Cancer Biomarkers - Volume 16, issue 3

Authors: Shaikh, Muhammad Vaseem | Kala, Manika | Nivsarkar, Manish

Article Type: Review Article

Abstract: Cancer Stem Cells (CSCs) have been recently identified and their role in carcinogenesis has been ascertained. CSCs have been correlated with high relapse in certain cancers, multiple drug resistance against chemotherapy and metastasis. Several markers such as CD133, CD24, CD44, EpCAM, and CD26 have been identified to isolate and characterize CSCs. None of these markers or their combinations are universal in nature and can be used to isolate CSCs from all types of cancer. CD90 is one such marker whose expression has been extensively studied in recent years. CD90+ cells have been isolated from several types of tumors and shown …to exhibit cardinal properties of CSCs such as proliferation, differentiation, spheroid formation, metastasis and ability to form tumor xenograft in immunodeficient mice. It is also found to be co-expressed with several other CSC markers. CD90 is therefore, suggested as a candidate marker as well as a potential therapeutic target for elimination of CSCs. Show more

Keywords: Tumors, cancer stem cells, cancer stem cell markers, CD90, THY1

DOI: 10.3233/CBM-160590

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 301-307, 2016

Authors: Gu, Jian-Jun | Gao, Guang-Zhong | Zhang, Shi-Ming

Article Type: Research Article

Abstract: BACKGROUND: Malignant glioma is the most common primary brain tumors directly correlated with the high mortality and poor prognosis in clinical practice. MicroRNAs (miRNAs or miRs) influence numerous cancer-relevant processes including cell proliferation, differentiation and metabolism. However, the role of microRNA in malignant glioma is largely unknown. This study aimed to study the role of miR-218, a tumor-suppressive microRNA, in glioma development both in vivo and in vitro . METHODS: The expression level of miR-218, Slit2 and Robo1 was examined by either quantitative (polymerase chain reaction) or western-blotting from both human glioma tissue and glioma …cell lines. U87 cells were transfected with miR-218 and then the expression levels of Slit2 and Robo1 were quantified. Cell proliferation was measured both by the in vitro proliferation assay and in vivo graft studies. The luciferase reporter assay was employed to validate the downstream target of miR-218. RESULTS: The expression of miR-218 was lower in glioma cell lines and glioma tissues from the patients with decreased Slit2 and increased Robo1 protein levels. The over-expression of miR-218 inhibited the tumorgenesis and proliferation of glioma cells remarkably. Furthermore, the over-expressing miR-218 in glioma cells results in the downregulation of Robo1 and upregulation of Slit2. Using luciferase reporter assays, we found that Robo1 was a direct downstream target of miR-218. CONCLUSION: Over-expression of miR-218 in glioma cells may inhibit the proliferation and tumorigenicity through targeting Robo1, suggesting that miR-218 could be a potential target for developing therapies in treating glioma. Show more

Keywords: miR-218, gliomas, proliferation, tumorgenesis, Slit2, Robo1

DOI: 10.3233/CBM-160568

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 309-317, 2016

Authors: Faryal, R. | Ishfaq, M. | Hayat, T. | Mahjabeen, I. | Kayani, M.A.

Article Type: Research Article

Abstract: BACKGROUND: Spleen Tyrosine Kinase (SYK) belongs to non-receptor tyrosine Kinase family, which normally expresses in epithelial breast tissues and acts as a tumor suppressor gene. OBJECTIVE: Analysis of mutations in the SYK gene and deregulation of SYK transcripts by miRNA in breast cancer was studied. METHODS: All exons and exon/intron boundaries of SYK gene were amplified and sequenced in blood samples of 207 breast cancer cases and 200 matched controls using PCR-single stranded conformational polymorphism method. RESULTS: Sequence analysis revealed 10 novel mutations in breast cancer patients. …Among these 6 mutations (Ala 161Pro, His162Tyr, Phe191Tyr, Val 535Gly, Ser 556lIe and Lys536Gln) were found in exonic region and 4 (26249 T>A, 63941 G>A, 63981G>C and 86548T>A) were found in intronic region. All of these mutations are associated with ∼ 5 folds (p< 0.0001) increase in breast cancer risk in present study cohort. Regulation of SYK transcripts by miRNA was also analyzed using in silico bioinformatics tools, exon 6's mutation (Phe191Tyr) was found to have altered interaction with miR-873. CONCLUSION: Overall novel mutations in SYK gene and in silico analysis revealed that these mutations are crucial and might be responsible for altered expression of SYK. Show more

Keywords: SYK gene, spleen tyrosine kinase, mutations, microRNA, breast cancer

DOI: 10.3233/CBM-160569

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 319-326, 2016

Authors: Cao, Changjun | Wang, Wei | Jiang, Pucha

Article Type: Research Article

Abstract: BACKGROUND: Medulloblastoma is one the most malignant paediatric brain tumours. Molecular subgrouping these medulloblastomas will not only help identify specific cohorts for certain treatment but also improve confidence in prognostic prediction. OBJECTIVE: Currently, there is a consensus of the existences of four distinct subtypes of medulloblastoma. We proposed a novel bioinformatics method, clustering of self-organizing map, to determine the subgroups and their molecular diversity. METHODS: Microarray expression profiles of 46 medulloblastoma samples were analysed and five clusters with distinct demographics, clinical outcome and transcriptional profiles were identified. RESULTS: The previously …reported Wnt subgroup was identified as expected. Three other novel subgroups were proposed for later investigation. CONCLUSIONS: Our findings underscore the value of SOM clustering for discovering the medulloblastoma subgroups. When the suggested subdivision has been confirmed in large cohorts, this method should serve as a part of routine classification of clinical samples. Show more

