Cancer Biomarkers - Volume 15, issue 5

Authors: Zheng, Haiyan | Ruan, Jian | Zhao, Peng | Chen, Shiping | Pan, Linglan | Liu, Jianqiao

Article Type: Research Article

Abstract: Heparanase(HPSE), an endo-β -D-glucuronidase, is found overexpressed in Ovarian cancer (OC). The purpose of our work was to investigate primitively the possible role of HPSE in the development of OC. In this study, RNA interference (RNAi) with a HPSE small hairpin RNAs(HPSE-shRNA) and plasmid with HPSE were used to identify the effects of HPSE on the regulation of malignant behaviors of OC. OV-90 and SKOV3 were selected as a cell model in vitro and in vivo . The results showed that down-regulation of HPSE can significantly inhibit the proliferative and invasive ability of SKOV3 cells, and up-regulation of HPSE …in OV-90 cells showed the opposite effects. Compared with the parental OC cells, HPSE silencing cells exhibited attenuated capacities in developing tumor in nude mice, while the growth tumors xenografts derived from these cells were dramatically regressed. In conclusion, our results suggest that HPSE contributes to the proliferation and metastasis of OC and HPSE might be a potent molecular target for OC treatment. Show more

Keywords: Ovarian cancer, heparanase, invasion, proliferation

DOI: 10.3233/CBM-150459

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 525-534, 2015

Authors: Wu, Z.Y. | Wang, S.M. | Chen, Z.H. | Huv, S.X. | Huang, K. | Huang, B.J. | Du, J.L. | Huang, C.M. | Peng, L. | Jian, Z.X. | Zhao, G.

Article Type: Research Article

Abstract: BACKGROUND: Analysis using publicly available algorithms has found that high mobility group AT-hook 2 (HMGA2), a key transcriptional regulatory factor, is a potential target of microRNA-204 (miR-204). Some studies have shown that both miR-204 and HMGA2 are associated with cancer development. OBJECTIVE: We examined the possible relationship between miR-204 and HMGA2 in the development of thyroid cancer. METHODS: We assessed miR-204 expression in thyroid cancer specimens and cell lines using real-time polymerase chain reaction (PCR). Luciferase reporter assay was used to confirm the target associations. The effect of miR-204 on cell proliferation was confirmed …with tetrazolium and colony formation assays. Gene and protein expression were examined using real-time PCR and western blotting, respectively. RESULTS: MiR-204 was downregulated in the thyroid cancer specimens and cell lines, and targeted the 3^\prime untranslated region of HMGA2 directly. MiR-204 overexpression decreased cyclin D1 and Ki67 expression and increased P21 expression, which subsequently inhibited thyroid cancer cell proliferation. CONCLUSIONS: Our findings suggest that miR-204 plays a protective role by inhibiting thyroid cancer cell proliferation, and may identify new targets for anti-cancer treatment. Show more

Keywords: MiR-204, HMGA2, proliferation, thyroid cancer

DOI: 10.3233/CBM-150492

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 535-542, 2015

Authors: Wang, Tao | Ji, Feng | Dai, Zhitang | Xie, Yue | Yuan, Dongtang

Article Type: Research Article

Abstract: BACKGROUND: MicroRNA (miR)-191 has been observed to be overexpressed in osteosarcoma cell lines in comparison with osteoblasts. OBJECTIVE: To investigate the clinical significance of miR-191 in human osteosarcomas. METHODS: Quantitative PCR was performed to detect miR-191 expression in osteosarcoma tissues and patients' sera. RESULTS: miR-191 expression levels, both in osteosarcoma tissues and patients' sera, were significantly higher than those in matched adjacent normal bone tissues and healthy controls (both P< 0.001). Importantly, miR-191 could efficiently screen osteosarcoma patients from healthy controls (Area under receiver operating characteristic curve, AUC = 0.808). Then, high serum …miR-191 expression was significantly associated with advanced clinical stage (P= 0.001), large tumor size (P= 0.01) and positive distant metastasis (P= 0.001). Moreover, overall and disease-free survival durations in patients with high miR-191 expression were both shorter than those with low miR-191 expression. Multivariate analysis further identified serum miR-191 level as an independent and significant prognostic factor for both overall survival (P= 0.01) and disease-free survival (P= 0.02). CONCLUSIONS: Our data provide new insights for the involvement of miR-191 in osteosarcoma and suggest that the increased expression of miR-191 may be associated with aggressive tumor progression and adverse outcome. Of note, serum miR-191 quantification may be a promising biomarker for the diagnosis and prognosis in osteosarcoma. Show more

Keywords: Osteosarcoma, serum, microRNA-191, diagnosis, prognosis, real-time quantitative RT-PCR

DOI: 10.3233/CBM-150493

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 543-550, 2015

Authors: Gul, Summer | Murad, Sheeba | Ehsan, Naureen | Bloodsworth, Peter | Sultan, Aneesa | Faheem, M.

