Cancer Biomarkers - Volume 15, issue 6

Authors: Cao, Xinguang | Zhao, Ruihua | Chen, Qiong | Zhao, Yuzhou | Zhang, Bin | Zhang, Yanzhen | Yu, Juan | Han, Guangsen | Cao, Wei | Li, Jiansheng | Chen, Xiaobing

Article Type: Research Article

Abstract: BACKGROUND: Recent studies have demonstrated that MALAT1 is involved in cancer metastasis and recurrence and it is up-regulated in cervical cancer, hepatocellular carcinoma, non-small cell lung cancer (NSCLC) and colorectal cancer. However, the role of MALAT1 in esophageal squamous cell carcinoma (ESCC) is still unclear. METHODS: The expression of MALAT1 was evaluated in cancer tissue and paired adjacent normal tissue samples from 77 middle thoracic ESCC patients who received radical surgical resection using QRT-PCR. The correlations between the expression levels of MALAT1 and clinical-pathological features and Patients' survival were also analysed. RESULTS: MALAT1 expression …was increased in ESCC tissue than in adjacent normal tissue samples (P< 0.001). MALAT1 level was positively related to pT stage (P= 0.01). Kaplan-Meier analysis showed high expression levels of MALAT1 ware correlated with poor prognosis in ESCC patients. Patients with a high level of MALAT1 had a shorter DFS and OS than those with low MALAT1 expression (P= 0.04 and 0.038, respectively). On Multivariate analysis, The HR of MALAT1 expression was 1.76 (95% CI = 0.97-3.21, P= 0.06) for DFS and 1.81 (95% CI = 0.97-3.41, P$=0.06) for OS. CONCLUSIONS: Our results showed that MALAT1 expression may serve as a predictive marker for middle thoracic ESCC patients who have been received radical resection. Show more

Keywords: Esophageal squamous cell carcinoma, long non-coding RNA, MALAT1

DOI: 10.3233/CBM-150513

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 717-723, 2015

Authors: Vlachostergios, Panagiotis J. | Oikonomou, Katerina G. | Gibilaro, Eugene | Apergis, George

Article Type: Research Article

Abstract: BACKGROUND: Hyperlactatemia with or without type B lactic acidosis is a rare complication of cancer, previously observed most often in hematological malignancies. The aim of this study was to assess the prognostic value of lactic acid (LA) in patients with metastatic lung cancer. METHODS: Patients diagnosed with stage IV non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (SCLC), were included in this single center retrospective study. Arterial and venous LA level, anion gap (AG), serum LDH and presence of urine ketones were recorded for each patient and their associations with demographic and …clinical data and overall survival (OS) were examined. RESULTS: Eighty-five patients (43 males, median age 74, range 45-96 years) were studied. The maximal levels of arterial or venous LA were significantly associated with presence of ≥ 2 metastatic sites (p= 0.001), ICU admission or transfer (p= 0.016), intubation (p= 0.029), elevated serum anion gap (p< 0.001) and LDH levels (p< 0.001). Hyperlactatemia (≥ 1.4 mmol/L) was associated with shorter OS (log-rank p< 0.001). In a multivariate model including LA, ICU, intubation, AG as well as other known prognostic factors of NSCLC and SCLC, including age, sex, smoking status, number and location of metastases, histologic type, performance status (PS), chemotherapy and LDH, LA retained its prognostic value (OR: 1.3; 95%CI: 1.082-1.561; p= 0.005), along with PS (p= 0.039) and chemotherapy (p= 0.039). CONCLUSIONS: The results of the study suggest that a high lactic acid level (≥ 1.4 mmol/L) is associated with significantly shorter overall survival in patients with metastatic non-small cell lung cancer and extensive stage small cell lung cancer. Hyperlactatemia is an independent predictor of poor survival in metastatic lung cancer patients. Show more

Keywords: Lactic acid, prognosis, survival, lung cancer, lactate, tumor

DOI: 10.3233/CBM-150514

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 725-734, 2015

Authors: Liu, Chun | Yang, Zhulin | Li, Daiqiang | Liu, Ziru | Miao, Xiongying | Yang, Leping | Zou, Qiong | Yuan, Yuan

Article Type: Research Article

Abstract: BACKGROUND: Approximately 80% of patients with pancreatic ductal adenocarcinoma (PDAC) have metastatic disease with poor prognosis, but clinically available markers have not yet been identified. OBJECTIVE: In this study, we investigated the expression of B2M and ALK7 in 106 PDACs compared to precursor lesions of the pancreas. METHODS: Immunohistochemistry was used to detect B2M and ALK7 protein expression. RESULTS: Positive B2M expression was significantly higher, while positive expression of ALK7 was significantly lower in PDAC than in precursor lesions (p < 0.01 or p < 0.001). Positive B2M expression was also significantly …higher, while positive ALK7 expression was significantly lower in cases with well-differentiated adenocarcinoma, small tumor mass, no-metastasis of the lymph node, no-invasion of regional tissues, and TNM I or II stage disease than in cases having poorly-differentiated adenocarcinoma, large tumor mass, with metastasis and invasion, and TNM stage III or IV stage disease (p < 0.01). Univariate Kaplan-Meier analysis showed that B2M overexpression (p < 0.001), but lack of ALK7 expression (p < 0.001) was significantly associated with shorter overall survival. Cox multivariate analysis showed that differentiation, tumor mass, lymph node metastasis, invasion, TNM stage, and B2M levels negatively correlated with overall survival. In contrast, ALK7 level positively correlated with overall survival. Positive B2M and negative ALK7 expression are poor prognostic factors in PDAC patients. CONCLUSIONS: B2M and ALK7 might be important biological markers involved in the carcinogenesis, metastasis, invasion, and prognosis of PDAC. Show more