Keywords: Medulloblastoma, subgroup, gene expression, self-organizing map

DOI: 10.3233/CBM-160570

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 327-332, 2016

Authors: Li, Yanyan | Liu, Xiaoxiao | Zhang, Jing | Yao, Weiqiang

Article Type: Research Article

Abstract: BACKGROUND: Systemic inflammation has been implicated in cancer development and progression. The aim of the present study was to evaluate whether pre-operative systemic inflammatory markers can predict outcomes in bone and soft tissue sarcomas. METHODS: Relevant literature was mainly identified using Pubmed, EMBASE and CNKI. Patients' clinical characteristics, overall survival (OS), disease/relapse free survival (DFS/RFS) with high-level CRP or neutrophils to lymphocytes ratio (NLR) were extracted. The statistics extracted from Kaplan-Meier survival curves with log-rank p value were calculated with methods developed by Parmar, Williamson, and Tierney; multivariate Cox hazard regression analysis data were used directly …in STATA 10.0. Pooled hazard ratio (HR) and 95% CI were calculated to evaluate the prognostic role of these systemic inflammatory markers (CRP/NLR). RESULTS: After full text review, 11 articles containing 1809 patients were identified as eligible articles. The meta-analysis for survival outcome showed significant prognostic value of systemic inflammatory markers including CRP and NLR in pre-operative blood. The combined HRs (95% CI) for five year overall survival (OS) and disease/recurrence free survival (DFS/RFS) were 2.54 [2.04, 3.16] and 2.28 [1.72, 3.04]. Specifically, higher NLR was associated with decreased 5-year OS (HR 3.75, 95% CI 1.24 to 11.37) and 3 year RFS/DFS (HR 2.43, 95% CI 0.84 to 7.05). Besides, the pooled HR showed a higher risk of 5-year disease progression (HR 2.55, 95% CI 1.60 to 4.08, I2 = 52%) and lower 5-year OS (HR 2.50, 95% CI 2.00 to 3.12, I2 = 0%) in sarcoma patients with high CRP level. We then grouped the meta-analysis by patient source (Asian and non-Asian), tumor stage (I/II or III/IV) and grade (high or low), respectively. All the subgroup analysis showed significant prognostic role in survival condition. The CRP/NLR levels are also found closely related with patient age, tumor stage and size. CONCLUSION: Higher level of pre-operative CRP and NLR demonstrated a significantly higher risk of recurrence and overall decreased survival rates in sarcomas. Show more

Keywords: CRP, prognostic factor, sarcoma, meta-analysis

DOI: 10.3233/CBM-160571

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 333-342, 2016

Authors: Sankiewicz, Anna | Guszcz, Tomasz | Mena-Hortelano, Rocio | Zukowski, Krzysztof | Gorodkiewicz, Ewa

Article Type: Research Article

Abstract: BACKGROUND: Podoplanin (PDP) is a mucin - a type of transmembrane protein expressed in numerous tissues during ontogeny and in adult animals, including the brain, heart, kidney, osteoblasts and lymphoid organs. OBJECTIVE: The aim of this study was to determine podoplanin concentration in the blood serum and urine of patients with bladder cancer. Quantifying podoplanin concentration and its correlation with various clinicopathological parameters may be useful for more accurate predictions and identifying high-risk patients. METHODS: The present study included 82 patients with bladder cancer confirmed by transurethral resection or cystectomy and 27 healthy …volunteers. The Surface Plasmon Resonance Imaging biosensor was applied for the detection of podoplanin in the serum and urine samples. RESULTS: Significant differences in serum and urine podoplanin concentration levels were observed between bladder cancer patients. The statistically significant higher values of PDP were detected in serum of patients with invasive, more aggressive, larger, multifocal tumors. CONCLUSIONS: The association between podoplanin concentration and clinicopathological features indicates that it might be useful while making therapeutic decisions. Show more

Keywords: Podoplanin, bladder cancer, surface plasmon resonance imaging biosensor, transitional cell carcinoma