Article Type: Research Article

Abstract: BACKGROUND: Bone morphogenetic proteins (BMPs) belong to the transforming growth factor beta (TGF-β) super family, which are primarily known for their inherent role in osteogenesis and ontogenesis. Accumulating evidence suggests the regulatory role of BMP-4 in cellular proliferation, apoptosis, differentiation and thus a possible oncogenic role. OBJECTIVE: Variable cellular expression and in vitro functional assays are indicative of the involvement of BMP related signaling in Breast cancer (BC). The differential expression of BMP-4 in the peripheral blood of BC patients may therefore be considered as a potential biomarker. Therefore, this study aimed to evaluate transcriptional …expression of BMP-4 and its cognate receptor BMPR-II in the peripheral blood from the BC patients in relation to the healthy individuals. METHODS: The expression pattern of BMP-4 and BMPR-II was analyzed in the blood of breast cancer patients (n= 22) and healthy controls (n= 22) through Semi Quantitative Reverse transcription Polymerase chain reaction. RESULTS: An up-regulated expression of BMP-4 and BMPR-II was observed in the peripheral blood of breast cancer patients especially in the advanced-stage of the disease. Moreover, BMP-4 and BMPR-II expressions were found to be correlated. CONCLUSION: The current preliminary results based on the transcriptional analysis suggest the prospective use of BMP4 as a biomarker, however further validation is required. Show more

Keywords: BMP-4, BMPR-II, breast cancer (BC), RT-PCR, Peripheral blood mononuclear cells (PBMCs)

DOI: 10.3233/CBM-150494

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 551-557, 2015

Authors: Erkut, Nergiz | Mentese, Ahmet | Ozbas, Hasan Mucait | Sumer, Aysegul | Orem, Asım | Topbas, Murat | Sonmez, Mehmet

Article Type: Research Article

Abstract: BACKGROUND: Hypoxia plays an important role in the development and progression of hematologic malignancies. OBJECTIVE: This study was intended to investigate the effectiveness of ischemia-modified albumin (IMA) for demonstrating hypoxia in patients with acute leukemia. METHODS: Blood specimens were collected from 132 subjects (44 acute leukemia patients, 40 iron deficiency anemia (IDA) patients and 48 healthy controls). Serum levels of IMA and malondialdehyde (MDA) were analyzed using conventional methods. RESULTS: Serum levels of IMA were higher in patients with acute leukemia than in those with IDA and healthy controls (acute leukemia patients; …0.69 ± 0.14 ABSUs, IDA patients; 0.61 ± 0.09 ABSUs, controls; 0.50 ± 0.09 ABSUs, respectively). There was a negative correlation between serum IMA levels and hemoglobin (Hb) values (r = - 0.312) and between serum IMA levels and hematocrit (Hct) values, (r = - 0.305) in patients with acute leukemia. Serum levels of MDA were higher in patients with acute leukemia than in those with IDA. But there was no difference in patients with acute leukemia and IDA compared to healthy controls (acute leukemia patients; 2.23 ± 1.82 nmol/mL, IDA patients; 1.36 ± 0.94 nmol/mL, healthy controls; 1.79 ± 0.78 nmol/mL, respectively). CONCLUSIONS: IMA can be effective for demonstrating hypoxia in patients with acute leukemia. Show more

Keywords: Ischemia-modified albumin, acute leukemia, hypoxia

DOI: 10.3233/CBM-150495

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 559-565, 2015

Authors: Hou, Ya-Chao | Deng, Jing-Yu | Zhang, Ru-Peng | Xie, Xing-Ming | Cui, Jing-Li | Wu, Wei-Peng | Hao, Xi-Shan | Liang, Han

Article Type: Research Article

Abstract: OBJECTIVE: To elucidate the clinical significance of the methylated status of CpG site count of PCDH10 promoter in the survival prediction in gastric cancer (GC). METHODS: In the previous study, we demonstrated that the methylated CpG site count was significantly associated with the overall survival (OS) of GC patients by using the bisulfite genomic sequencing (BGS) with no less than five clones per sample. It was so complex and expensive for patients to undergo the BGS clones. In this study, we detected the different CpG site counts (hypermethylated and hypomethylated) of PCDH10 DNA promoter in GC …samples of 471 patients by directly bisulfite genomic sequencing (D-BGS) without any clone. Furthermore, we evaluated the relationships between the methylated status of PCDH10 promoter and OS. RESULTS: Two hundred and fifty-seven of 471 (54.6%) GC patients were identified to present with PCDH10 promoter methylation by D-BGS. Patients who presented with 5 or more methylated CpG site counts of PCDH10 promoter had significantly poorer prognosis than patients who with less than 5 methylated CpG site counts of PCDH10 promoter (p= 0.039). With the multivariate survival analysis, we demonstrated that T stage, N stage and the hypermethylated CpG site counts of PCDH10 DNA promoter were the independent predictors of OS of GC patients. In addition, the hypermethylated CpG site counts of PCDH10 DNA promoter had smaller Akaike information criterion (AIC) and Bayesian information criterion (BIC) values than the other two independent predictors of the OS, indicating the hypermethylated CpG site counts of PCDH10 DNA promoter as the best prognostic predictor of GC. CONCLUSIONS: Our present findings suggested that the hypermethylated CpG site counts of PCDH10 DNA promoter for evaluating the prognosis of GC was reasonable by using the D-BGS. Show more

