Cancer Biomarkers - Volume 22, issue 3

Authors: Liu, Zhuo | Ma, Min | Yan, Lei | Chen, Shilin | Li, Sha | Yang, Darong | Wang, Xiaohong | Xiao, Hua | Deng, Hongyu | Zhu, Haizhen | Zuo, Chaohui | Xia, Man

Article Type: Research Article

Abstract: BACKGROUND: Interferon-α (IFN-α ) is an adjuvant to chemotherapy and radiotherapy for hepatocellular carcinoma (HCC), but some HCC patients do not respond to treatment with IFN-α . METHODS: We performed loss-of-function and gain-of-function experiments to examine the role of ISG15 in the IFN-α sensitivity of LH86, HLCZ01, SMMC7721, and Huh7 cell lines and tumor samples. RESULTS: The overexpression of ISG15 reduced apoptosis in Huh7 and LH86 cells in the presence of IFN-α , whereas the shRNA-mediated knock down of ISG15 expression …increased apoptosis in both Huh7 and LH86 cells. We identified a putative miR-370 target site in the 3’-UTR in the ISG15 mRNA, and the level of miR-370 expression in HCC cell lines reflected the level of IFN-α -induced apoptosis exhibited by each. Both HCC cell lines and tumor samples had significantly lower levels of miR-370 than the control cells and tissues (P < 0.05). The overexpression of miR-370 in IFN-α -treated LH86 and Huh7 cells increased apoptosis and reduced the volume of LH86- and Huh7-derived xenograft tumors in mice treated with IFN-α compared with the control tumors. CONCLUSIONS: Our findings suggest that miR-370 functions as an HCC tumor suppressor and regulator of IFN-α sensitivity and that miR-370 might be a useful prognostic marker for HCC patients. Show more

Keywords: Hepatocellular carcinoma cells, interferon-α, ISG15, miR-370, prognostic marker

DOI: 10.3233/CBM-171075

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 453-466, 2018

Authors: Zhuo, Minglei | Chen, Hanxiao | Zhang, Tianzhuo | Yang, Xue | Zhong, Jia | Wang, Yuyan | An, Tongtong | Wu, Meina | Wang, Ziping | Huang, Jing | Zhao, Jun

Article Type: Research Article

Abstract: BACKGROUND: The PD-L1 antibody atezolizumab has shown promising efficacy in patients with advanced non-small cell lung cancer. But the predictive marker of clinical benefit has not been identified. OBJECTIVE: This study aimed to search for potential predictive factors in circulating blood of patients receiving atezolizumab. METHODS: Ten patients diagnosed with advanced non-small cell lung cancer were enrolled in this open-label observing study. Circulating immune cells and plasma tumor markers were examined in peripheral blood from these patients before and after atezolizumab treatment respectively. Relation between changes in circulating factors and anti-tumor efficacy were …analyzed. RESULTS: Blood routine test showed that atezolizumab therapy induced slightly elevation of white blood cells count generally. The lymphocyte ratio was increased slightly in disease controlled patients but decreased prominently in disease progressed patients in response to atezolizumab therapy. Flow cytometric analysis revealed changes in percentage of various immune cell types, including CD4 + T cell, CD8 + T cell, myeloid-derived suppressor cell, regulatory T cell and PD-1 expressing T cell after atezolizumab. Levels of plasma tumor marker CEA, CA125 and CA199 were also altered after anti-PD-L1 therapy. In comparison with baseline, the disease progressed patients showed sharp increase in tumor marker levels, while those disease controlled patients were seen with decreased regulatory T cell and myeloid-derived suppressor cell ratios. CONCLUSIONS: The circulating immune cell ratios and plasma tumor marker levels were related with clinical efficacy of atezolizumab therapy. These factors could be potential predictive marker for anti-PD-L1 therapy in advanced non-small cell lung cancer. Show more

Keywords: Circulating immune cell, immunotherapy, non-small cell lung cancer, PD-L1, tumor marker