DOI: 10.3233/CBM-160572

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 343-350, 2016

Authors: Mao, Yunhua | Li, Ke | Lu, Li | Si-tu, Jie | Lu, Minhua | Gao, Xin

Article Type: Research Article

Abstract: OBJECTIVES: This study was aimed to explore Cdc20 expression and its correlation with clinicopathological characteristics and biochemical recurrence (BCR) after laparoscopic radical prostatectomy (LRP) in clinically localized prostate cancer (PCa). METHODS: Cdc20 expression was examined by immunohistochemistry in 166 cases, including 60 cases of benign hyperplasia of prostate (BPH) patients treated by transurethral resection and 106 cases of consecutive PCa patients treated by LRP without neoadjuvant therapy in a single Chinese institution. The correlation with clinicopathological features and the predictive value for BCR were statistically analyzed. RESULTS: Cdc20 expression was detected in 52 …(86.7%) BPH and 97 (91.5%) PCa samples, which was statistically insignificant (P= 0.323). The rate of patients with high expression of Cdc20 was 21.7% in BPH and 37.7% in PCa (P= 0.033). A correlation was revealed between Cdc20 expression and postoperative Gleason scores (P= 0.046), positive surgical margin (P< 0.001). BCR-free survival was significantly lower in patients with high Cdc20 expression than those with low Cdc20 expression (P= 0.018). Univariate analysis indicated pTstage, post operative Gleason score, seminal vesicle invasion, lymph node invasion, surgical margin and Cdc20 expression significantly influenced BCR. Multivariate analysis revealed that postoperative Gleason score, seminal vesicle invasion, lymph node invasion, surgical margin and Cdc20 expression were independent predictors for BCR. After stratified by Gleason score and surgical margin status, Cdc20 expression and lymph node invasion remained significant in Cox regression analysis. CONCLUSIONS: Overexpression of Cdc20 may serve as an independent predictor for BCR in patients of clinically localized PCa undergoing LRP without neoadjuvant therapy. Show more

Keywords: Prostatic neoplasms, cell division cycle 20, biochemical recurrence, radical prostatectomy

DOI: 10.3233/CBM-160573

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 351-358, 2016

Authors: Zhang, Jinkun | Shi, Huihai | Xue, Mei | Yu, Qiang | Yang, Liu | Zheng, Shudan | Zhou, Chunxiao

Article Type: Research Article

Abstract: OBJECTIVE: The aim of the study was to evaluate whether the insertion/deletion polymorphism (rs3783553) locating in the 3' untranslated region (3'UTRs) of IL-1A was related to the risk of gastric cancer (GC) in a Chinese population and explore the possible molecular mechanism. METHODS: Genomic DNA was extracted from peripheral venous blood of 519 GC patients and 536 healthy control individuals. The IL-1A rs3783553 polymorphism was genotyped by using a polymerase chain reaction assay. The vectors containing the insertion or deletion allele were constructed, and luciferase assay was used to detect the effect of the …polymorphism on the transcriptional activity of IL-1A . RESULTS: Strong evidence of association was observed between the IL-1A rs3783553 polymorphism and susceptibility to GC in the study. In addition, the `TTCA' insertion allele of rs3783553 disrupts the binding site for miR-122 and miR-378, thereby increasing transcription of IL-1α in vitro. CONCLUSION: These findings suggest that functional polymorphism rs3783553 in IL-1A could contribute to GC susceptibility, possibly or at least partially through affecting the transcriptional activity of IL-1A . Show more

Keywords: Insertion/deletion polymorphism, rs3783553, interleukin-1A, gastric cancer

DOI: 10.3233/CBM-160574

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 359-365, 2016

Authors: Nouraee, Nazila | Khazaei, Samaneh | Vasei, Mohammad | Razavipour, Seyedeh Fatemeh | Sadeghizadeh, Majid | Mowla, Seyed Javad

Article Type: Research Article

Abstract: BACKGROUND: miRNAs have recently been implicated in tumor's microenvironment remodeling and tumor-stromal cells interactions. We have previously reported a signaling role for miR-21, as a secretory molecule released by cancer associated fibroblasts (CAF) adjacent to esophagus tumor cells. OBJECTIVE: To discover other potential signaling miRNAs, we employed a co-culture system of esophageal cancer cell line and normal fibroblasts to mimic the tumor microenvironment. METHODS: We measured the expression profile of secretory miRNAs in the conditioned media (CM) of our co-culture system using a panel PCR array. We used pathway enrichment analysis to define …potential pathways regulated by these miRNAs. Then using ultracentrifugation, we purified exosomes secreted to the CM of co-cultured cell lines and evaluated exosomal secretion of these miRNAs. RESULTS: We found 18 miRNAs which were significantly up/down-regulated in the CM of co-culture system. Pathways related to cell adhesion, endocytosis and cell junctions were among the enriched pathways that might be related to CAF phenotype and tumor progression. Moreover, we detected higher exosomal levels of miR-33a and miR-326 in the purified exosomes both in co-cultured and untreated CM. So, these miRNAs are mainly secreted into the CM by means of exosomes. CONCLUSIONS: Briefly, our data shed more light on the role of CAFs through secretion of miRNAs within tumor microenvironment and propose novel therapeutic targets for esophageal and probably other cancer types. Show more

Keywords: Esophageal cancer, secretory microRNA, profiling, tumor microenvironment, stroma, exosome, cancer associated fibroblasts

DOI: 10.3233/CBM-160575

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 367-376, 2016

Authors: Al-Amri, Ali M. | Vatte, Chittibabu | Cyrus, Cyril | Chathoth, Shahanas | Hashim, Tariq Mohammad | Mohamed, Yehia S. | Ali, Rudaynah Al | Alsaid, Abir | Ali, Amein Al