Keywords: Pancreatic ductal adenocarcinoma, immunohistochemistry, B2M, ALK7

DOI: 10.3233/CBM-150515

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 735-743, 2015

Authors: Rabi, Zaki Abu | Todorović-Raković, Nataša | Vujasinović, Tijana | Milovanović, Jelena | Nikolić-Vukosavljević, Dragica

Article Type: Research Article

Abstract: BACKGROUND: Cancer progression and metastasis are complex processes, dependent of molecules involved in inflammation, degradation and invasion. These molecules can be used as prognostic indicators to single out patients with higher risk of recurrence. Interleukin-8 (IL-8) has a role in inflammation, urokinase plasminogen activator (uPA), plasminogen activator inhibitor type-1 (PAI-1) and matrix metalloproteinase-2, -9 have a decisive part in the process of degradation and invasion, while vascular endothelial growth factor (VEGF) is consequential for angiogenesis. OBJECTIVES: Aim of our study is to determine relations between IL-8, uPA, PAI-1, MMP-2, -9, VEGF as their prognostic significance in …terms of recurrence free survival. METHODS: This study included 91 untreated patients with lymph node negative (N0) primary breast cancer. RESULTS: Patients with higher levels of uPA (p= 0.05), PAI-1 (0.05), MMP2 (p= 0.05) and IL-8 (p= 0.02) have a poor prognosis. Positive correlations were found between ER - PR, uPA - PAI-1, uPA - MMP9, PAI-1 - IL-8, MMP9 - IL-8, MMP9 - VEGF. Negative correlations were found between ER - IL-8, uPA - IL-8, MMP2 - VEGF. CONCLUSIONS: Higher concentrations of IL-8, uPA, PAI-1 and MMP2, as is MMP9 and VEGF, confirmed aggressive phenotype and poor prognosis in different subgroups. Show more

Keywords: Breast cancer, prognostic markers, progression, lymph node, interleukin 8, plasminogen activator, matrix metalloproteinase

DOI: 10.3233/CBM-150516

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 745-754, 2015

Authors: Shi, Zhi-Zhou | Shang, Li | Jiang, Yan-Yi | Shi, Feng | Xu, Xin | Wang, Ming-Rong | Hao, Jia-Jie

Article Type: Research Article

Abstract: BACKGROUND: At present no objective prognostic biomarkers have been established in esophageal squamous cell carcinoma (ESCC). OBJECTIVE: To identify the genomic biomarkers associated with clinicopathological factors and prognosis of ESCCs. METHODS: Real-time PCR was used to analyze the copy number change and mRNA expression of genes. The survival curves were plotted according to Kaplan-Meier method and checked by log-rank test. RESULTS: We revealed the copy number increase of CACNA1C (12p13.33) and MRPL21 (11q13.2) as well as decrease of VIPR2 (7q36.3) and MAP3K7 (6q15) in ESCC by Real-time PCR, and also found that …MRPL21 was significantly overexpressed and VIPR2 was underexpressed in ESCC. Gain of CACNA1C was significantly associated with differentiation (P = 0.043), and loss of VIPR2 was significantly linked with good prognosis (P = 0.016). Most importantly, we revealed that loss of MAP3K7 was significantly correlated with good prognosis in ESCC patients (n = 159, P = 0.004), especially in Grade II and pN0 patients (n = 76, P = 0.005 and n = 74, P = 0.024). Multivariate analysis confirmed that MAP3K7 loss provided prognostic information in ESCC (HR, 0.454; 95% CI: 0.208-0.995; P = 0.048). CONCLUSIONS: Loss of MAP3K7 may be a candidate prognostic factor in ESCC. Show more

Keywords: Esophageal squamous cell carcinoma, MAP3K7, prognosis, biomarker

DOI: 10.3233/CBM-150517

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 755-761, 2015

Authors: Maragh, Samantha | Veltri, Robert W. | Lund, Steven P. | Mangold, Leslie | Isharwal, Sumit | Christudass, Christhunesa S. | Partin, Alan W. | Humphreys, Elizabeth B. | Sorbara, Lynn | Srivastava, Sudhir | Wagner, Paul D.