Keywords: PCDH10, methylation, direct bisulfite genomic sequencing, prognosis, gastric cancer

DOI: 10.3233/CBM-150496

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 567-573, 2015

Authors: Jakubauskienė, Eglė | Peciuliene, Inga | Vilys, Laurynas | Mocevicius, Paulius | Vilkaitis, Giedrius | Kanopka, Arvydas

Article Type: Research Article

Abstract: BACKGROUND: Cell lines derived from human tumors have been extensively used as experimental models of neoplastic disease. Although such cell lines differ from both normal and cancerous tissue. OBJECTIVE: The data obtained used DNA and RNA microarray systems does not give full information about protein expression levels in cells and tissues. We present experimental evidence that splicing factor SRSF1, SRSF2, U2AF35, U2AF65 and KHSRP expression levels in gastrointestinal tract (colon, gastric and pancreatic) tumors differ compare to healthy tissues and in cell lines, derived from corresponding organs. METHODS: Protein expression was analyzed using Western …blots. RT-PCR method was used for Fas and Rac splicing analysis. RESULTS: Obtained results provided a novel molecular characterization of this important group of human cell lines and their relationships to tumors in vivo . Expression levels of individual splicing factors in tumors might serve as tumor markers. Not all experimental results obtained from cell lines reflect changes that occur in tumors. Also Fas and Rac, cancer associated genes, tumor associated sFas and Rac1b mRNA isoform profiles in cell lines do not correspond to profiles that are observed in tumors. CONCLUSIONS: Not all experimental results obtained in cell lines reflect changes that occur in real tumors. Show more

Keywords: Tumor, colon, gastric, pancreatic, splicing factor, Fas, Rac, mRNA, cell lines, SR proteins

DOI: 10.3233/CBM-150497

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 575-581, 2015

Authors: Masood, Nosheen | Mubashar, Aroosha | Yasmin, Azra

Article Type: Research Article

Abstract: BACKGROUND: GSTM1 and GSTT1 are phase II enzymes which provide chemical defense to cells. OBJECTIVE: This study was designed to evaluate association of GSTM1 and GSTT1 deletion along with epidemiological factors with risk of colon and rectum cancers. METHODOLOGY: Multiplex PCR was used for cancer patients as well as age and gender matched cancer free controls. RESULTS: Mean age of patients and controls was 45.5 (± 14.6) and 43.5 (± 18.08) years respectively. Among epidemiological factors; gender, age ≥ 50 years, active/passive smoking, naswar addiction, residential area, family history, red meat, fruit …and vegetable intake showed no association with CRC (P ≥ 0.05). Symptoms of CRC like altered bowel habits (70%) was more common compared with other symptoms. GSTM1 (P ≤ 0.05) and GSTT1 (P ≤ 0.05) deletions were found to be significantly associated with CRC compared with controls. Association of epidemiological factors like gender, active/passive smoking, naswar addiction, residential area and family history were associated neither with GSTM1 deletion nor to GSTT1 deletion in both cancers (P ≥ 0.05). Significant association was present between stage III and GSTM1 (CI 95% 0.15-1.39) as well as GSTT1 (CI 95% 0.14-2.44) deletion in CRC. CONCLUSION: These results suggest that GSTM1 and GSTT1 deletion were associated with increased risk of colon and rectum cancer in Pakistani population. Show more