Article Type: Research Article

Abstract: BACKGROUND: HNSCC is the sixth most common human cancer globally. In Saudi Arabia, HNSCC accounts for seven percent of all newly diagnosed cancer cases. The PIK3CA is one of the most commonly mutated oncogene in human malignancies, including HNSCC. OBJECTIVE: The objective of this study is to identify mutations in exon 9 and exon 20 of the PIK3CA gene among Saudi HNSCC patients, determine the frequency of these mutations and correlate with clinical and pathological findings. METHODS: Histopathologically confirmed paraffin embedded HNSCC tumor tissues from 48 patients were obtained. Capillary sequencing method was …used to sequence exons 9 and 20 of the PIK3CA gene. Concurrently, the expression analysis of the PIK3CA and PTEN genes were performed using real-time PCR. RESULTS: Sixty percent of the samples studied were of pharyngeal cancer. A total of seven mutations were identified in exons 9 and 20 of the PIK3CA gene in 14 HNSCC tumor tissue specimens. The seven mutations encompassed one hot spot mutation E542K, a common mutation T1025T and the five novel mutation comprising three missense and two silent mutations. Interestingly, eight out of the 14 samples with a mutation were of patients with pharyngeal cancer. CONCLUSION: PIK3CA gene plays a crucial role in carcinogenesis in general and HNSCC in particular. The identification of five novel mutations suggest that Saudis may have different frequencies of somatic genetic alterations that may influence HNSCC compared to other populations. Show more

Keywords: HNSCC, pharyngeal cancer, PIK3CA, mutation, PTEN, gene expression

DOI: 10.3233/CBM-160576

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 377-383, 2016

Authors: Petrović, Nina | Kolaković, Ana | Stanković, Aleksandra | Lukić, Silvana | Řami, Ahmad | ivković, Maja | Mandušić, Vesna

Article Type: Research Article

Abstract: BACKGROUND: Breast carcinoma is heterogeneous disease. Understanding the process of invasion and metastasis and the selection of the therapy for patients with breast carcinomas still remains difficult. MicroRNAs are powerful gene expression regulators. Because of inconsistent findings, we have analyzed potential difference in miR-155 levels in three breast cancer groups. OBJECTIVES: Our goals were to examine miR-155 expression levels in normal tissue, non-invasive and invasive breast carcinomas, and their association with standard clinical and pathological parameters and oncomiR-21, and to investigate the ability of miR-155 to separate invasive breast carcinomas with non-invasive component from pure invasive. …METHODS: In the group of 40 breast tissue samples, relative expression levels of miR-155 were examined with stem-loop quantitative real-time PCR using TaqMan technology. RESULTS: The significant difference among four examined groups of the breast tissue was detected (p = 0.001). In the group of pure invasive tumors, patients with positive nodal status had significantly higher miR-155 levels (p = 0.046). CONCLUSION: Our results suggest that miR-155 might be involved in breast cancer pathogenesis and in tumor spreading to the lymph nodes, and that it might be used as biomarker for additional stratification of patients with invasive breast carcinomas with non-invasive component. Show more

Keywords: miR-155, , breast cancer, , microRNA expression levels

DOI: 10.3233/CBM-160577

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 385-394, 2016

Authors: Gu, Xi | Xue, Jin-Qi | Han, Si-Jia | Qian, Song-Ying | Zhang, Wen-Hai

Article Type: Research Article

Abstract: OBJECTIVE: We aimed to explore the potential application of circulating microRNA-451 (miR-451) in serum in predicting the resistance to neoadjuvant chemotherapy (NACT) in breast cancer (BC). METHODS: Eighty-two BC patients who underwent NACT were recruited in our study, including 41 NACT-sensitive patients (NACT-sensitive group) and 41 NACT-resistant patients (NACT-resistant group). Additionally, 60 healthy subjects were selected as normal controls. Epirubicin-resistant MCF-7 BC cell line (MCF-7/EPI) and docetaxel-resistant MCF-7 BC cell line (MCF-7/DOC) were cultured in our study. MTT assay was applied to calculate the survival rates of MCF-7 cells, MCF-7/DOC cells and MCF-7/EPI cells. The expression …levels of miR-451 in normal controls, NACT-sensitive group, NACT-resistant group, MCF-7 cells, MCF-7/DOC cells and MCF-7/EPI cells were measured by qRT-PCR method. RESULTS: The proliferation rates of both the MCF-7/DOC and MCF-7/EPI cells were significantly restrained at the drug concentration of 10 ng/ml, 50 ng/ml, 100 ng/ml and 200 ng/ml. However, the proliferation rates of MCF-7/DOC and MCF-7/EPI cells both increased significantly at the drug concentration of 500ng/ml. Furthermore, the IC50 of MCF-7/DOC cells was 23.603 ng/ml and the IC50 of MCF-7/EPI cells was 3.209 ng/ml. The relative expression of miR-451 was significantly lower in both the NACT-resistant group and the NACT-sensitive group than the normal control group. We also found that the relative expression level of miR-451 was significantly lower in the NACT-resistant group than that in the NACT-sensitive group. The expression of miR-451 in the MCF-7/EPI and the MCF-7/DOC cell lines was significantly lower than that in the MCF-7 cell lines. CONCLUSION: We supported the view that the relative expression level of miR-451 was lower in the NACT-resistant BC patients, suggesting the circulating miR-451 may have a functional significance in predicting the resistance to NACT in BC patients. We laid a foundation for further research on the resistance to NACT in BC treatment. Show more