Article Type: Research Article

Abstract: BACKGROUND: A 3.4kb deletion (3.4kbΔ ) in mitochondrial DNA (mtDNA) found in histologically normal prostate biopsy specimens has been reported to be a biomarker for the increased probability of prostate cancer. Increased mtDNA copy number is also reported as associated with cancer. OBJECTIVE: Independent evaluation of these two potential prostate cancer biomarkers using formalin-fixed paraffin-embedded (FFPE) prostate tissue and matched urine and serum from a high risk cohort of men with and without prostate cancer. METHODS: Biomarker levels were detected via qPCR. RESULTS: Both 3.4kbΔ and mtDNA levels were significantly higher …in cancer patient FFPE cores (p= 0.045 and p= 0.070 respectively at > 90% confidence). Urine from cancer patients contained significantly higher levels of mtDNA (p= 0.006, 64.3% sensitivity, 86.7% specificity). Combining the 3.4kbΔ and mtDNA gave better performance of detecting prostate cancer than either biomarker alone (FFPE 73.7% sensitivity, 65% specificity; urine 64.3% sensitivity, 100% specificity). In serum, there was no difference for any of the biomarkers. CONCLUSIONS: This is the first report on detecting the 3.4kbΔ in urine and evaluating mtDNA levels as a prostate cancer biomarker. A confirmation study with increased sample size and possibly with additional biomarkers would need to be conducted to corroborate and extend these observations. Show more

Keywords: Prostate, cancer, biomarker, mitochondrial DNA, 3.4kb deletion, urine, serum, FFPE, NIST, EDRN

DOI: 10.3233/CBM-150518

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 763-773, 2015

Authors: Krivokuca, Ana | Yanowski, Kira | Rakobradovic, Jelena | Benitez, Javier | Brankovic-Magic, Mirjana

Article Type: Research Article

Abstract: BACKGROUND: In 2010 an important finding was published showing that heterozygous mutations in RAD51C were highly penetrant and were able to confer an increased risk for breast and ovarian cancers. The role of possible third high penetrance breast cancer susceptibility gene was assigned to RAD51C . OBJECTIVE: Because of its rising importance in breast cancer development and the lack of information about RAD51C in Slavic populations, our goal was to identify potential population specific mutations in this gene in order to determine more detailed genetic screening strategy and breast cancer risk assessment. METHODS: …The study included 55 females from Serbian hereditary breast/ovarian cancer families negative for sequence alterations and large genomic rearrangements in BRCA1 /2 genes. Whole coding region and exon-intron boundaries of RAD51C were analyzed by dHPLC. All mutations were confirmed by Sanger sequencing. SIFT and Polyphen were used to predict possible impact of non-synonymous variants. RESULTS: We found 5 variants in RAD51C including two missense, one intronic, one in the 5'UTR and one variant in the promoter region of the gene. Three detected variants are common - c.1-118G>A (rs16943176, MAF = 0,203); c.1-26C>T (rs12946397, MAF = 0,207) and c.904+34T>C (rs28363318, MAF = 0,186). We detected two missense variants, c.790G>A (p.Gly264Ser) in exon 5 and c.859A>G (p.Thr287Ala) in exon 6. Both of them were previously shown to exhibit reduced protein function but their contribution to cancer risk is still unknown. CONCLUSIONS: Although the initial reports implied that RAD51C might be promising candidate for next high penetrance breast cancer susceptibility gene, lack of confirmation suggested that RAD51C mutations are not as common as expected. Our study did not reveal truncating mutations in RAD51C suggesting that other breast cancer susceptibility genes may account for the increased susceptibility in our cohort of high-risk BRCA1 /2 negative families. Show more

Keywords: RAD51C, hereditary breast/ovarian cancer, dHPLC, sequencing

DOI: 10.3233/CBM-150519

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 775-781, 2015

Authors: Bager, C.L. | Willumsen, N. | Leeming, D.J. | Smith, V. | Karsdal, M.A. | Dornan, D. | Bay-Jensen, A.C.

Article Type: Research Article

Abstract: BACKGROUND: During cancer the otherwise tightly controlled homeostasis of the extracellular matrix (ECM) is disturbed. The protein composition changes, the ECM stiffens and increased levels of proteases are secreted. The combination of these processes result in release of specific protein fragments (e.g. collagens) to the circulation, which when measured may reflect disease pathogenesis. OBJECTIVE: To investigate if biomarkers of protease-degraded collagen could differentiate ovarian and breast cancer patients from healthy controls when measured in serum. METHODS: The levels of markers reflecting MMP-degradation of type I (C1M), type III (C3M) and type IV (C4M, C4M12) …collagen were assessed in serum from ovarian cancer patients (n= 10), breast cancer patients (n= 14) and healthy controls (n= 49) using validated ELISAs. The markers were compared using one way ANOVA and AUC was calculated. RESULTS: All markers were significantly elevated in serum from ovarian cancer patients (p< 0.0001) and breast cancer patients (p< 0.04-0.0001) compared to healthy controls. Furthermore, diagnostically the markers were able to differentiate ovarian (AUROC 90%-93%) and breast cancer patients (AUROC 76%-93%) from healthy controls, with C1M being the strongest differentiator of disease vs. controls. CONCLUSION: Four serum biomarkers reflecting altered MMP-mediated collagen turnover were able to differentiate ovarian and breast cancer patients from healthy controls. Show more

Keywords: Cancer, extracellular matrix, collagen, biomarkers, breast cancer, ovarian cancer, matrix metalloproteinase, degradation, remodeling, tumor microenvironment

