gastric cancer. Show more

Keywords: miR-539, gastric cancer, prognosis, proliferation, migration, invasion

DOI: 10.3233/CBM-190384

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Jiao, Xuelong | Lu, Jie | Huang, Yichuan | Zhang, Jinna | Zhang, Hongmei | Zhang, Kejun

Article Type: Research Article

Abstract: OBJECTIVE: To investigate the diagnostic and prognostic values of long non-coding RNA H19 (H19) in patients with papillary thyroid carcinoma (PTC). METHODS: This retrospective, nonrandomised study included 410 patients with PTC and 89 patients with benign thyroid nodes (BTN)who underwent standard total thyroidectomy. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect H19 expression in these tissues. The relationship between H19 expression and the patients’ clinicopathological factors, including histopathological characteristics of the tumour, diagnosis and prognosis was explored. RESULTS: Expression of H19 was lower in the PTC tissues (1.259 ± …1.15) compared to the BNT tissues (2.8347 ± 2.176) (p = 0.001). Low expression of H19 was associated with patient’s age, tumor size, extrathyroid extension, pathological lateral node metastasis (pN1b), histological aggressive type and poorer disease-free survival (p < 0.0001). The sensitivity for distinguishing PTC from benign was 81.3%. H19 was found to be an independent risk factor for extrathyroidal extension, lymph node metastasis. CONCLUSIONS: H19 may serve as a potential predictor of poor prognoses in patients with PTC. Show more

Keywords: Papillary thyroid carcinoma, diagnosis, prognosis, long non-coding RNA H19

DOI: 10.3233/CBM-190273

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-5, 2019

Authors: Zheng, Chenghao | Guo, Kai | Chen, Binshen | Wen, Yong | Xu, Yawen

Article Type: Research Article

Abstract: OBJECTIVES: In men, human prostate cancer (PCa) has become the second most common cancer. miRNAs are short non-coding RNAs that can inhibit target gene mRNAs. Studies have showed that the alternation of miRNAs expression in cancer is relevant to pathogenesis of tumor. In present study, we aimed to investigate functions of miR-214-5p in PCa. MATERIALS AND METHODS: 10 paired human prostate tumor tissues and homologous para-tumor tissues were recruited, and the levels of miR-214-5p and CRMP5 were respectively determined by qRT-PCR assay. Luciferase activity analysis was performed to explore the regulation of CRMP5 mRNA 3’UTR by …miR-214-5p. Then, cell experiments, including cell proliferation, apoptosis, cell cycle, migration and colony formation ability, were performed after proper plasmids or RNAs transfection. RESULTS: In PCa tissues and cell lines, expression of miR-214-5p was decreased compared with para-tumor tissues or normal prostate epithelial cell lines. Luciferase activity assay showed a direct combination of miR-214-5p and CRMP5 mRNA 3’UTR, and indicated that the absence of miR-214-5p in PCa cells may contributes to a high level of CRMP5. Cell experiments showed that miR-214-5p can induce inhibition of tumor cell growth, migration and colony forming efficiency, promotion of apoptosis and G1-phase arrest, on the other hand, co-expression of CRMP5 somewhat counteracted these phenotype induced by miR-214-5p. CONCLUSION: Taken together, miR-214-5p shows tumor suppression effects in PCa cells. Loss expression of miR-214-5p in PCa increase levels of CRMP5 through regulating CRMP5 3’UTR, which could be a potential therapy target for PCa. Show more

Keywords: Human prostate cancer, miR-214-5p, CRMP5, cell proliferation, apoptosis, migration

DOI: 10.3233/CBM-190128

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Chen, Yan | Ye, Xiabin | Xia, Xuemei | Lin, Xuefang

Article Type: Research Article

Abstract: OBJECTIVE: This study aimed to explore the correlation of circular RNA ABCB10 (circ-ABCB10) expression with clinicopathological features and survival, as well as its impact on regulating cell proliferation and apoptosis in epithelial ovarian cancer (EOC). METHODS: A total of 103 EOC patients were consecutively recruited, then their tumor tissues were obtained for circ-ABCB10 detection using qRT-PCR. Additionally, 53 EOC adjacent tissues were collected as control. Patients’ clinicopathological and survival data were recorded. In vitro , circ-ABCB10 expression was detected in OVCAR3, UWB1.289, SKOV3, CAOV3 and IOSE80 cell lines by RT-qPCR, and the effect of circ-ABCB10 on …cell proliferation and apoptosis was detected through circ-ABCB10 overexpression and silencing by plasmids transfection into SKOV3 cells. RESULTS: Circ-ABCB10 was upregulated in tumor tissues compared with adjacent tissues, and presented with good value in distinguishing tumor tissues from adjacent tissues (AUC = 0.766, 95% CI: 0.690–0.842). Circ-ABCB10 high expression was correlated with poor differentiation, large tumor size and advanced International Federation of Gynecology and Obstetrics (FIGO) stage in EOC patients. As for survival, circ-ABCB10 was correlated with worse OS. In vitro experiments revealed that circ-ABCB10 was upregulated and promoted cell proliferation but reduced cell apoptosis, and negatively regulated miR-1271, miR-1252 and miR-203 in EOC cells. CONCLUSIONS: Circ-ABCB10 correlates with advanced clinicopathological features and unfavorable survival, and promotes proliferation, reduces apoptosis and negatively regulated miR-1271, miR-1252 and miR-203 in EOC. Show more