Keywords: Breast cancer, microRNA-451, neoadjuvant chemotherapy, drug tolerance, circulating serum level, epirubicin-resistant MCF-7 cell line, docetaxel-resistant MCF-7 cell line

DOI: 10.3233/CBM-160578

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 395-403, 2016

Authors: Xie, Bin-Hui | He, Xiao | Hua, Rui-Xi | Zhang, Bing | Tan, Guo-Sheng | Xiong, Shi-Qiu | Liu, Liang-Shuai | Chen, Wei | Yang, Jian-Yong | Wang, Xiao-Nong | Li, He-Ping

Article Type: Research Article

Abstract: microRNAs (miRNAs) dysregulation is widely involved in cancer progression and contributed to sustained cell proliferation by directly targeting multiple targets. Therefore, better understanding the underlying mechanism of miRNA in carcinogenesis may improve diagnostic and therapeutic strategies for malignancy. In our study, we found that mir-765 is upregulated in both hepatocellular carcinoma (HCC) cell lines and tissues, compared to human normal liver cell line and adjacent non-cancerous tissues, respectively. Overexpression of mir-765 increased HCC cells proliferation and tumorigenicity, whereas inhibition of mir-765 reverses this effect. Furthermore, we demonstrated that INPP4B as a direct target of mir-765 and ectopic expression of mir-765 …repressed INPP4B expression, resulting in upregulation of p-AKT, Cyclin D1, and downregulation of p-FOXO3a, p21 expression in HCC. Strikingly, we found that silencing the expression of INPP4B is the essential biological function of miR-765 during HCC cell proliferation. Collectively, our findings reveal that miR-765 is a potential onco-miR that participates in carcinogenesis of human HCC by suppressing INPP4B expression, and might represent a potential therapeutic target for HCC patients. Show more

Keywords: miR-765, INPP4B, proliferation, human hepatocellular carcinoma

DOI: 10.3233/CBM-160579

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 405-413, 2016

Authors: Zhang, Xiuxiu | Guo, Mengfei | Fan, Jinshuo | Lv, Zhilei | Huang, Qi | Han, Jieli | Wu, Feng | Hu, Guorong | Xu, Juanjuan | Jin, Yang

Article Type: Research Article

Abstract: BACKGROUND: Lactare dehydrogenase (LDH) has been proven to be a prognostic and a potential pro-tumor factor in patients with lung cancer. But the prognostic value of serum LDH in small cell lung cancer (SCLC) has not been quantified systematically. OBJECTIVE: Thus, this study was to evaluate the correlations between serum LDH and overall survival of SLCLC by systematic review with meta-analysis. METHODS: PubMed, EMBASE, Cochrane Library, Web of Science databases were searched from inception to October 2014 and references in those publications would be included if the association between serum LDH and overall …survival of SCLC can be derived. Quality assessment and data extraction were performed in the articles selected according to inclusion and exclusion criteria. RESULTS: Twenty-eight studies including 4785 patients with SCLC were deemed eligible. Pooled results showed that SCLC patients with elevated LDH levels were associated with an increased hazard ratio (HR 1.45, 95%CI 1.27∼ 1.66) of overall survival. CONCLUSIONS: The study suggests significant correlations between elevated serum LDH levels and poor overall survival in patients with SCLC. And serum LDH levels can be measured combining with other tools for assessing the risk stratification and prognosis of SCLC, which shows directions for treatments of SCLC. Show more

Keywords: Serum LDH levels, small cell lung cancer, prognosis, meta-analysis

DOI: 10.3233/CBM-160580

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 415-423, 2016

Authors: Park, Sehhoon | Park, Seongyeol | Lee, Se-Hoon | Suh, Beomseok | Ock, Chan-Young | Keam, Bhumsuk | Kim, Tae Min | Kim, Dong-Wan | Kim, Young Whan | Heo, Dae Seog

Article Type: Research Article

Abstract: BACKGROUND: A low albumin-to-globulin ratio (AGR) has been known as a prognostic factor for cancer-related mortality. However, no study has elucidated its usefulness as a predictive factor in the era of targeted therapy, and so, we evaluated this in the present study. METHODS: We retrospectively analyzed 2012 non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Among these patients, 645 patients who had EGFR mutation and suitable pretreatment laboratory values were included. AGR was calculated 2 months before treatment and 4 months after treatment in each patient. …The optimal cutoff value of AGR, and progression free survival (PFS) were also determined. RESULTS: The optimal cutoff value of AGR was 1.17, which yielded a highest HR of 1.89 (P< 0.001) for poor PFS. The median PFS was 9.5 months (95% confidential interval [CI] 7.0-10.4) in patients with pretreatment AGR < 1.17 and 13.5 months (95% CI 11.9-14.7) in those with pretreatment AGR ≥ 1.17. Pretreatment AGR showed an independent predictive value (adjusted HR 1.80, P < 0.001) when age, performance status, and pre-TKI systemic treatment was adjusted for. CONCLUSIONS: We suggest that patients with NSCLC with EGFR mutations who have AGR values lower than 1.17 at the beginning of EGFR TKI treatment should be considered to have a high risk of early EGFR TKI failure. Show more