DOI: 10.3233/CBM-150520

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 783-788, 2015

Authors: Miyata, Yukinaga | Kumagai, Kenichi | Nagaoka, Tomoko | Kitaura, Kazutaka | Kaneda, Goro | Kanazawa, Hideki | Suzuki, Satsuki | Hamada, Yoshiki | Suzuki, Ryuji

Article Type: Research Article

Abstract: BACKGROUND: Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, and novel effective treatments and diagnostic tools are urgently required. OBJECTIVE: The selection of appropriate targeting tumor-associated antigens (TAAs) is critical for immunotherapy. Therefore, we analyzed TAA expression levels and investigated their relationship with clinical factors in adjacent normal mucosa (ANM) and CRC tissue. METHODS: We obtained specimens of CRC primary tumors and matched ANM from 137 patients with CRC who underwent surgical resection. The mRNA levels of seven TAAs, Wilms' tumor gene (WT1 ), kinetochore associated-2 (KNTC2 ), cell division cycle …associated-1 (CDCA1) , M phase phosphoprotein-1 (MPHOSPH1 ), DEP domain-containing 1 (DEPDC1 ), 34-kDa translocase of the outer mitochondrial membrane (TOMM34 ) and ring finger protein-43 (RNF43 ), were analyzed using quantitative real-time reverse transcription-polymerase chain reaction, and their relationships with clinicopathological factors and the cell cycle were analyzed. RESULTS: The expression levels of all seven TAAs were significantly higher in CRC tissues than in ANM. Expression levels of WT1 in CRC tissues did not correlate with the cell cycle. Furthermore, WT1 expression in CRC tissues was significantly related to tumor progression, lymph node metastasis, distant metastasis and clinical stage. CONCLUSIONS: WT1 is a potential marker for prognosis and tumor progression in CRC. Show more

Keywords: Colorectal cancer, tumor-associated antigens, Wilms' tumor gene

DOI: 10.3233/CBM-150521

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 789-797, 2015

Authors: Wang, Xu-Liang | Wang, Yu-Yong | He, Hua-Dong | Xie, Xi | Yu, Zhi-Jian | Pan, Yu-Ming

Article Type: Research Article

Abstract: BACKGROUND: Adrenomedullin levels in the peripheral blood are associated with prognosis of some cancers. Intermedin is structural similarities to adrenomedullin. OBJECTIVE: The current study aimed to investigate the prognostic value of plasma intermedin levels for progression and distant metastasis in prostate cancers. METHODS: This study included 218 patients undergoing radical prostatectomy for localized prostatic cancer and 218 age-matched healthy men. Plasma intermedin levels were measured using radioimmunoassay. The relationships between plasma intermedin levels and 5-year progression and 5-year distant metastasis were evaluated using a multivariate analysis. RESULTS: Plasma intermedin levels were markedly …higher in all patients than in healthy men. Patients with Gleason score ≥ 7, tumor node metastasis stage T2, organ unconfined, present extra-prostatic extension, seminal vesicle invasion or positive lymph node had higher intermedin levels. Intermedin was identified as a prognostic predictor for 5-year progression and 5-year metastasis. Under receiver operating characteristic curves, intermedin had high predictive values for 5-year progression and 5-year metastasis. CONCLUSIONS: Elevated plasma intermedin levels are independently associated with long-term recurrence and distant metastasis of prostate cancer and intermedin has potential to be a prognostic predictive biomarker for prostate cancer. Show more

Keywords: Prostate cancer, recurrence, metastasis, intermedin

DOI: 10.3233/CBM-150523

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 799-805, 2015

Authors: Li, Hai | Zhou, Xin | Zhu, Jun | Cheng, Wenfang | Zhu, Wei | Shu, Yongqian | Liu, Ping

Article Type: Research Article

Abstract: BACKGROUND: MiR-4728 was recently identified to be related with HER2 in several cell lines and limited tissue samples. OBJECTIVE: To investigate whether miR-4728 could predict HER2 status in a larger cohort. METHODS: The expression of miR-4728-3p and miR-4728-5p was identified in breast cancer (BC) and gastric cancer (GC) tissues with different HER2 status using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH). An additional 22 plasma samples was investigated to explore the potential application of miR-4728 as a non-invasive biomarker in predicting HER2 status. RESULTS: MiR-4728-3p and …miR-4728-5p were significantly up-regulated in HER2-positive patients compared with HER2-negative patients. Compared with the expression in adjacent normal tissues, miR-4728-3p and miR-4728-5p were both elevated in HER2-negative and HER2-positive GC tissues but only miR-4728-3p in HER2-positive BC tissues. Further analyses revealed that miR-4728-3p had greater ability than miR-4728-5p in discriminating subgroups with different intensity of HER2 staining in both BC and GC patients. In addition, miR-4728-3p but not miR-4728-5p was significantly up-regulated in plasma of BC patients with positive HER2. CONCLUSIONS: MiR-4728-3p had better ability in distinguishing patients with different status of HER2 than miR-4728-5p. And plasma miR-4728-3p might act as a non-invasive biomarker in predicting HER2 status. Show more