Keywords: GSTM1, GSTT1, epidemiology, colon cancer, rectum cancer

DOI: 10.3233/CBM-150498

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 583-589, 2015

Authors: Song, Yan | Liu, Dan | He, Guoping

Article Type: Research Article

Abstract: BACKGROUND: The significance of transketolase-like enzyme 1 (TKTL1) and p63 in the clinical progression and prognosis of gastric cancer patients has not been established. OBJECTIVE: This study investigated the expression of TKTL1 and p63 in gastric cancer and their clinical significance. METHODS: TKTL1 and p63 expression in 101 gastric cancer tissue specimens and 25 normal gastric mucosa tissues were detected by immunohistochemistry (IHC). RESULTS: The percentage of positive TKTL1 and p63 expression in gastric carcinomas was significantly higher than that in normal gastric mucosa tissues (P < 0.05). Positive TKTL1 and p63 …expression significantly correlated with larger tumor size, deeper invasion, higher TNM stage, and lymph node metastasis (P< 0.05). The expression of TKTL1 significantly correlated with p63 expression in gastric cancer tissues (r = 0.476, P < 0.01). Univariate analysis revealed that positive TKTL1 and/or positive p63 expression correlated significantly with shorter survival and lower 5-year survival rate (P = 0.001). Cox multivariate analysis demonstrated that expression of TKTL1 and p63 is an independent prognostic factor (P < 0.05) in gastric cancer. CONCLUSIONS: Both TKTL1 and p63 are independent prognostic factors of the poor outcome of gastric cancer patients. Show more

Keywords: TKTL1, p63, gastric cancer, prognosis

DOI: 10.3233/CBM-150499

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 591-597, 2015

Authors: Bai, Juanjuan | Zhang, Zhongling | Li, Xing | Liu, Huifan

Article Type: Research Article

Abstract: OBJECTIVE: The role of miR-365 in cancer cells seemed controversial in previous studies. We thereby in this article aimed to define the role of miR-365 in malignant melanoma (MM) pathogenesis. METHODS: We detected miR-365 expression in malignant melanoma cell lines and then investigated the effects of miR-365 on the metastasis and malignancy of melanoma cells. The correlation between miR-365 level and NRP1 (neuropilin1) was further investigated in clinical malignant melanoma specimens. RESULTS: MiR-365 was strongly down-regulated in malignant melanoma (MM) tissues and cell lines, and its expression levels were associated with lymph node metastasis …and clinical stage, as well as overall survival and replase-free survival of MM. We also found that ectopic expression of miR-365 inhibited MM cell proliferation and MM metastasis in vitro and in vivo . We further identified a novel mechanism of miR-365 to suppress MM growth and metastasis. NRP1 was proved to be a direct target of miR-365, using luciferase assay and western blot. NRP1 over-expression in miR-365 expressing cells could rescue invasion and growth defects of miR-365. In addition, miR-365 expression inversely correlated with NRP1 protein levels in MM. CONCLUSION: Our data suggest that miR-365 functions as a tumor suppressor in MM development and progression, and holds promise as a prognostic biomarker and potential therapeutic target for MM. Show more

Keywords: Malignant melanoma (MM), neuropilin1 (NRP1), miR-365, invasion and metastasis, pathogenesis, target therapy, cancer biomarker

DOI: 10.3233/CBM-150500

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 599-608, 2015

Authors: Zhang, Jun | Yu, Xiao-Ling | Zheng, Guo-Feng | Zhao, Fei

Article Type: Research Article

Abstract: OBJECTIVE: This meta-analysis investigated the correlation between the promoter methylation of death-associated protein kinase (DAPK ) and the clinicopathological features in patients with non-small cell lung cancer (NSCLC). METHOD: Scientific literature databases were exhaustively searched to retrieve published studies relevant to DAPK methylation and NSCLC. Retrieved studies published in English and Chinese languages were screened according to the stringent predefined inclusion and exclusion criteria, and high quality studies were selected for meta-analysis. All statistical analyses were performed utilizing STATA software (Version 12.0, Stata Corporation, College Station, TX, USA). RESULTS: A total of 14 …published studies (5 in English and 9 in Chinese) were enrolled in the present meta-analysis, and contained 1238 patients with NSCLC. The results indicated that NSCLC patients with metastatic phenotype were strongly associated with significantly higher methylation rate of DAPK compared to NSCLC patients without metastasis. Additionally, in NSCLC patients carrying tumors with DAPK methylation, the 5-year survival rate was remarkedly lower than NSCLC patients without DAPK methylation. However, we did not find significant correlation between DAPK methylation and histological stage or tumor node metastasis (TNM) stage in NSCLC patients. CONCLUSION: Our meta-analysis results reveal that DAPK promoter methylation might be associated with tumor metastasis and poor prognosis in NSCLC patients, although no correlation with histological types and TNM stage in NSCLC patients were found. Show more

Keywords: Death-associated protein kinase (DAPK), non-small cell lung cancer, clinicopathological features, prognosis, meta-analysis