Keywords: Albumins, globulins, non-small-cell lung carcinoma, tyrosine kinases inhibitor, epidermal growth factor receptor, disease-free survival

DOI: 10.3233/CBM-160581

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 425-433, 2016

Authors: Li, Ri-Heng | Zhang, Ai-Min | Li, Shuang | Li, Tian-Yang | Wang, Lian-Jing | Zhang, Hao-Ran | Li, Ping | Jia, Xiong-Jie | Zhang, Tao | Peng, Xin-Yu | Liu, Min-Di | Wang, Xu | Lang, Yan | Xue, Wei-Lan | Liu, Jing | Wang, Yan-Yan

Article Type: Research Article

Abstract: BACKGROUND: Rectal cancer is an important contributor to cancer mortality. OBJECTIVE: The objective of this paper is to identify key genes across three phenotypes (fungating, polypoid and polypoid & small-ulcer) of rectal cancer based on multiple differential expression networks (DENs). METHODS: Differential interactions and non-differential interactions were evaluated according to Spearman correlation coefficient (SCC) algorithm, and were selected to construct DENs. Topological analysis was performed for exploring hub genes in largest components of DENs. Key genes were denoted as intersections between nodes of DENs and rectal cancer associated genes from Genecards. …Finally, we utilized hub genes to classify phenotypes of rectal cancer on the basis of support vector machines (SVM) methodology. RESULTS: We obtained 19 hub genes and total 12 common key genes of three largest components of DENs, and EGFR was the common element. The SVM results revealed that hub genes could classify phenotypes, and validated feasibility of DEN methods. CONCLUSIONS: We have successfully identified significant genes (such as EGFR and UBC ) across fungating, polypoid and polypoid & small-ulcer phenotype of rectal cancer. They might be potential biomarkers for classification, detection and therapy of this cancer. Show more

Keywords: Rectal cancer, differential interactions, non-differential interactions, differential expression network, genes

DOI: 10.3233/CBM-160582

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 435-444, 2016

Authors: Ni, Zhenhua | Chen, Qingge | Lai, Yiming | Wang, Ziyuan | Sun, Li | Luo, Xuming | Wang, Xiongbiao

Article Type: Research Article

Abstract: BACKGROUND: CLPTM1L (Cleft lip and palate transmembrane protein 1-like) has been previously shown to be overexpressed in lung cancer and is involved in regulating cisplatin sensitivity. In this study, we assessed the relationship between CLPTM1L expression and prognosis of lung cancer in patients and explored its role in regulating cell migration and invasion. METHODS: Immunohistochemistry was used to examine CLPTM1L expression levels on a tissue microarray containing 73 sets of human lung cancer specimens with adjacent normal tissue. The correlation between CLPTM1L expression and patient survival was analysed by the Kaplan-Meier method. In addition, CLPTM1L-knockdown lung …cells were used to investigate the effect of CLPTM1L on cell migration and invasion in vitro . RESULTS: The results of immunohistochemical analysis showed that CLPTM1L was overexpressed in lung cancer tissues compared with adjacent normal tissues. Kaplan-Meier analyses revealed that patients with high CLPTM1L expression showed poorer survival than those with low CLPTM1L expression. In addition, in vitro studies revealed that the knockdown of CLPTM1L expression in 95-D lung cancer cells suppressed cell migration and invasion. Further, the loss of CLPTM1L resulted in decreased matrix metalloproteinase-2 (MMP-2) expression in these cells. CONCLUSION: Our data demonstrate that CLPTM1L overexpression can predict poor prognosis in patients with lung cancer and suggest that CLPTM1L might be associated with the regulation of cell migration and invasion. Show more

Keywords: Lung cancer, CLPTM1L, prognosis, migration, invasion

DOI: 10.3233/CBM-160583

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 445-452, 2016

Authors: Asanuma, Kunihiro | Matsumine, Akihiko | Nakamura, Tomoki | Matsubara, Takao | Asanuma, Yumiko | Oi, Toru | Goto, Mikinobu | Okuno, Kazuma | Kakimoto, Takuya | Yada, Yuuki | Sudo, Akihiro