Keywords: miR-4728, marker, HER2

DOI: 10.3233/CBM-150524

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 807-814, 2015

Authors: Lee, Yu-Ting | Liu, Hsueng-Mei | Lee, Li-Hsuan | Liu, Chia-Jen | Lin, Jeong-Shi | Chao, Ta-Chung | Tzeng, Woan-Fang | Chiou, Tzeon-Jye

Article Type: Research Article

Abstract: BACKGROUND: The polymorphic CAG repeats of the androgen receptor (AR) gene have been suggested to affect the risk of breast cancer, but the results are controversial. In addition, the relationship between patients' CAG genotype and the prognosis has not been investigated. OBJECTIVE: The purpose of this study is to access the association between the polymorphic CAG repeats and the incidence and prognosis of breast cancer. METHODS: One hundred and fifty-six breast cancer cases and 108 healthy controls from Taipei Veteran General Hospital were enrolled. The length of CAG repeats was analyzed among by means …of PCR amplification. The logistic regression model was used for cross-sectional analyses of prevalent breast cancer. Furthermore, we categorized the cases according to the average length of both CAG alleles (CAGn ≥ 23 versus < 23). Outcomes were disease-free survival and mortality. The Cox proportional hazards model and Kaplan-Meier estimate were used for survival analysis. RESULTS: The median age was 56 (51-64) and 46 (37-52) in breast cancer patients and healthy controls, respectively. The median of CAGn was 22.5 (21.5-24) in study group and 23 (21.5-24) in controls. Our study showed the length of CAG repeats did not contribute to breast cancer or benign breast tumors (HR 1.01; 95% CI, 0.90-1.13). In the median follow-up of 6.59 years, we found the CAGn ≥ 23 (n = 75) could be a poor prognosis (adjust HR, 3.08; 95% CI, 1.42-6.67, p = 0.004). CONCLUSION: The CAG polymorphism is not associated with development of breast cancer, but patients with more CAG repeats of the AR gene are prone to poor prognoses. Show more

Keywords: Prognostic factor, CAG repeat, CAG polymorphism, androgen receptor, breast cancer

DOI: 10.3233/CBM-150525

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 815-822, 2015

Authors: He, Qingqing | Peng, Bo | Zhuang, Dayong | Xiao, Lei | Zheng, Luming | Fan, Ziyi | Zhu, Jian | Xu, Benmei | Xu, Cheng | Zhao, Jiangman | Wu, Liming | Zhou, Peng | Hou, Lei | Yu, Fang | Zhao, Guowei

Article Type: Research Article

Abstract: BACKGROUND: The molecular classification of breast cancer mainly focuses on estrogen receptor (ER), Progesterone receptor (PgR), and Human Epidermal Growth Factor Receptor 2(HER2/Neu) status detected by immunohistochemistry (IHC) analysis. The β -tubulin isotype III (TUBB3) gene was thought to be a marker of taxane resistance or cancer aggressiveness. METHODS: To evaluate the clinicopathological significance of TUBB3 expression in breast cancer patients, we measured TUBB3 mRNA levels in 92 breast cancer patients by Quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and examined their correlation with ER, PgR, and HER2 status detected by IHC. RESULTS: We observed …a significant positive correlation between the TUBB3 mRNA expression and the immunohistochemical positivity of both PgR (p= 0.000) and HER2 (p= 0.001). In addition, TUBB3 mRNA expression was associated with lymph nodes status (P= 0.008) and tumor stages (0.029), but no correlation was found with other clinicopathological features, such as age, pathohistological grades and tumor size. CONCLUSIONS: In conclusion, TUBB3 expression correlated significantly with molecular markers of breast cancer, such as PgR and HER2, suggesting that TUBB3 mRNA level facilitate the identification of a subset of patients who respond to Taxane treatment in addition to hormonal therapy and trastuzumab. Show more

Keywords: Breast cancer, ER, PgR, HER2, β -tubulin isotype III

DOI: 10.3233/CBM-150526

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 823-831, 2015

Authors: Chen, Guo-Hui | Xue, Qian-Qian | Li, Jun | Gao, Tian-Le | Sun, Qing-Shun | Bai, Guang-Ping

Article Type: Research Article

Abstract: AIMS: To clone and express Siva1 protein, and to investigate the role of Siva1 protein in proliferation, apoptosis, invasion, and migration of human nasopharyngeal carcinoma cell line CNE-2 in vitro and in vivo . METHODS: The PCR fragment of Siva1 from human nasopharyngeal carcinoma cell line CNE-2 were double digested with BamHI and SalI and then induced into the pQE30 vector double digested by the same enzymes. The pQE30 vector harboring Siva1 was introduced into M15 competent cells and then induced by isopropyl β -D-1-thiogalactopyranoside (IPTG). The Siva1 fusion protein was identified by 12% sodium …dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and then separated and purified by Ni-affinity chromatography. Subsequently, the effects of recombinant Siva1 protein on proliferation, apoptosis, invasion and migration were assayed in vitro and in vivo . RESULTS: The transformed cells expressed Siva1 fusion protein with a molecular weight of approximately 12 kDa. Cell counting kit-8 (CCK-8) assay showed that the Siva1 protein significantly inhibited the proliferation of the CNE-2 cells at a concentration of 10 μ mol/L. In addition, compared to the control, the Siva1 protein promoted the apoptosis of the cancer cells. And, the Siva1 protein greatly suppressed the invasion and migration of the cancer cells. In vivo , the Siva1 protein significantly inhibited the tumor growth of the tumor-bearing mice. Further, the Siva1 treatment markedly upregulated Bax, caspase-3, and downregulated Bcl-2 protein levels in the transplanted tumor tissue. CONCLUSIONS: The Siva1 protein has a significant anticancer activity on human nasopharyngeal carcinoma cell line CNE-2 including inhibiting proliferation, invasion, migration and promoting apoptosis of the cancer cells. Show more