DOI: 10.3233/CBM-171089

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 467-476, 2018

Authors: Huang, Qing-Xing | Ma, Jun | Wang, Yu-Sheng

Article Type: Research Article

Abstract: BACKGROUND: Oxidative stress plays an important role in promoting proliferation and metastases of cancer, which can be represented by ischemia-modified albumin (IMA). The purpose of this study was to evaluate serum IMA level in patients with operable advanced gastric cancer and analyze its prognostic significance. MATERIALS AND METHODS: A total of 274 patients with primary stage III gastric cancer underwent curative operation were enrolled in this study. Serum IMA level was measured within 24 hours before surgery, comparing with 112 healthy donors. The correlation between serum IMA level and survival outcome was analyzed by the Kaplan-Meier …with Log-Rank test and Cox’s regression methods, respectively. RESULTS: Serum IMA level from gastric cancer was higher than healthy control (0.41 ± 0.12 VS 0.23 ± 0.08; P < 0.001). Finally, 173 and 181 patients out of all 274 patients studied had died and recurrent, respectively. All patients were stratified into two groups using the optimal cutoff value (0.45) of IMA level using a sensitivity of 92.5% and a specificity of 65.2% as optimal conditions from receiver operating curve analysis. Patients with a IMA ⩾ 0.45 had poorer mean overall survival (44.68 months VS 30.94 months, P = 0.010) and mean recurrence free survival (42.36 months VS 28.82 months, p = 0.01) than patients with a IMA < 0.45 in univariate analysis and IMA also been confirmed as independent predictor for survival for GC patients in multivariate analysis (OR, 0.731; 95% CI: 0.329–1.282; p = 0.023). CONCLUSIONS: Serum IMA level can be considered as an independent prognostic factor for operable and advanced gastric cancer. Show more

Keywords: Ischemia-modified albumin, survival, gastric cancer

DOI: 10.3233/CBM-171090

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 477-485, 2018

Authors: Liu, Wenjun | Xu, Yongmei | Guan, Hongliang | Meng, Hongwei

Article Type: Research Article

Abstract: BACKGROUND: Breast cancer remains the most invasive female malignancy worldwide. Functional role of microRNA-940 (miR-940) have been investigated in various cancer. The purpose of this study was to assess the serum miR-940 expression and its clinical significance in breast cancer. METHODS: Expression of miR-940 was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The diagnostic value of miR-940 was analyzed with receiver operating characteristics (ROC) analysis. To explore the prognostic performance of miR-940, Kaplan-Meier survival assay and Cox regression analysis were performed. RESULTS: Downregulated miR-940 was detected in the breast cancer patients compared …with the healthy controls (P < 0.001). The miR-940 expression was correlated with lymph node metastasis (P = 0.014) and TNM stage (P = 0.003). The area under the ROC curve (AUC) was 0.905, with sensitivity and specificity of 94.5% and 78.6%. From the survival curves, patients with low miR-940 expression had poor overall survival compare with those with high expression (log-rank P = 0.009). The Cox analysis indicated that miR-940 was an independent prognostic factor (HR = 2.645, 95% CI = 1.426–4.906 and P = 0.002). Decreased miR-940 expression was also been found in triple-negative breast cancer (TNBC) samples, and might predict poor prognosis in TNBC patients. CONCLUSIONS: Serum downregulated miR-940 may serve as a reliable diagnostic and prognostic biomarker in breast cancer patients. Show more

Keywords: MiR-940, diagnosis, prognosis, breast cancer

DOI: 10.3233/CBM-171124

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 487-493, 2018

Authors: Li, Yanshi | Liu, Chuan | Wang, Zhihai | Hu, Guohua

Article Type: Research Article

Abstract: Protocadherin8 (PCDH8), an integral membrane protein, was reported to be a tumor suppressor involved in tumorigenesis in cancers. We aimed to investigate the expression of PCDH8 and its clinicopathological significance in hypopharyngeal carcinoma. We also examined the possible inactivation mechanism of PCDH8. A total of 80 pairs of hypopharyngeal carcinoma tumor tissues and non-tumor tissues were investigated to examine the immunohistochemical expression of PCDH8. Prognostic value and clinicopathological significance of PCDH8 expression were examined by Kaplan-Meier and log-rank test and Cox’s ones. Ten pairs of tumor tissues and non-tumor tissues were analyzed by RT-PCR and 4 pairs by Western blot …respectively. Promoter methylation of PCDH8 was observed in 14 pairs of tumor tissues and non-tumor tissues by methylation-specific PCR (MSP). The expression of PCDH8 in tumor tissues was depressed immunohistochemically when compared with non-tumor tissues and was significantly lower in the advanced pathological stage. Meanwhile, the expression of PCDH8 served as an independent prognostic risk factor for overall survival of hypopharyngeal carcinoma. The mRNA and protein levels of PCDH8 in tumor tissues was also down-regulated than in non-tumor tissues. Moreover, aberrant promoter methylation of PCDH8 occurred frequently in tumor tissues, rather than in non-tumor tissues. For the first time, our study demonstrates the tumor-suppressive function of PCDH8 and its epigenetic inactivation by promoter methylation in hypopharyngeal carcinoma. It suggests that PCDH8 may serve as a useful prognostic biomarker and a potential therapeutic target for hypopharyngeal carcinoma patients. Show more

