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