Article Type: Research Article

Abstract: BACKGROUND: Fibrinogen, a 340 kDa glycoprotein synthesized in the liver, is known to be involved in tumor angiogenesis, enlargement, and metastasis. Elevated plasma fibrinogen levels are associated with tumor progression in many cancer patients. However, there are no reports about differences in fibrinogen levels between benign and malignant soft tissue tumors. OBJECTIVES: The purpose of this study was to clarify whether preoperative plasma fibrinogen levels can be used for differential diagnosis of benign or malignant soft tissue tumors. METHODS: The plasma fibrinogen levels from 102 primary soft tissue tumor patients were measured before …biopsy or treatment. Fibrinogen levels were analyzed and compared to various clinical parameters. RESULTS: According to receiver operating characteristic (ROC) curve analysis, a threshold of serum fibrinogen of 315 mg/dL identified malignant patients with 60.9% sensitivity and 87.5% specificity. The diagnostic accuracy was evaluated by area under the curve (AUC: 0.805). Over 315 mg/dL of fibrinogen was associated with a significantly increased risk of malignancy by multiple logistic regression analysis (OR: 6.452, p= 0.0004). CONCLUSIONS: We demonstrated that plasma fibrinogen levels have a relationship with tumor malignancy of soft tissue tumors. High fibrinogen levels can be a helpful subsidiary tool for the prediction of malignant soft tissue tumors with other diagnostic tools. Show more

Keywords: Fibrinogen, soft tissue tumor, malignant, sarcoma, logistic analysis, receiver operating characteristic (ROC)

DOI: 10.3233/CBM-160584

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 453-458, 2016

Authors: Wang, Guanghui | Shen, Wei | Cui, Long | Chen, Wei | Hu, Xuguang | Fu, Jihong

Article Type: Research Article

Abstract: BACKGROUND: Our previous study found ANLN was over-expressed in colorectal cancer(CRC), however the role of ANLN in CRC remained unknown. OBJECTIVE: To investigate the relationship of ANLN expression in CRC with clinical features and to determinate the prognostic significance of ANLN expression in CRC. METHODS: The ANLN expression in CRC tissue and adjacent normal colorectal mucosa were measured, the relationship between ANLN expression and clinical features as well as overall survival were analyzed. RESULTS: ANLN was overexpressed in CRC. ANLN expression was associated with tumor invasion and enlarged tumor size. …Furthermore, Kaplan-Meier survival analysis revealed that higher expression of ANLN was associated with poorer overall survival. Multi-variate analysis suggested that higher expression of ANLN, preoperative CEA level and distant metastasis were independent prognostic factor in patients with CRC CONCLUSIONS: ANLN expression is elevated in CRC and has a strong potential to act as a biomarker for the prognosis of CRC. Show more

Keywords: Colorectal cancer, ANLN, prognosis

DOI: 10.3233/CBM-160585

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 459-465, 2016

Authors: Xu, Xiao-Feng | Lu, Ren-Quan | Xiao, Ran | Zhou, Lei | Zhao, Xin-Min | Hu, Xi-Chun | Gao, Xiang | Guo, Lin

Article Type: Research Article

Abstract: BACKGROUND: Nasopharyngeal carcinoma (NPC) is a common type of head and neck cancer. OBJECTIVE: This study aimed to detect the expression of Epstein-Barr viral Rta protein in patients with untreated NPC, and compare the serum Rta-IgG with the VCA-IgA in patients with NPC. METHODS: In the current work, the nasopharyngeal tissues of untreated NPC patients (n= 13) and non-NPC controls (n= 10) were collected for the immunohistochemical (IHC) staining to analyze the levels of Rta protein expression, meanwhile serum samples from the participants were prepared to assess the roles of Rta-IgG level with …Enzyme-linked immunosorbence assay (ELISA) in diagnosis of NPC including the patients with NPC, the patients with other cancers, and normal volunteers. RESULTS: The levels of serum Rta-IgG in 26 NPC patients were monitored at pre- and post-treatments, as well as one to two year after. We found that there was a significant difference of the expression levels of Rta protein between NPC and non-NPC groups (P< 0.05). Correspondingly, the levels of serum Rta-IgG in NPC patients (3.05, 1.19-4.95) were significantly higher than those of non-NPC participants (0.15, 0.08-0.30, P< 0.05) including the patients with lung cancer (0.14, 0.08-0.19), the patients with breast carcinoma (0.17, 0.10-0.25), the patients with gastric carcinoma (0.08, 0.05-0.16), the patients with malignant lymphoma (0.13, 0.08-0.20), the patients with benign nasopharyngeal disease (1.65, 0.74-1.93) and healthy volunteers (0.22, 0.13-0.32), respectively. With a receiver operation characteristic (ROC) analysis, the cut-off value to discriminate NPC patients from the controls was established at 0.92 (S/CO) for Rta-IgG (sensitivity 83.6%; specificity 82.4%), the diagnosis efficacy of Rta-IgG was higher than VCA-IgA. The positive rates of Rta-IgG were related to clinical stage, but not metastatic sites. Serum concentrations of Rta-IgG were decreased in NPC patients with effective radiation, and slightly raised or with no change with ineffective radiation. CONCLUSIONS: Rta expression levels are elevated in the patients with NPC, and serum Rta-IgG is a promising biomarker in both differential diagnosis and therapy-monitoring of the patients with NPC. Show more

Keywords: Nasopharyngeal carcinoma, Epstein-Barr virus, Rta protein, VCA-IgA, Enzyme-linked immunosorbent assay (ELISA)

