Cancer Biomarkers - Volume 16, issue 1

Authors: Zavala, Valentina | Pérez-Moreno, Elisa | Tapia, Teresa | Camus, Mauricio | Carvallo, Pilar

Article Type: Research Article

Abstract: BACKGROUND: Mechanisms that lead to the reduced expression of BRCA1 in triple-negative breast cancer (TNBC) tumors are not fully understood. A possible cause is overexpression of miR-146a and miR-638, which regulate BRCA1 expression in other cancers. OBJECTIVE: To evaluate the expression of these microRNAs in relation to BRCA1 expression in TNBC tumors. METHODS: Expression of both microRNAs was assessed by real time qPCR using Taqman microRNA assays in TNBC tumors. Results were related to protein expression of BRCA1 and patient's survival. RESULTS: miR-146a and miR-638 were overexpressed in 36% and …59% of TNBC tumors, respectively. Overexpression was preeminent in BRCA1-deficient tumors and significantly associated to a better overall survival. CONCLUSION: Both miRNAs are potential biomarkers for improved overall survival in patients with BRCA1-deficient TNBC tumors. Show more

Keywords: BRCA1, breast cancer, microRNA, miR-146a, miR-638, triple negative breast cancer

DOI: 10.3233/CBM-150545

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 99-107, 2016

Authors: Eskandari-Nasab, Ebrahim | Hashemi, Mohammad | Ebrahimi, Mahboubeh | Amininia, Shadi

Article Type: Research Article

Abstract: Nuclear factor kappaB (NF-kB) plays a key role in mammary gland development and breast cancer (BC) progression. A functional -94 insertion/deletion ATTG polymorphism (rs28362491) in the promoter of the NFKB1 gene was reported to affect NF-KB1 expression and confer susceptibility to different types of cancer. The current study aimed to assess the association of NFKB1 -94 insertion/deletion ATTG promoter polymorphism and BC risk in an Iranian population. A total of 439 subjects including on 236 BC patients and 203 healthy women were recruited. The NF-KB1 -94ins/del ATTG polymorphism was genotyped by Allele-Specific polymerase chain reaction (AS-PCR) method. Our results demonstrated …that the NF-KB1 -94ins/del ATTG polymorphism was associated with a reduced risk of BC in Codominant (Ins/Ins vs. Del/Del: OR = 0.33, 95%CI = 0.17-0.64; P= 0.001), dominant (Ins/Ins vs. Ins/Del+Del/Del: OR = 0.64, 95%CI = 0.42-0.97; P= 0.027) and recessive (Ins/Del+Del/Del vs. Del/Del: OR = 0.40, 95%CI = 0.21-0.75; P= 0.002) tested inheritance models. Additionally, the Del allele of NF-KB1 -94ins/del ATTG variation with a higher prevalence in the control group compared to the BC patients (43.3% vs. 33.5%) was associated with a decreased risk of BC (OR = 0.66, 95%CI = 0.50-0.86, P= 0.003). In conclusion, our findings for the first time, suggest that the NF-KB1 -94ins/del Del allele and Del/Del genotype were associated with a reduced risk of BC which may contribute as protective factors against BC. Show more

Keywords: NF-kB, breast cancer, deletion polymorphism

DOI: 10.3233/CBM-150546

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 109-115, 2016

Authors: Bergis, Dominik | Kassis, Valentin | Radeke, Heinfried H.

Article Type: Research Article

Abstract: BACKGROUND: Gastric cancer (GC) is one of the most common and devastating tumor conditions. Its development is closely linked to an infection with Helicobacter pylori and chronic, cytokine-driven inflammation. The proinflammatory cytokine Interleukin-33 (IL-33), its membrane bound cellular receptor ST2L and its soluble receptor sST2 have recently been identified as important factors in various tumor conditions, but their role in GC remains ill-defined. METHODS: Thirty patients with adenocarcinoma of the stomach or the esophagogastric junction were prospectively enrolled in the current study. 51 patients with Helicobacter pylori positive or negative gastritis and 40 healthy volunteers served …as control group. Levels of IL-33 and sST2 were determined by ELISA and their relation to HP-status, tumor stage and survival was assessed. RESULTS: Soluble ST2 levels in GC were significantly higher than in gastritis or healthy controls (p< 0.0001). Furthermore, higher levels of sST2 were seen in patients with lower degree of tumor differentiation. Soluble ST2 was significantly associated with a more advanced tumor stage (p= 0.018), metastatic disease (p= 0.014) and significantly correlated with the duration of the disease (p= 0.0017). Calculating the ratio of IL-33/sST2 allowed the discrimination of tumor and non-tumor patients. CONCLUSION: Soluble ST2 is associated with advanced and metastatic disease in GC patients and significantly correlates with the duration of the disease. The IL-33/sST2 ratio may offer a new, interesting approach in identifying GC patients. Show more