Keywords: Hypopharyngeal carcinoma, protocadherin8, tumor suppressor gene

DOI: 10.3233/CBM-171137

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 495-502, 2018

Authors: Mekky, Mohamed A. | Salama, Rgaa H. | Abdel-Aal, Mahmoud F. | Ghaliony, Mohamed A. | Zaky, Saad

Article Type: Research Article

Abstract: BACKGROUND: Data about the molecular pathogenesis of hepatitis C-related hepatocellular carcinoma (HCC) are still challenging. OBJECTIVES: Therefore, we tried to investigate the epigenetic study of three nominated genes (APC, P14, and E-cadherin) in the pathogenesis of HCV-related HCC in Egyptian. METHODS: Between March 2016 and March 2017, the DNA methylation, and quantification using (epigenetic ELISA kit) for E-cadherin, APC, and P14 genes were studied in three groups of patients: HCV related liver cirrhosis without HCC group (LC-group; n = 20), HCC on top of HCV-related cirrhosis (HCC-group; n …= 20), and a third apparently healthy control group (control-group; n = 10). RESULTS: E-cad methylation showed non-significant differences between groups. P14 methylation was occurred only in HCC-group (45%). APC methylation was the highest in HCC group (70%). Methylation level was high in HCC group in comparison to both LC and control groups (P < 0.001). DNA methylation at a cutoff point > 2.9 ng/ml predicts HCC in LC-group with 90% sensitivity and 80% specificity and at level > 2.3 ng/ml had 95% sensitivity and 90% specificity in control-group. The pooled sensitivity, specificity, positive and negative predictive values and accuracy were 90%, 60%, 69.2, 85.7 and 75% respectively. CONCLUSION: Aberrant DNA methylation of multiple genes is associated with disease progression in HCV related cirrhosis. Moreover, early detection of promotor methylation of these may sever as good biomarker for early detection and therapeutic targets in high risk patients. Show more

Keywords: Hepatocellular carcinoma, liver cirrhosis, epigenetics

DOI: 10.3233/CBM-171156

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 503-509, 2018

Authors: Zhang, Liang | Huang, Yi | Ling, Junjun | Zhuo, Wenlei | Yu, Zhen | Shao, Mengmeng | Luo, Yunbo | Zhu, Yi

Article Type: Research Article

Abstract: BACKGROUND: Liver carcinoma is a major cause of cancer-related death worldwide. Up to date, the mechanisms of liver cancerigenesis and development have not been fully understood. Multi-genes and pathways were involved in the tumorigenesis of liver cancer. OBJECTIVE: The aim of the present study was to screen key genes and pathways in liver cancerigenesis and development by using bioinformatics methods. METHODS: A dataset GSE64041 were retrieved from GEO database and the differentially expressed genes (DEGs) were screened out. Then the DEG functions were annotated by gene ontology (GO) and pathway enrichment analysis, respectively. …The hub genes were further selected by protein-protein interaction (PPI) analysis. Afterwards, the mRNA and protein expressions as well as the prognostic values of the hub genes were assessed. RESULTS: As a result, 208 up-regulated and 82 down-regulated genes were screened out. These DEGs were mainly enriched in cell cycle and metabolism-related pathways. Through PPI analysis, TOP2A, PRDM10, CDK1, AURKA, BUB1, PLK1, CDKN3, NCAPG, BUB1B and CCNA2 were selected as hub genes, which were all over-expressed in liver cancers relative to those in normal tissues, respectively. Among them, PLK1 and CCNA2 were suggested to be prognostic factors for liver carcinoma. CONCLUSION: In conclusion, the present study identified several hub genes, and cell cycle and metabolism-related pathways that may play critical roles in the tumorigenesis of liver cancer. Future validation laboratory experiments are required to confirm the results. Show more