DOI: 10.3233/CBM-160586

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 467-476, 2016

Authors: Li, Zhen | Shu, Jinian | Zhang, Peng | Sun, Wanqi | Yang, Bo | Zhang, Haixu

Article Type: Research Article

Abstract: BACKGROUND: Identifying endogenous volatile organic compounds (VOCs) as markers for different cancers currently requires time-consuming procedures and specialized operators. OBJECTIVE: The objective of this study was to develop a rapid and simple method for measuring VOCs at trace levels. METHODS: A simple vacuum ultraviolet photoionization mass spectrometer (VUV-PIMS) was used to detect trace levels of dimethyl trisulfide (DMTS), dimethyl sulfide (DMS), and 2-butanone, which correspond to volatile biomarker candidates present in the exhaled breath of patients with breast, liver, and lung cancers, respectively. The practicality of measuring endogenous VOCs using VUV-PIMS was confirmed …by detecting them in cultured cell lines. RESULTS: The abovementioned VOCs were detected with high sensitivity by VUV-PIMS. The limits of detection (LODs) for DMTS, DMS, and 2-butanone were 3.1, 3.9, and 23.2 pptv, respectively, under ambient conditions, which surpass the sensitivity of nearly all other MS-based techniques. Moreover, relatively high concentrations of 2-butanone and DMS were observed in VOCs emitted from the A549 lung cancer cell line and the HepG2 liver cancer cell line, respectively. CONCLUSIONS: Our results show that VUV-PIMS may serve as a reliable method for real-time measurement of endogenous volatile cancer biomarkers. Show more

Keywords: VUV-PIMS, cancer, endogenous VOCs, cell measurement

DOI: 10.3233/CBM-160587

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 477-487, 2016

Authors: Kanmaz, Zehra Dilek | Aras, Gülfidan | Tuncay, Esin | Bahadır, Ayşe | Kocatürk, Celalettin | Yaşar, Zehra Asuk | Öz, Büge | Özkurt, Canan Ünlü | Gündoğan, Cihan | Çermik, Tevfik Fikret

Article Type: Research Article

Abstract: AIM: The aim of this study is to evaluate the diagnostic value of PET-CT scan for the prediction of EGFR mutation status and the contribution of TTF-1 expression to PET-CT scan. METHODS: We retrospectively studied 218 cases with a diagnosis of pulmonary adenocarcinoma between 2012-2014 which underwent EGFR analysis, TTF-1 and PET-CT before treatment. RESULTS: The EGFR mutation was present in 28.9% (n= 63) of cases. TTF-1 positivity was 66.9% (n= 105). Standardized uptake value (SUV max) was 16.7 ± 6.8 in EGFR mutant type, 13.8 ± 7.6 in cases having no …EGFR mutations. According to our evaluations, high SUVmax is positively correlated with EGFR mutation status. TTF-1 expression in multivariate analysis strengthens the accuracy of detecting an EGFR mutation. CONCLUSION: PET-CT FDG uptake may, together with TTF-1 expression, help diagnosis in lung adenocarcinoma cases when evaluating for EGFR mutation status. Show more

Keywords: Lung cancer, EGFR, TTF-1

DOI: 10.3233/CBM-160588

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 489-498, 2016

Authors: Kazemzadeh, Mina | Safaralizadeh, Reza | Feizi, Mohammad Ali Hosseinpour | Ravanbakhsh, Reyhaneh | Somi, Mohammad Hossein | Hashemzadeh, Shahryar

Article Type: Research Article

Abstract: Colorectal cancer (CRC) is one of the most common cancers in the world; therefore, extensive research is needed to find new molecular therapeutic targets and biomarkers. LncRNA (long non-coding RNA), a new class of non-coding RNAs, has a crucial role in the onset and progression of various cancersincluding colorectal cancer. Research on lncRNA is still at initial stages and underlying molecular mechanisms of the vast majority of lncRNA have remained unclear. LOC100287225 is one of these novel lncRNAs (long intergenic non-coding RNA) located in the long arm of the chromosome 18. The purpose of this study was to determine the …expression of LOC100287225 in colorectal tissue, and its misregulation in CRC patients. Quantitativereal-time-PCR (qRT-PCR) was used to investigate the LOC100287225 expression in pairs of tumorous and adjacent tumor-free tissues of 39 colorectal cancer patients. Also, the relationship between the clinicopathology and expression of LOC100287225 was determined. QRT-PCR results revealed that not only is LOC100287225 expressed in the intestinal tissue, but has also been misregulated during tumorigenesis. Moreover, LOC100287225 RNA relative expression levels were significantly lower in tumor tissues compared with adjacent tumor-free tissues (P< 0.001). RNA expression level of LOC100287225 did not show significant correlation with clinical characteristics. In conclusion, our study demonstrated that LOC100287225 misregulation couldbe a potential target for gene therapy in colorectal cancer. Show more

Keywords: CRC, lincRNA, LOC100287225, qRT-PCR

DOI: 10.3233/CBM-160589

Citation: Cancer Biomarkers, vol. 16, no. 3, pp. 499-505, 2016