Keywords: Circ-ABCB10, EOC, disease risk, OS, cell proliferation and apoptosis

DOI: 10.3233/CBM-190064

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Feng, Fan | Zhang, Dongjing | Han, Fangkai | Zhang, Xingtao | Duan, Tengfei | Zhang, Xiuwen

Article Type: Research Article

Abstract: The triple negative breast cancer (TNBC) accounts for 15% to 20% of the total number of breast cancer diagnosed. A number of clinical studies have shown that TNBC has a high risk of early recurrence and distant metastasis, and a low rate of disease free survival and total survival. The premise of TNBC deterioration was abnormal proliferation and migration of tumor cells, and this study firstly showed that GATS gene could promote proliferation of MDA-MB-231 breast cancer cells. Through lentiviral expression system, the GATS gene was konckdown by shGATS lentivirus infection in the MDA-MB-231 cells, and the …result indicated it could remarkably decrease the ability of cell proliferation and migration. Real-time PCR, western blot and immunofluorescence experiments showed the expressions of protein LC3, and p-Akt in shGATS cell group were lower than the shCtrl group. Therefore, we suggest the GATS could promote the MDA-MB-231 cell proliferation, migration and clonogenicity through cell autophagy by the PI3K/Akt pathway, which paved the way for further study the function of GATS in TNBC, and GATS may potentially be a target for gene therapy against triple negative breast cancer. Show more

Keywords: Triple negative breast cancer, cell proliferation, autophagy, PI3K/Akt signal pathway

DOI: 10.3233/CBM-181681

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Feng, Runhua | Li, Jianfang | Sah, Birendra K. | Yuan, Fei | Jin, Xiaolong | Yan, Min | Liu, Bingya | Li, Chen | Zhu, Zhenggang

Article Type: Research Article

Abstract: BACKGROUND: The signaling adapter protein CrkL plays vital roles in multiple cancers. However, the expression pattern of CrkL protein and its clinical significance have not been well characterized in human gastric cancer (GC) so far. OBJECTIVE: To investigate the association of tissue-based CrkL protein expression level with the clinicopathological characteristics and prognosis of GC patients. METHODS: The expression level of CrkL protein in 380 GC patients was analyzed by immunohistochemistry. The associations of CrkL protein expression level with clinicopathologicalal characteristics and clinical outcome were evaluated. RESULTS: Compared with the matched …adjacent non-tumor tissues, CrkL protein expression level was significantly up-regulated in tumor tissues. In addition, there was a positive correlation between CrkL and Ki67 expression levels in GC patients. An elevated CrkL level statistically correlated with aggressive clinicopathologicalal characteristics, such as larger tumor size, deeper local invasion, more lymph node metastasis, advanced TNM stage, and poorer prognosis. Notably, multivariate analysis identified tissue-based CrkL level as an independent predictor for the unfavorable prognosis of GC. CONCLUSIONS: These results indicate that CrkL protein may serve as a novel prognostic biomarker in GC. Show more

Keywords: Gastric cancer, CrkL, tumorigenesis, immunohistochemistry, prognosis

DOI: 10.3233/CBM-192435

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Ren, Xiaolu | Zhang, Yixun | Ly, Yi | Jin, Baoli | Guo, Hongxia | Wu, Jing | Li, Xiaomin | Liu, Xuejun