Keywords: Liver carcinoma, hub genes, cell cycle, prognosis, bioinformatics

DOI: 10.3233/CBM-171160

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 511-521, 2018

Authors: Ji, Yu | Shao, Zhenzhen | Liu, Junjun | Hao, Yujuan | Liu, Peifang

Article Type: Research Article

Abstract: This study aimed to analyze the correlation between mammographic density obtained by density analysis software (DAS)/radiologists visual (RV) classification with molecular subtype, and the expression levels of estrogen receptor (ER), progesterone receptor (PR), Ki67 antigen (Ki-67), p53 gene (p53), and human epidermal growth factor receptor-2 (HER2). A total of 688 breast cancer patients with digital mammography and complete molecular pathological results in Tianjin Medical University Cancer Institute and Hospital between February 2015 and February 2016 were collected. The DAS-density grade (DASD) and the radiologists visually classified density grade (RVD) were evaluated by 3 radiologists. The correlation between density grade and …the expression levels of ER, PR, Ki-67, p53, HER2 and breast cancer molecular subtype (PMS) were analyzed. The agreement between DASD and RVD was explored. ER, PR and HER-2 positive rate were significantly different among patients with different RVD grades (P < 0.05). HER2 positive rates showed an increasing trend following RVD upgrading (P 𝑡𝑟𝑒𝑛𝑑 < 0.05). HER-2 positive rate in RVD D1 + D2 was 7.69%, which was higher than that in D3 + D4 (P < 0.05). The ER and Ki-67 expressions in patients were markedly different among DASD (P = 0.009 and 0.002) and RVD (P = 0.012 and 0.036) with different grades. The kappa value of each DASD to RVD was 0.31 (P < 0.01). The RVD 3 proportion was 14.58% (63/432) in HER2 Over-expressing subtype, which was apparently higher than RVD1 (2.43%, 1/41) (P < 0.05). Breast density may be partial correlated with molecular pathology in breast cancer. Show more

Keywords: Breast cancer, mammographic density, molecular pathology, correlation

DOI: 10.3233/CBM-181185

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 523-531, 2018

Authors: Wang, Qiang | Peng, Ruixian | Wang, Boshi | Wang, Jifeng | Yu, Wandong | Liu, Yongzhong | Shi, Guowei

Article Type: Research Article

Abstract: BACKGROUND: Krüppel-like factor 13 (KLF13), a member of the KLF family, is involved in the development of immunological diseases and tumor progression. However, the expression patterns and potential functions of KLF13 in prostate carcinoma are still unknown. Here, we aimed to study the roles and mechanisms of KLF13 in prostate cancer. METHODS: The expression levels of KLF13 was detected by Immunohistochemistry in prostate tumor tissues and the paired non-tumor tissues. The effects of KLF13 up-regulation was tested by performing CCK8, cell colon formation, flow cytometric analysis and measurement of tumor proliferation in nude mice. Signaling pathway …was analyzed by Western blot. RESULTS: The current study, for the first time, found that KLF13 was downregulated in prostate tumor tissues as compared to the paired non-tumor tissues. The overexpression of KLF13 dramatically inhibited cell proliferation and induced apoptosis by suppressing the AKT pathway in human prostate cancer cells. Moreover, the ectopic expression of KLF13 efficiently delayed the onset of PC3 xenografts and inhibited the tumor growth in vivo. CONCLUSIONS: KLF13 functions as a tumor suppressor protein in PCa, and the pharmacological activation of KLF13 might represent a potential approach for the treatment of prostate cancer. Show more

Keywords: Immunohistochemistry, prostate cancer, apoptosis, AKT pathway, Krüppel-like factor 13

DOI: 10.3233/CBM-181196

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 533-541, 2018

Authors: Jiang, Sixiong | Tian, Feng | Wang, Qi | Cheng, Wen | Wang, Longxin | Wang, Ying | Sun, Weibing

Article Type: Research Article

Abstract: BACKGROUND: Spindle and kinetochore-associated protein 1 (SKA1) is a component of SKA, which is essential for proper chromosome segregation. Recently, SKA1 was found to be over-expressed in several types of human cancers. However, reports on the relationship between SKA1 expression and the prognosis of bladder cancer, in particular, are lacking. OBJECTIVES: To clarify the clinical significance of SKA1 as a prognostic biomarker for early recurrence and progression of patients with non-muscle invasive bladder cancer (NMIBC). METHODS: The differential expression levels of SKA1 of 148 NMIBC tissues were determined by immunohistochemical staining. Quantitative real-time …PCR and western blot analysis were further performed to confirm the immunohistochemistry results. Recurrence and progression free interval were assessed by Kaplan-Meier method and differences between groups calculated by log-rank statistics. The prognostic value of SKA1 for early recurrence and progression was analyzed by multivariate Cox proportional hazard regression models. RESULTS: SKA1 expression was significantly different in various NMIBC tissues. Kaplan-Meier analysis revealed that patients with high SKA1 expression showed high early recurrence (p < 0.001) and progression (p < 0.05) rates. Although univariate Cox regression analysis revealed that several other factors had an impact on recurrence and progression, upon multivariate analysis, high SKA1expression was the only independent predictor for early recurrence (hazards ratio [HR], 0.246; 95% confidence interval [CI], 0.131–0.461; p = 0.000) and progression (HR, 0.194; 95% CI, 0.052–0.715; p = 0.014). CONCLUSIONS: High SKA1 expression is associated with early recurrence and progression in patients with NMIBC, indicating SKA1 may serve as a promising prognostic biomarker for this disease. Show more

Keywords: Non-muscle invasive bladder cancer, SKA1, recurrence, progression, biomarker

DOI: 10.3233/CBM-181202

Citation: Cancer Biomarkers, vol. 22, no. 3, pp. 543-549, 2018