Keywords: Siva1, nasopharyngeal carcinoma, proliferation, invasion, migration

DOI: 10.3233/CBM-150527

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 833-841, 2015

Authors: Aravantinos, G. | Isaakidou, A. | Karantanos, T. | Sioziou, A. | Theodoropoulos, G.E. | Pektasides, D. | Gazouli, M.

Article Type: Research Article

Abstract: BACKGROUND: Bevacizumab, an angiogenesis inhibitor is used in regimens for metastatic colorectal cancer (CRC). A minority of cancer cells with characteristics of cancer stem cells (CSC) may be responsible for progression and development of chemotherapy resistance in this disease. CD133 is a well-known CSC marker and is associated with angiogenesis, poor prognosis and resistance to chemotherapy. OBJECTIVE: The purpose of our study was to evaluate the association between the rs3130 and rs2286455 polymorphisms of the CD133 gene and the response, toxicity, and overall survival of patients with CRC on bevacizumab-based treatment. METHODS: Forty-three patients …receiving bevacizumab, irinotecan and capecitabine and 15 patients receiving bevacizumab, irinotecan and 5-FU were included. Efficacy and toxicity were evaluated. KRAS mutation analysis and rs3130 and rs2286455 polymorphisms genotyping in the tumors and peripheral blood respectively were performed with PCR-RFLP. RESULTS: No association between KRAS mutated alleles and response was found. The rs3130 CC genotype was associated with reduced toxicity of treatments (p= 0.0017), and with lower overall survival on bevacizumab (p= 0.002). CONCLUSIONS: The CC genotype of rs3130 polymorphism in the CD133 gene can predict poorer overall survival in patients with metastatic CRC on bevacizumab which cannot be attributed to increased treatment toxicity. Show more

Keywords: Colorectal cancer, bevacizumab, CD133 polymorphisms

DOI: 10.3233/CBM-150528

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 843-850, 2015

Authors: Ayremlou, Nooshin | Mozdarani, Hossein | Mowla, Seyed Javad | Delavari, Alireza

Article Type: Research Article

Abstract: BACKGROUND: MicroRNAs can function as oncogenes and tumor suppressor genes in human cancers. The expression of miR-107 is high in various types of solid tumors. OBJECTIVE: The aim of this study was to evaluate the tumor and serum level of miR-107 and its correlation to HIF-1α expression in gastric cancer patients. METHODS: Quantitative real-time PCR was used to analyze the expression of miR-107 and HIF-1α in 36 pairs of fresh gastric cancer and matched adjacent normal tissue specimens and the serum of these patients compared to age matched controls. RESULTS: …The expression level of miR-107 was significantly higher in tumor tissues compared to adjacent normal tissue (p= 0.04). For serum, the expression level of miR-107 was significantly higher in gastric cancer patients than in age matched controls (p= 0.04). The correlation between tumor and serum expression of miR-107 with tumor hypoxia was found to be significant (p≤ 0.001). CONCLUSION: The overexpression of miR-107 in tumors and serum of gastric cancer patients and its correlation with HIF-1α expression in tumor tissues was indicated that miR-107 may have a potential to use as a biomarker for detection of gastric cancer patients and hypoxia in gastric cancer tumor. Show more

Keywords: Gastric cancer, miR-107, hypoxia

DOI: 10.3233/CBM-150529

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 851-860, 2015

Authors: Askeland, Eric J. | Chehval, Vincent A. | Askeland, Ryan W. | Fosso, Placede G. | Sangale, Zaina | Xu, Nafei | Rajamani, Saradha | Stone, Steven | Brown, James A.

Article Type: Research Article

Abstract: BACKGROUND: The outcome of surgically resected, apparently localized, clear cell renal carcinoma (ccRCC) is uncertain. OBJECTIVE: To evaluate if cell cycle progression (CCP) gene expression can predict future metastasis. METHODS: Pathologic T2a-T3b tumors at University of Iowa were reviewed. Patients with known or suspected metastasis, lymph node involvement or who received neoadjuvant or adjuvant radiation, chemotherapy or immunotherapy were excluded. Case and control cohorts were defined as those who did or did not develop metastatic disease within 5 years. Measured levels of 31 cell cycle genes and 15 control genes from the tumor …were calculated as a CCP score. Additionally, gene expression data for a separate ccRCC cohort was downloaded from The Cancer Genome Atlas (TCGA). RESULTS: Univariate analysis of 26 cases and 38 controls revealed that the CCP score predicted progression to metastasis (OR 2.65, p = 0.0091). In multivariate logistic regression modeling, CCP expression remained a significant independent predictor for progression (p = 0.026). The CCP score was also significantly associated with distant metastasis in the TCGA renal cancer cohort in both univariate (p = 1.0 × 10-9 ) and multivariate (p = 5.6 × 10-3 ) analysis. CONCLUSION: The CCP score has prognostic value in predicting metastatic progression after resection of organ-confined ccRCC. Show more