Article Type: Research Article

Abstract: BACKGROUND: No tumor biomarker (TM) is available for de novo metastatic lung adenocarcinoma. OBJECTIVE: To examine the serum levels of carcinoembryonic antigen (CEA), cytokeratin-19 fragments (CYFRA21-1), neuron-specific enolase (NSE), carbohydrate antigen (CA) 19-9, CA125, tissue polypeptide antigen (TPA), tissue polypeptide specific antigen (TPS), and lactate dehydrogenase (LDH) to predict de novo metastatic lung adenocarcinoma. METHODS: This was a retrospective study of geriatric (> 60 years of age) patients with lung cancer diagnosed at Shanxi Cancer Hospital from 02/2012 to 12/2017. CEA, CYFRA21-1, CA199, NSE, CA125, TPA, and TPS were detected …by ELISA and LDH was detected by LDH kit. Their predictive value was assessed using receiver operating characteristic (ROC) curves and multivariable logistic regression. RESULTS: The positive rates of LDH and TMs were higher in the metastatic group (all P < 0.05). The best single TMs were CYFRA21-1 (70.5% sensitivity) and CA199 (92.0% specificity). When using any two, the best were CYFRA21-1+ TPA (77.1% sensitivity) and CA199+ TPA or NSE (both 84.1% specificity). High LDH and CA125 statuses were each independently associated with brain, bone, liver, and lung metastases (all P < 0.05). CONCLUSIONS: Abnormal level of LDH and TMs, alone or in combination, had predictive value for metastasis in geriatric patients with lung adenocarcinoma; these indicators were also associated with the metastatic site. Show more

Keywords: Lung adenocarcinoma, lactate dehydrogenase, tumor marker, metastasis, elderly

DOI: 10.3233/CBM-190201

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Asanuma, Kunihiro | Nakamura, Tomoki | Asanuma, Yumiko | Kakimoto, Takuya | Yada, Yuki | Hagi, Tomohito | Kita, Kouji | Matsumine, Akihiko | Sudo, Akihiro

Article Type: Research Article

Abstract: BACKGROUND: Thrombomodulin (TM) has multiple biological functions and modulates not only anti-coagulation, but also cell proliferation, adhesion, and anti-inflammation activities. The main function of TM is to activate the anticoagulant pathway of protein C. Soluble TM is related to metastasis by its inactivation of thrombin. OBJECTIVES: To clarify the correlation between serum TM levels and clinicopathological parameters. METHODS: The plasma TM levels (FU/ml) of 135 primary soft tissue tumors (benign, 67; soft tissue sarcoma (STS), 68) were measured before biopsy or treatment. TM levels were analyzed and compared to various clinicopathological parameters. Log-rank test …and Cox proportional analysis were used to evaluate recurrence-free survival, metastasis-free survival, and overall survival. RESULTS: STS tumors had significantly higher TM values (15.9) than benign tumors (13.7) (p = 0.0138). 5-year MFS was 81.1% in low TM and 40.0% in high TM (p = 0.00671), and 5-year OS was 85.5% in low and 52.5% in high TM in grades 1–3 (p = 0.0673). In multivariate COX proportional analysis, high-TM showed a significant difference (MFS: HR 4.37, p = 0.0147; OS: HR 3.60, p = 0.0557) in grades 1–3. CONCLUSIONS: We demonstrated that a high level of soluble TM has the potential to be a significant predictor of metastasis and poor prognosis in STS patients. TM is a candidate molecular marker for high metastatic potential and can be clinically useful for guiding therapeutic strategy. Show more

Keywords: Thrombomodulin, soft tissue tumor, soft tissue sarcoma, metastasis, prognosis

DOI: 10.3233/CBM-182075

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Ye, Tianyi | Yao, Hongwen | Xu, Yang | Zhao, Xiaohang | Lu, Haizhen | Zhang, Rong

Article Type: Research Article

Abstract: Neoadjuvant chemotherapy (NACT) followed by radical surgical hysterectomy and pelvic lymph node dissection is considered an effective method to treat patients with bulky stage IB–IIA cervical cancer, but not all patients benefit from NACT. Apoptotic proteins play important roles in the progression of chemotherapy, and second mitochondria-derived activator of caspase (Smac) may have a cooperative relationship with Omi/HtrA2, leading to carcinogenesis and chemotherapy resistance. Chemosensitivity is an important prognostic factor for cervical cancer patients. The aim of this study was to evaluate the significance of Smac, survivin, X-linked inhibitor-of-apoptosis protein (XIAP), and Omi/HtrA2 expression in predicting the response to neoadjuvant …chemotherapy and the prognostic significance of te expression of these proteins in cervical cancer patients. Our findings showed that low expression levels of survivin and high expression levels of Omi/HtrA2 in chemotherapy-responsive cervical carcinoma patients significantly increased chemosensitivity. Show more

Keywords: Cervical carcinoma, chemosensitivity, apoptotic proteins, IHC

DOI: 10.3233/CBM-182165

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Wu, You-Jun | Hu, Zi-Long | Hu, Shi-Dong | Li, Yu-Xuan | Xing, Xiao-Wei | Yang, Yu | Du, Xiao-Hui