DOI: 10.3233/CBM-150501

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 609-617, 2015

Authors: Danish, Qazi | Mokhdomi, Taseem A. | Bukhari, Shoiab | Ahmad, Raies

Article Type: Research Article

Abstract: Lung cancer is the major cause of cancer-related mortality worldwide owing to its late-stage detection and aggressive behavior. Epidemiologically, several genetic and epigenetic factors contribute to the development of lung cancer. Angiogenesis, a critical process in tumor progression has become an important target for anti-cancer therapy particularly in lung cancer. Besides commercially available angiogenic inhibitors, numerous anti-angiogenic therapies have been developed to limit tumor growth, although, most of them have not proved beneficial in terms of long-term survival. Despite, logical advances in treatment strategies, NSCLC still remains a major health concern due to poor prognosis of the diseases state. This …calls for a comprehensive analysis of signaling processes governing tumor angiogenesis and treatment options available thereof for development of a sustainable strategy to control cancer. In this review, several aspects of lung cancer have been discussed starting from its pathological characterization to the development of modern therapeutics. Show more

Keywords: Lung cancer, angiogenesis, VEGF receptors

DOI: 10.3233/CBM-150502

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 619-633, 2015

Authors: Wang, Yunchao | Lu, Janice | Zhao, Xia | Feng, Yu | Lv, Shuzhen | Mu, Ying | Wang, Dandan | Fu, Hui | Chen, Yizhi | Li, Yanping

Article Type: Research Article

Abstract: AIM: To explore the correlation between Ubiquilin1 (UBQLN1) expression and clinicopathological characteristics and determine its prognostic significance in patients with breast cancer. METHODS: UBQLN1 expression was evaluated by immunohistochemistry in 125 invasive breast cancer samples. The association between UBQLN1 and clinicopathological parameters and prognosis of breast cancer were detected. RESULTS: The UBQLN1 protein was overexpressed in breast cancer samples (68/125) and associated with tumor size (P = 0.034), lymph node metastasis (P = 0.035), TNM stage (P = 0.049) and vascular invasion (P = 0.003). The DFS and OS rates at 5 years were …27.7% and 48.7% for UBQLN1 positive patients compared with 49.6% and 77.4% for UBQLN1 negative patients, respectively (both P = 0.001). Multivariate analyses revealed that UBQLN1 was an independent prognostic factor for overall survival (hazard ratio, 2.416; 95% CI, 1.134-5.149, P= 0.022) and disease-free survival (hazard ratio, 2.113; 95% CI, 1.203-3.709, P= 0.009). Furthermore, UBQLN1 overexpression was associated with poor prognosis in patients without lymph node metastasis (DFS 35 months vs 62 months, P = 0.005; OS 68 months vs 72 months, P = 0.017). CONCLUSION: The expression level of UBQLN1 and prognosis in breast cancer is clarified for the first time and UBQLN1 seems to be a novel molecular marker to predict poor prognosis in breast cancer. Show more

Keywords: Breast cancer, UBQLN1, prognosis

DOI: 10.3233/CBM-150503

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 635-643, 2015

Authors: He, Yi | Chen, Xi | Liu, Hao | Xiao, Haibo | Kwapong, William Robert | Mei, Ju

Article Type: Research Article

Abstract: BACKGROUND: Matrix-remodeling associated 5 (MXRA5) has recently been one of the frequently mutated gene but its role in non-small cell lung cancer (NSCLC) remains unclear. OBJECTIVE: To identify whether MXRA5 could be applied as a novel prognostic marker for NSCLC. METHODS AND RESULTS: In this study, we proved that mRNA and protein expression of MXRA5 in 166 NSCLC patients' tissues by Quantitative Real-Time PCR and immunohistochemical staining respectively. Moreover, the correlation between MXRA5 protein expression and clinicopathological features and prognosis in NSCLC patients was evaluated. Our results revealed that the over-expression of MXRA5 was …significantly correlated with age (P= 0.049), differentiation (P= 0.003), tumor-node-metastasis (TNM) stage (P= 0.017) and smoking cigarette (P= 0.007). In addition, it also showed that patients with higher MXRA5 protein expression had significantly shorter overall survival (P < 0.001). Multivariate analysis indicated that over-expression of MXRA5 protein was an independent prognostic factor for NSCLC. CONCLUSIONS: MXRA5 protein is aberrantly expressed in NSCLC and the high MXRA5 expression is correlated with tumor progression and overall survival. These results indicated the potential value of MXRA5 as a novel therapeutic target for the treatment of NSCLC. Show more

Keywords: Matrix-remodeling associated 5, non-small cell lung cancer, prognosis, biomarker

DOI: 10.3233/CBM-150504

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 645-651, 2015

Authors: Aljada, Ahmad | Saleh, Ayman M. | Al-Aqeel, Suliaman M. | Shamsa, Heba Bani | Al-Bawab, Ahmad | Dubayee, Mohammed Al | Ahmed, Altayeb Abdalla