Keywords: Clear cell renal cell carcinoma, kidney cancer, metastasis, biological markers

DOI: 10.3233/CBM-150530

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 861-867, 2015

Authors: Amara, Sameh | Chaar, Ines | Khiari, Meriem | Ounissi, Donia | Weslati, Marwa | Boughriba, Rahma | Hmida, Abdelmajid B. | Bouraoui, Saadia

Article Type: Research Article

Abstract: BACKGROUND: Recent studies suggest that SDF-1 and CXCR4 are expressed in certain cancer cells, and malignant cells use this chemokine/receptor system to promote tumor progression and metastasis. However, the pathophysiological significance of their expression in colorectal cancer (CRC) tissue has not been fully elucidated. OBJECTIVE: The purpose of this study was to assess SDF-1/CXCR4 expression and to explore its contribution to colorectal cancer. METHODS: We examined SDF-1 and CXCR4 mRNA expression in 124 primary colorectal tumour and 35 liver metastases tissues and matched adjacent noncancerous tissues by reverse transcriptase PCR (RT-PCR). Furthermore, their …expression was analyzed by immunohistochemistry. The relationship between SDF-1/CXCR4 expression and clinicopathological features were analyzed by appropriate statistics. X2 test and Kaplan-Meier analysis were used to investigate the correlation between the ligand-receptor expression and prognosis of colorectal cancer patients. RESULTS: The relative mRNA expression of SDF-1 and CXCR4 was significantly elevated in colorectal cancer tissues as compared with adjacent noncancerous tissues (P < 0.001). The high expression of proteins expression in colorectal cancer tissues was significantly correlated with tumor grade (P = 0.0001), clinical stage (P < 0.05), and lymphatic invasion (P < 0.05). Furthermore, patients with CXCR4 nuclear-type expression showed more frequent lymph node metastasis (p = 0.021), advanced clinical stage (p = 0.001) and lymphatic invasion (p = 0.03) than those with cytoplasm staining-type. Kaplan-Meier survival analysis revealed that high expression of the couple SDF-1/CXCR4 correlated with poor prognosis of colorectal cancer patients (P < 0.001). CONCLUSION: SDF-1 and CXCR4 may play an important role in the progression of colorectal cancer. The present data suggest that there is a significant association between SDF-1/CXCR4 to enhance the liver metastases causing poor prognosis. Those proteins may potentially be used as an independent biomarker for the prognostic evaluation of colon cancer in the Tunisian cohort. Show more

Keywords: Colorectal cancer, chemokineschemokines receptor, liver metastases

DOI: 10.3233/CBM-150531

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 869-879, 2015

Authors: Li, Yongqing | Xu, Yadong | Yu, Chundong | Zuo, Wenshu

Article Type: Research Article

Abstract: BACKGROUND: MicroRNAs (miRNA) expression profiles might be useful novel biomarkers for tumor diagnostic and histological characterization. OBJECTIVE: Associations of miR-146 expression and breast cancer in very young women needed to be elucidated. METHODS: We investigated expressions of miR-146a, miR-146b and IL-6 in tissues between 120 young women with primary breast cancer and 130 patients with breast fibroadenoma by RT-PCR. The associations between the expression of miR-146, IL-6 and clinical parameters of breast cancer were analyzed. RESULTS: Levels of miR-146a and miR-146b in breast cancer tissues were lower while level of …IL-6 was higher compared to the fibroadenoma tissues and pericancerous breast tissues (P< 0.05). Positive associations were found between levels of miR-146a/b and IL-6 in breast cancer tissues and ER-PgR-, HER2/neu -, Ki-67 index ≥ 20%, tumor size > 2 cm, positive distant metastasis and lymph node metastasis, advanced clinical TNM stages (III-IV) and basal-like phenotype (P< 0.05). CONCLUSION: Down-regulations of miR-146a and miR-146b expression in breast tissues were related to development and deterioration of breast cancer. miR-146a and miR-146b might act as potential biomarkers for young women with breast cancer. Show more

Keywords: Breast cancer, miR-146a, miR-146b, RT-PCR

DOI: 10.3233/CBM-150532

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 881-887, 2015

Authors: Zheng, Chen-Guo | Chen, Rong | Xie, Jie-Bin | Liu, Chang-Bao | Jin, Zhao | Jin, Chun