Article Type: Research Article

Abstract: Glutamate dehydrogenase (GDH) is a key enzyme in glutaminolysis and can regulate allosteric functions. Immunohistochemical study found that GDH expressed in gastric cancer cell cytoplasm and membrane, and a few located in the nucleus, ranging from light yellow to tan to sepia. According to the analysis by Kaplan Meier survival curve and the Log-Rank test, the median survival of GDH high expression in patients was 51.7 months with 95% confidence intervals (CI) was 41.138–55.262. The expression level of GDH was significantly reduced after silencing GDH gene in gastric cancer cells and tissues. Further, after silencing GDH gene, gastric cancer cell …migration and invasion ability were decreased significantly. Protein expression of. In addition, tumor growth was significantly reduced after silencing GDH gene. In vivo and in vitro experiments suggest that GDH can decrease gastric cancer cell migration and invasion, thus inhibiting tumor growth. Show more

Keywords: Glutamate dehydrogenase, notch signaling pathways, gastric cancer cell, invasion, migration

DOI: 10.3233/CBM-190022

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Zhu, Pengfeng | Tan, Qingqing | Jiang, Wen | Ou, Yangjun | Xu, Peizhen | Yuan, Lei

Article Type: Research Article

Abstract: OBJECTIVE: This study aimed to detect the expression of eukaryotic translation initiation factor 3B (EIF3B) and investigate its correlation with tumor features and survival in cervical cancer patients. METHODS: This study retrospectively reviewed 187 cervical cancer (squamous cell carcinoma) patients underwent tumor resection. Immunohistochemistry was performed to determine the expression of EIF3B in tissue samples. Besides, disease free survival (DFS) and overall survival (OS) were calculated. The median follow-up duration was 69 months, and the last follow-up date was 2017/12/31. RESULTS: EIF3B expression was higher in tumor tissue compared to paired adjacent tissue …(45.5% vs. 32.1%, P = 0.015). Besides, EIF3B high expression was associated with higher Federation of Gynecology and Obstetrics (FIGO) Stage (P = 0.001) and presence of lymph node metastasis (P = 0.002). As to survival profiles, Kaplan-Meier curves disclosed that DFS (P < 0.001) and OS (P < 0.001) were both shorter in EIF3B high expression group compared to EIF3B low expression group. Multivariate Cox’s regression analysis disclosed that EIF3B high expression, pathological grade III (vs I/II) and FIGO Stage III/IV (vs I/II) were independent predictive factors for unfavorable DFS as well as OS in cervical cancer patients (all P value < 0.05). CONCLUSION: EIF3B is overexpressed, and its high expression correlates with higher FIGO Stage, lymph node metastasis and unfavorable survival profiles in cervical cancer patients. Show more

Keywords: Eukaryotic translation initiation factor 3B (EIF3B), cervical cancer, survival, prognosis

DOI: 10.3233/CBM-182114

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Wei, Juan | Wei, Wei | Xu, Hanfeng | Wang, Zhaojing | Gao, Wen | Wang, Tianjun | Zheng, Qin | Shu, Yongqian | De, Wei

Article Type: Research Article

Abstract: BACKGROUND: Circular RNAs (circRNA) play key regulatory roles in cancer progression. Human circRNA microarray was performed to screen for abnormally expressed circRNA in gastric cancer tissues. In this study, we found circRNA102958 was up-regulated in gastric cancer tissues and cell lines. METHODS: The hsa_circRNA_102958 levels were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in gastric tissue and cell. Then, the association between the expression level of hsa_circRNA_102958 and the clinicopathological features of patients with gastric cancer was further analyzed. Finally, a network of hsa_circRNA_102958-miRNA-mRNA interactions was predicated. RESULTS: In this study, we …analyzed 30 patients and found that hsa_circRNA_102958 was significantly overexpressed in gastric cancer tissues compared with paired adjacent normal tissues. Clinicopathological features showed that hsa_circRNA_102958 level in GC tissues was positively associated with TNM stage (p = 0.032). The area under the ROC curve was 0.74. Finally, a total of 5 miRNAs were predicted to have an interaction with hsa_circRNA_102958. CONCLUSIONS: hsa_circRNA_102958 may be a potential novel and stable biomarker for the diagnosis of gastric carcinoma. Show more

Keywords: Gastric cancer, hsa_circRNA_102958, diagnosis, miRNA, mRNA

DOI: 10.3233/CBM-182029

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-7, 2019