Article Type: Research Article

Abstract: BACKGROUND: The mature human insulin receptor (INSR) has two isoforms: The A isoform and the B isoform. INSR upregulation has been suggested to play a role in cancer. OBJECTIVE: To establish quantitative PCR method for INSR transcript variants and examine their differential expression as a diagnostic tumor marker in breast cancer. METHODS: The differential expression of IR-A and IR-B were evaluated by TaqMan qRT-PCR assay in the commercially available Breast Cancer Disease cDNA and Cancer Survey cDNA arrays. RESULTS: The mRNA expression levels of IR-A was statistically significantly higher in breast cancer …when compared to normal breast tissue while IR-B mRNA expression was down regulated significantly in breast cancer. Stratification of patients into groups according to metastatic stages indicated statistically significantly higher levels of IR-A mRNA in clinical stage (CS)-IV, and lower IR-B levels in CS-IIA, CS-IIIB and CS-IIIC. However, IR-A:IR-B ratio showed a statistically significant increase in all stages. Cancer Survey cDNA array demonstrated lower levels of IR-B mRNA in breast adenocarcinoma, liver carcinoma and lung carcinoma only while IR-A expression was significantly altered in kidney carcinoma without any significant differences in IR-A:IR-B ratios. CONCLUSIONS: The results demonstrate an increased IR-A:IR-B ratio in all clinical stages of breast cancer. Thus, IR-A:IR-B ratio may have a diagnostic biomarker utility in breast cancer. Show more

Keywords: Insulin receptor (INSR), IR-A, IR-B, breast cancer, metastasis, cDNA arrays

DOI: 10.3233/CBM-150505

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 653-661, 2015

Authors: Wang, Xu | Cui, Jiuwei | Gu, Jingkai | He, Hua | Li, Biao | Li, Wei

Article Type: Research Article

Abstract: BACKGROUND: The association between vitamin D levels and lung cancer risk varies among distinct demographic populations; however, whether vitamin D levels are related to the risk of lung cancer in Chinese population is unknown. OBJECTIVE: We aimed to elucidate the association of plasma 25-hydroxyvitamin D [25(OH)D] level with the risk of non-small cell lung cancer (NSCLC) in a Chinese population. METHODS: A total of 100 NSCLC patients and, 100 age-, gender-, blood-collection-season- and resident area-matched, cancer-free controls were recruited. Plasma 25(OH)D2 and 25(OH)D3 levels were measured by LC/MS/MS mass spectrometry and HPLC. A logistic …regression model was applied to estimate the association between 25(OH)D concentrations and NSCLC risk. RESULTS: Multivariable analysis showed that smoking history, and 25(OH)D deficiency (< 20 ng/mL) were related to a higher risk of NSCLC (P= 0.03). In addition, late stage (stage IIIB-IV) NSCLC was associated with lower 25(OH)D levels, as indicated by univariate analysis. Similarly, multivariate analysis showed that late stage (IIIB-IV) NSCLC was related to 25(OH)D deficiency. CONCLUSIONS: Plasma 25(OH)D deficiency is significantly associated with a higher risk of NSCLC, specifically late stage NSCLC. Show more

Keywords: 25-hydroxyvitamin D, lung cancer, non-small cell lung cancer

DOI: 10.3233/CBM-150506

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 663-668, 2015

Authors: Brentnall, Adam R. | Vasiljevic, Natasa | Scibior-Bentkowska, Dorota | Cadman, Louise | Austin, Janet | Cuzick, Jack | Lorincz, Attila T.

Article Type: Research Article

Abstract: BACKGROUND: Persistent infection %by with high risk human papillomavirus (hrHPV) types causes cervical cancer but most women who test positive are at very low risk of neoplasia. Strategies are needed which can retain high sensitivity of hrHPV testing but reduce the number of false-positives. We showed previously that a combination DNA methylation triage assay for HPV types 16, 18 and 31 and human gene EPB41L3 was useful to identify high grade cervical lesions. OBJECTIVE: Assess whether measurement of DNA methylation in HPV type 33 can improve the previous classifier. METHODS: A London colposcopy …referral group of 1493 women of whom 556 (37%) had histologically-confirmed CIN (cervical intraepithelial neoplasia) 2 or 3 that included 114 HPV33 positive women with methylation measured for three L2 CpGs 5557, 5560 and 5566. Discrimination performance was assessed for the new classifier S5, built by adding HPV33 to the earlier classifier. RESULTS: HPV33 methylation measurement improved prediction among HPV33 positive women. Receiver operating characteristic analyses showed an area under the curve (AUC) for HPV33 methylation of 0.68 (95% CI 0.57-0.78). The earlier risk score was significantly improved by HPV33 methytlation (AUC = 0.82 vs 0.80; P < 0.001). For 90% sensitivity the specificity for CIN2/3 was 49% (95% CI 46-52%). CONCLUSIONS: Measurement of HPV33 DNA methylation contributes independent diagnostic information to EPB41L3 and HPV16, HPV18 and HPV31, and is superior to genotyping. Other HPV and human methylation target regions might be useful to further improve S5. Show more