Article Type: Research Article

Abstract: BACKGROUND: Activation of Notch and NF-κB signaling has been frequently observed in colorectal cancer (CRC) patients and contributes to the chemo-resistance and treatment failure. However, the relationship between these signaling pathways and CRC has not been clearly described. OBJECTIVE: To investigate the expression of Notch1, Jagged1, NF-κB and MMP-9 in CRC patients and analyze their correlation with clinicopathological factors. METHODS: Expression of Notch1, Jagged1, NF-κB and MMP-9 was visualized by immune-histology in the tumor tissue, adjacent and distant normal tissues from 47 CRC patients without receiving chemotherapy or radiotherapy. RESULTS: …Notch1 (80.8%), Jagged1 (80.8%), NF-κB (70.2%) and MMP-9 (76.6%) were overexpressed in cancer tissues compared normal tissues (P< 0.05). The intensity of Notch1, Jagged1 and NF-κB expression was associated with histological grading, depth of invasion, TNM staging and lymph node metastasis of CRC. MMP-9 was intimately correlated with depth of invasion, TNM staging and lymph node metastasis. NF-κB, MMP-9 and Notch1 expression was positively correlated (P< 0.05), and the same positive correlation was found among NF-κB, MMP-9 and Jagged1 expression (P< 0.05). CONCLUSION: Notch1, Jagged1, NF-κB and MMP-9 probably play a pivotal role during the CRC development, serving as biomarkers for early detection of the recurrence and metastasis and prognosis of CRC. Show more

Keywords: Colorectal cancer, notch, jagged, NF-κB, MMP-9

DOI: 10.3233/CBM-150533

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 889-897, 2015

Authors: Lian, Lian | Xia, You-You | Zhou, Chong | Shen, Xiao-Ming | Li, Xiang-Li | Han, Shu-Guang | Zheng, Yan | Mao, Zhong-Qi | Gong, Fei-Ran | Wu, Meng-Yao | Chen, Kai | Tao, Min | Li, Wei

Article Type: Research Article

Abstract: BACKGROUND: Gastric cancer is the fourth most frequent cancer and the second cause of cancer-related deaths worldwide. China has a high incidence of gastric cancer. Inflammation is a critical component of tumor progression. It has been widely accepted that gastric cancer is an inflammation-driven cancer. In this study, we investigated the application value of systemic inflammatory response (SIR) markers, platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR), in early diagnosis and prognostic prediction in patients with resectable gastric cancer. MATERIALS AND METHODS: One hundred and sixty-two patients with resectable gastric cancer were included …and separated into groups according to median pre-operative PLR or NLR values (PLR low: < 208 or PLR high: ≥ 208, and NLR low: < 4.02 or NLR high: ≥ 4.02, respectively). To evaluate the changes in PLR or NLR values after operation, we introduced the concept of postpre-operative PLR or NLR ratios (< 1 indicated PLR or NLR values were decreased after operation, while ≥ 1 suggested not decreased PLR or NLR values). RESULTS: Pre-operative PLR and NLR levels were significantly higher in gastric cancer patients compared with the healthy subjects. Low pre-operative PLR and NLR levels correlated with better clinicopathological features, including decreased depth of invasion, less lymph node metastasis and early tumor stage. Kaplan-Meier plots illustrated that higher pre-operative NLR and PLR had decreased overall survival (OS) and disease-free survival (DFS). Surgical tumor resection resulted in a significant CONCLUSIONS: PLR and NLR measurements can provide important diagnostic and prognostic results in patients with resectable gastric cancer. Show more

Keywords: Gastric cancer, platelet to lymphocyte ratio (PLR), neutrophil to lymphocyte ratio (NLR)

DOI: 10.3233/CBM-150534

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 899-907, 2015

Authors: Zhu, Hong | Peng, Yi-Gen | Ma, Shao-Gang | Liu, Hong

Article Type: Case Report

Abstract: BACKGROUND: The thyroperoxidase (TPO ) genetic variants in thyroid carcinoma is scarcely reported. OBJECTIVE: We report on a pedigree of thyroid papillary carcinoma and hypoechoic thyroid nodules with the TPO gene mutations. METHODS: The compound heterozygotic mutations of the TPO gene (c.2268-2269 insT and c.2090 G>A) in two patients with congenital goiters hypothyroidism were demonstrated. Fifteen family members of the proband and 105 control individuals were enrolled. The participants underwent clinical examination and molecular screening for TPO mutation. The hypoechoic thyroid nodules underwent fine needle aspiration biopsy. RESULTS: The …mutation c.2268-2269 insT was detected in the four family members with normal thyroid hormone levels. The other two members harbored the c.2090 G>A mutation. The heterozygotes had degeneratively hypoechoic thyroid nodules. The control individuals showed no mutation. The maternal grandfather developed a multifocal papillary thyroid carcinoma with lymph gland and nerve invasion in the left lobe of the thyroid gland. The maternal grandfather harbored the TPO c.2268-2269 insT mutation but without BRAF V600E mutation. Malignant cells were not observed in other members by fine needle aspiration biopsy. CONCLUSION: TPO genetic variants may be associated with thyroid carcinoma and hypoechoic thyroid nodules in a few cases. Long-term follow-up in the pedigree with congenital goiter is reasonable. Show more

Keywords: Papillary thyroid carcinoma, thyroperoxidase, mutation

DOI: 10.3233/CBM-150522

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 909-913, 2015

Article Type: Other

DOI: 10.3233/CBM-150556

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 915-920, 2015

Article Type: Other

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 921-931, 2015