Keywords: Gastric cancer, inflammation, interleukin-33, sST2, Helicobacter pylori

DOI: 10.3233/CBM-150547

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 117-125, 2016

Authors: He, Ying-Chun | Shen, Yi | Cao, Yu | Tang, Fang-Qing | Tian, Dao-Fa | Huang, Chen-Fei | Tao, Huai | Zhou, Fang-Liang | Zhang, Bo | Song, Lan | He, Lan | Lin, Li-Mei | Lu, Fang-Guo | Liao, Duan-Fang | Cao, Deliang

Article Type: Research Article

Abstract: BACKGROUND: Nasopharyngeal carcinoma (NPC) is one of the most common cancers in Southern China. Aldo-keto reductase 1B10 (AKR1B10) is upregulated in multiple tumors and plays an oncogenic role. OBJECTIVE: To examine the expression of AKR1B10 at mRNA and protein levels in nasopharyngeal tumors and correlate its expression with clinicopathological parameters. METHODS: A tissue microarray, paraffin blocks, and frozen surgical nasopharyngeal samples were procured. Western blot and immunohistochemistry were used to estimate AKR1B10 protein expression, and mRNA levels were detected by real time RT-PCR. RESULTS: We found that AKR1B10 expression was …increased in malignant tissues compared to the normal tissues (p= 0.000). In NPC tissues, AKR1B10 expression appeared high specifically in squamous cell carcinoma, but low in basal cell carcinoma, adenoid cystic carcinoma, adenocarcinoma and undifferentiated carcinoma (p= 0.000). AKR1B10 expression also demonstrated correlation with tumor differentiation, with a high level in well and moderately differentiated but a low level in poorly differentiated carcinoma (p= 0.000). AKR1B10 was also upregulated in hyperplasia and benign tumors (p= 0.000), and demonstrated a specific nuclear distribution in these non-cancerous diseases. CONCLUSIONS: AKR1B10 is overexpressed in nasopharyngeal hyperplasia, benign tumors, and carcinomas, being a potential new biomarker. Show more

Keywords: Aldo-keto reductase 1B10, AKR1B10, nasopharyngeal carcinoma, hyperplasia, biomarker

DOI: 10.3233/CBM-150548

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 127-135, 2016

Authors: Li, Ke-Yi | Zhang, Jie | Jiang, Li-Cheng | Zhang, Bin | Xia, Chun-Peng | Xu, Kai | Chen, Hai-Ying | Yang, Qiao-Zhi | Liu, Shu-Wei | Zhu, Hong

Article Type: Research Article

Abstract: This article has been retracted, and the online PDF has been watermarked ``RETRACTION''. The retraction notice is available at http://doi.org/10.3233/CBM219904.

Keywords: Drug target, oral squamous cell carcinoma, RNA interference, ubiquitin-specific proteases 39

DOI: 10.3233/CBM-150549

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 137-144, 2016

Authors: Nomura, Hiroyuki | Kataoka, Fumio | Aoki, Daisuke | Jinno, Hiromitsu | Kitagawa, Yuko | Sato, Yuji | Womack, Chris | Wombwell, Helen | Hodgson, Darren | O'Connor, Mark | Harbron, Chris | Yin, Xiaolu

Article Type: Research Article

Abstract: BACKGROUND: Poly(ADP)-ribose polymerase (PARP) inhibitors such as olaparib can induce cell death in cancer cells with homologous recombination (HR) DNA repair deficiencies, such as BRCA1/2 mutations. AIM: To identify prognostic biomarkers of long-term outcomes in cancer patients. METHODS: Immunohistochemistry was used to analyse expression of key HR pathway proteins (ATM, ATR, BRCA1, MDC1, MRE11) and PARP-1 in 100 serous ovarian cancer (SOC) and 100 triple-negative breast cancer (TNBC) tumour samples from Japanese patients. RECIST assessment was used. RESULTS: Patient demographic data and BRCA1/2 mutation status were unavailable. Most …proteins listed previously were detected in > 80% of tissue samples, with BRCA1 expression detected in 60-65%. A potential link between BRCA1 expression and overall survival (M stage adjusted) in SOC patients was observed, but was not statistically significant after multiple testing adjustment. Correlations between other biomarker expression and survival were not observed. In TNBC patients, MDC1 staining was associated with progressive disease, but this was not statistically significant; the analysis did not identify significant correlations between biomarker expression and disease control. Limited event numbers prevented assessment of the prognostic value of BRCA1 in TNBC. CONCLUSION: BRCA1 expression may be a candidate for a prognostic biomarker in SOC. Further studies are warranted. Show more