Keywords: Cervical intraepithelial neoplasia, DNA methylation, early detection of cancer, human papillomavirus 33, human papillomavirus DNA tests, uterine cervical neoplasms

DOI: 10.3233/CBM-150507

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 669-675, 2015

Authors: Zhao, Yunsheng | Wang, Meng | Cui, Chenying | Zhang, Lina | Liao, Fei | Li, Hongchen | Wu, Xia

Article Type: Research Article

Abstract: BACKGROUND: The most practical serum biomarker AFP is negative in 80% patients with small tumor in the early stage of primary hepatocellular carcinoma (PHC). OBJECTIVE: To investigate significance of combined tests of serum golgi glycoprotein 73 (GP73), lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3), glypican 3 (GPC3), des-gamma-carboxy prothrombin (DCP), CA199, ferritin (FER) and carcinoembryonic antigen (CEA) in diagnosis of small PHC with negative AFP. METHODS: A total of 50 cases of small PHC, 60 cases of non-PHC digestive system disorders and 40 cases of healthy controls were collected. Serum GP73, GPC3 and DCP were analyzed …by enzyme-1inked immunosorbent assay. AFP-L3 was separated by microspincolumn; the levels of CA199, FER, CEA, AFP-L3 and total AFP were quantified by electrochemiluminescence immunoassays; percentage of AFP-L3 to total AFP was calculated. RESULTS: Levels of those biomarkers except FER were all significantly different among three groups (P < 0.01). Positive detection rates of seven biomarkers in PHC were higher than other groups (P < 0.01). In individual detection, the highest sensitivity, accuracy rate and area under ROC curve were 72.0%, 86.7% and 0.826 by GP73 and the highest specificity was 98.0% by GPC3. In combined detection with those seven biomarkers, the sensitivity, specificity, accuracy rate and area under ROC curve were 82.0%, 95.0%, 90.1% and 0.884. CONCLUSIONS: GP73 and AFP-L3 are superior biomarkers to aid the diagnosis of small PHC with negative AFP. The combined detection of biomarkers improved the diagnostic accuracy. Show more

Keywords: Primary hepatocellular carcinoma, biomarkers, combined detection, diagnosis

DOI: 10.3233/CBM-150508

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 677-683, 2015

Authors: Malisic, Emina J. | Krivokuca, Ana M. | Boljevic, Ivana Z. | Jankovic, Radmila N.

Article Type: Research Article

Abstract: OBJECTIVE: The polymorphic variations of DNA repair genes may contribute to functional deficiencies in DNA repair processes increasing susceptibility to cancer. We aimed to investigate the impact of 135G>C RAD51 and XRCC1 Arg399Gln polymorphisms on ovarian carcinoma risk in Serbian women. METHODS: The study included 50 ovarian carcinoma samples and 78 cervical swabs of gynecologically healthy age-matched controls. RAD51 G135C and XRCC1 Arg399Gln polymorphisms were determined by PCR-RFLP. Deviations of the genotype frequencies from Hardy-Weinberg equilibrium were assessed using the χ 2 test. The allele- and genotype-specific risks were estimated as …odds ratios with 95% confidence intervals. RESULTS: RAD51 135C and XRCC1 Arg allele are associated with ovarian carcinoma [OR (95% CI): 2.54 (1.22-5.29) for C vs . G; 2.64 (1.53-4.55) for Arg vs . Gln]. RAD51 C exerts its effect in dominant (CC plus GC vs . GG) [OR (95% CI): 2.83 (1.21-6.62], while XRCC1 Arg in dominant (ArgArg plus ArgGln vs . GlnGln) [OR (95% CI): 4.76 (1.69-13.42)] and recessive model (ArgArg vs. ArgGln plus GlnGln) [OR (95% CI): 2.21 (1.07-4.56)]. CONCLUSION: The results suggest that the RAD51 G135C and XRCC1 Arg399Gln polymorphisms could be biomarkers of susceptibility for ovarian carcinoma development. Further larger case-control study is needed to confirm our findings. Show more

Keywords: DNA repair, ovarian carcinoma, RAD51 G135C polymorphism, XRCC1 Arg399Gln polymorphism

DOI: 10.3233/CBM-150509

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 685-691, 2015

Authors: Li, Junfeng | Wei, Feng

Article Type: Research Article

Abstract: OBJECTIVE: To investigate the relationship between the expression of transforming growth factor β 1 (TGF-β 1) and thyroid lesions by retrospective analysis in patients with thyroidectomy. METHODS: Immunohistochemical analyses of TGF-β 1 were performed with 120 archived formalin-fixed and paraffin-embedded thyroid resection tissue samples that included 60 cases of thyroid cancers (papillary thyroid carcinoma, follicular thyroid carcinoma), 14 cases of nodular goiter (NG), 16 cases of thyroid adenoma, 15 cases of Graves disease, 15 cases of Hashimoto's thyroiditis. RESULTS: The pathological analysis of resection thyroid showed a high coincidence with that diagnosed by preoperative …fine needle aspiration biopsy (FNAB), with coincidence rate of 84.48%. The results showed that the expressions of TGF-β 1 in the thyroid cancers were significantly higher than in other benign thyroid lesions and normal thyroid tissues (P< 0.05). Moreover, high expression of TGFβ 1 was found to closely related with the occurrence of thyroid cancers, while there was no significant difference of TGFβ 1 expression between different thyroid cancers. CONCLUSION: The overexpression of TGF-β 1 is associated with the occurrence of thyroid cancer, which can be used as a candidate for the diagnosis and prognosis of thyroid cancer. Show more

Keywords: Thyroid cancer, fine needle aspiration biopsy (FNAB), transforming growth factor-β 1, diagnosis

DOI: 10.3233/CBM-150510

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 693-698, 2015

Authors: Gutiérrez-Monreal, Miguel A. | Villela, Luis | Baltazar, Severiano | Perfecto-Avalos, Yocanxochitl | Cardineau, Guy A. | Scott, Sean-Patrick

Article Type: Research Article

Abstract: BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma. Presently, one of the most important clinical predictors of survival in DLBCL patients is the International Prognostic Index (IPI). Circadian rhythms are the approximate 24 hour biological rhythms with more than 10 genes making up the molecular clock. OBJECTIVE: Determine if functional single nucleotide polymorphism in circadian genes may contribute to survival status in patients diagnosed with diffuse large B-cell lymphoma. METHODS: Sixteen high-risk non-synonymous polymorphisms in circadian genes (CLOCK, CRY2, CSNK1E, CSNK2A1, NPAS2, PER1, PER2, PER3, PPP2CA, and TIM) …were genotyped by screening PCR. Results were visualized by agarose gel electrophoresis and confirmed by two-direction sequencing. Clinical variables were compared between mutated and non-mutated groups. LogRank survival analysis and Kaplan-Meier method were used to calculate the overall survival. RESULTS: PER3 rs10462020 variant showed significant difference in overall survival between patients containing mutated genotypes and those with non-mutated genotypes (p = 0.047). LDH levels (p = 0.021) and IPI score (p < 0.001) also showed differences in overall survival. No clinical differences were observed in mutated vs. non-mutated patients. CONCLUSIONS: This work suggests a role of PER3 rs10462020 in predicting a prognosis in DLBCL overall survival of patients. Show more

Keywords: Circadian rhythm, single nucleotide polymorphism, diffuse large B-cell lymphoma, PER3, survival, biomarker

DOI: 10.3233/CBM-150511

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 699-705, 2015

Authors: Xia, Zongjiang | Duan, Fujiao | Jing, Chang | Guo, Zhihua | Nie, Changfu | Song, Chunhua

Article Type: Research Article

Abstract: BACKGROUND: DNA methyltransferase 3B (DNMT3B) has been discovered to play an important role in tumorigenesis. However, the association between DNMT3B -579G>T and the cancer risk has not been demonstrated. OBJECTIVE: The aim of this study is to provide a precise quantification for the association between DNMT3B -579G>T and the cancer susceptibility. METHODS: We performed a systematic literature review and assessed the methodological quality of included case-control designed studies based on Newcastle-Ottawa Scale (NOS). Pooled odds ratios (ORs) and corresponding 95% confidence intervals (95%CIs) were calculated to assess the strengths of the association. …RESULTS: We identified 18 studies for pooled analyses. Overall, the results demonstrated that the DNMT3B -579G>T polymorphism was significantly associated with a subtly decreased cancer risk (GT vs TT: OR = 0.78, 95%CI: 0.70-0.87, P< 0.01; GT + GG vs TT: OR = 0.81, 95%CI: 0.68-0.97, P= 0.02), especially in the Asian population and in colorectal cancer subgroup. In addition, when stratified for source of controls, the results of population-based subgroup showed the GT genotype might have a significantly decreased cancer risk, but not hospital-based subgroups. CONCLUSIONS: DNMT3B -579G>T polymorphism might contribute to the susceptibility of cancers especially in the Asian population and for colorectal cancer. Show more

Keywords: DNMT3B, polymorphism, cancer, quantitative assessment

DOI: 10.3233/CBM-150512

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 707-716, 2015