Keywords: BRCA, ovarian cancer, breast cancer, biomarker

DOI: 10.3233/CBM-150550

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 145-152, 2016

Authors: Lyubchenko, Ludmila | Emelyanova, Marina | Shamanin, Vladimir | Demidov, Lev | Zasedatelev, Alexander | Nasedkina, Tatyana

Article Type: Research Article

Abstract: BACKGROUND: The activating mutation BRAF V600E is considered to be a diagnostic cutaneous melanoma (CM) marker important for prognosis and targeted therapy. OBJECTIVE: The aim of this study was to determine the frequency of the V600E mutation in CM patients in Russia and to estimate the influence of the BRAF gene mutation status on prognosis and clinical outcome. METHODS: To ensure mutation detection in FFPE tissue, interlaboratory validation was performed using three different methods: allele-specific hybridisation on a biochip, allele-specific real-time PCR and, in some cases, direct sequencing. RESULTS: …Mutation V600E was detected in 49% of patients. The age of disease manifestation was significantly lower in mutated (MT) BRAF patients, and the median age difference between the wild-type (WT) and MT BRAF groups (P= 0.002) was 10 years. A tumour thickness more than 1 mm was also more frequently observed in the MT BRAF group (P= 0.059). Patients from the MT BRAF group were more likely to have ulceration compared to the WT group (P= 0.088). No statistically significant differences were found between the relapse-free, progression-free or overall survival of CM patients in the MT BRAF and WT BRAF groups. CONCLUSIONS: The data obtained show that the V600E BRAF mutation occurred in about half of melanoma patients; it was associated with earlier manifestation of melanoma and likely with more aggressive clinical features. Show more

Keywords: Cutaneous melanoma, BRAF gene, V600E mutation, molecular diagnostics, clinical features

DOI: 10.3233/CBM-150551

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 153-160, 2016

Authors: Qin, Meilin | Liu, Gang | Huo, Xisong | Tao, Xuemei | Sun, Xiaomeng | Ge, Zhouhong | Yang, Juan | Fan, Jia | Liu, Lei | Qin, Wenxin

Article Type: Research Article

Abstract: BACKGROUND: It has been shown that circular RNA (circRNA) is associated with human cancers, however, few studies have been reported in hepatocellular carcinoma (HCC). OBJECTIVE: To estimate clinical values of a circular RNA, Hsa_circ_0001649, in HCC. METHODS: Expression level of hsa_circ_0001649 was detected in HCC and paired adjacent liver tissues by real-time quantitative reverse transcription-polymerase chain reactions (qRT-PCRs). Differences in expression level of hsa_circ_0001649 were analyzed using the paired t-test. Tests were performed between clinical information and hsa_circ_0001649 expression level by analysis of variance (ANOVA) or welch t-test and a receiver operating characteristics …(ROC) curve was established to estimate the value of hsa_circ_0001649 expression as a biomarker in HCC. RESULTS: hsa_circ_0001649 expression was significantly downregulated in HCC tissues (p = 0.0014) based on an analysis of 89 paired samples of HCC and adjacent liver tissues and the area under the ROC curve (AUC) was 0.63. Furthermore, hsa_circ_0001649 expression was correlated with tumor size (p = 0.045) and the occurrence of tumor embolus (p = 0.017) in HCC. CONCLUSIONS: We first found hsa_circ_0001649 was significantly downregulated in HCC. Our findings indicate hsa_circ_0001649 might serve as a novel potential biomarker for HCC and may function in tumorigenesis and metastasis of HCC. Show more

Keywords: Circular RNA, hsa_circ_0001649, hsa_circ_001599, hepatocellular carcinoma, biomarker

DOI: 10.3233/CBM-150552

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 161-169, 2016

Authors: Saito, Masaya | Yano, Yoshihiko | Hirano, Hirotaka | Momose, Kenji | Mouri, Kentaro | Hishimoto, Akitoyo | Yoshida, Masaru | Azuma, Takeshi

Article Type: Research Article

Abstract: BACKGROUND AND AIM: Alcoholic liver disease (ALD) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Des-gamma-carboxy prothrombin (DCP) is elevated in many patients with HCC, but also in severe alcoholics without HCC. We aimed to clarify whether the DCP/NX-DCP ratio (NX-DCP-R) could have a high specificity in ALD patients without HCC. METHODS: We performed a prospective cohort study on a total of 703 consecutive outpatients of liver diseases including severe alcoholics and healthy volunteers, who underwent blood biochemical examinations at Kobe University Hospital. Serum DCP was measured by electrochemiluminescence immunoassay (ECLIA) using a monoclonal …antibody, MU-3. A novel parameter, serum NX-DCP, which represents predominantly DCP caused by reduced vitamin K availability, was also measured by ECLIA using monoclonal antibodies P-16 and P-11. The diagnostic accuracy of DCP and NX-DCP-R in patients with and without excessive alcohol intake was statistically examined. RESULTS: DCP was significantly higher in alcoholics than in non-alcoholics (p= 0.005), whereas the NX-DCP-R did not differ between alcoholics and non-alcoholics (p= 0.375). DCP was significantly increased in the serum of each patient with alcoholic hepatitis and alcoholic cirrhosis (p< 0.05), whereas the NX-DCP-R was not increased (p> 0.05). CONCLUSIONS: NX-DCP-R, but not DCP, was not increased in alcoholics without HCC. As for negative screening for HCC, the specificity of the NX-DCP-R in alcoholics without HCC was better than that of DCP in alcoholics without HCC, and so could be a useful negative screening tool for HCC in millions of alcoholics worldwide. Show more

Keywords: NX-PVKA, vitamin K deficiency, warfarin, Tumor Node Metastasis, Child's grade

DOI: 10.3233/CBM-150553

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 171-180, 2016

Authors: Makhlouf, Manal Mohamed

Article Type: Research Article

Abstract: BACKGROUND: Abnormalities in the control of apoptosis play an important role in leukemogenesis. Survivin is a member of inhibitor of apoptosis proteins family, it prevents apoptosis by blocking caspase activity and play a role in cell proliferation. While, cyclin E2 is one of the cyclins proteins family that controls progression of cell cycle by activation of cyclin dependant-kinase. OBJECTIVE: Was to assess survivin and cyclin E2 genes expression in acute leukemia (AL) patients, and to define their role in the susceptibility of AL, and their correlation with the clinical presentation, laboratory findings, as well as treatment …outcome. PATIENTS AND METHODS: This study included 60 de novo AL patients and 40 control subjects to study the expression of survivin and cyclin E2 genes using RT-PCR. RESULTS: Survivin and cyclin E2 genes expression was significantly higher in leukemic patients compared with control subjects (P< 0.001), both genes separately were associated with increased risk of leukemia development and treatment failure (P< 0.01). Moreover, when combining the 2 genes expression, a significant elevation of the risk of leukemia and treatment failure was found (P < 0.01). CONCLUSIONS: Survivin and cyclin E2 genes expression may have clinical relevance and can be considered as molecular risk factors for AL. Also they may be useful as predictive markers for treatment outcome in leukemic patients. Show more

Keywords: Survivin, cyclin E2, acute leukemia, RT-PCR

DOI: 10.3233/CBM-150554

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 181-189, 2016

Authors: Reyes, Niradiz | Benedetti, Ines | Bettin, Alfonso | Rebollo, Juan | Geliebter, Jan

Article Type: Research Article

Abstract: BACKGROUND: Fibromodulin is a small leucine-rich proteoglycan important for extracellular matrix organization and essential for tissue repair in multiple organs. The main function of this proteoglycan is the regulation of collagen fibrillogenesis; however, more recently described roles for fibromodulin have expanded to include regulation of angiogenesis, reprogramming of human fibroblasts into pluripotent cells, modulation of TGF-β activity, inflammatory processes and association with metastatic phenotypes. Additionally, fibromodulin has been identified as a novel tumor-associated antigen in leukemia, lymphoma, and leiomyoma. Knowledge about its expression in the prostate is limited. METHODS: Fibromodulin expression was analyzed in two …different malignant and one non-tumorigenic prostatic cell lines in culture, and in benign and malignant human prostate tissue. Expression was analyzed by real time PCR, immunocytochemistry, and immunohistochemistry. DNA sequencing was performed on a PCR fragment amplified with primers specific for the FMOD gene from cDNA obtained from the cultured cell lines. RESULTS: Both immunostaining and real time PCR analysis of cell lines indicated that fibromodulin was differentially expressed in the cancerous cell lines compared to the non-tumorigenic cell line. Likewise, cancerous tissue expressed significantly higher levels of intracellular fibromodulin compared to matched, benign tissue from the same patients, as well as compared to tissue from patients with only benign disease. CONCLUSIONS: The expression of fibromodulin was higher in prostatic cancer cells (cell-lines and human tissue) than in normal/benign prostatic cells. Additional studies are required to determine the biological and clinical significance and whether this proteoglycan has a role in carcinogenesis of the prostate or in prostate cancer related inflammatory processes. Show more

Keywords: Fibromodulin, extracellular matrix, inflammation, immunohistochemistry, corpora amylacea, prostate cancer

DOI: 10.3233/CBM-150555

Citation: Cancer Biomarkers, vol. 16, no. 1, pp. 191-202, 2016