Cancer Biomarkers - Volume 19, issue 4

Authors: Ding, Jennifer | Karp, Judith E. | Emadi, Ashkan

Article Type: Research Article

Abstract: Metabolism of neoplastic cells is shifted toward high glucose uptake and enhanced lactate production. Lactate dehydrogenase (LDH), which is comprised of two major subunits, LDH-A and LDH-B, reversibly catalyzes the conversion of pyruvate to lactate or lactate to pyruvate. LDH-A has a higher affinity for pyruvate and is a key enzyme in the glycolytic pathway. Elevated LDH is a negative prognostic biomarker not only because it is a key enzyme involved in cancer metabolism, but also because it allows neoplastic cells to suppress and evade the immune system by altering the tumor microenvironment. LDH-A alters the tumor microenvironment via increased …production of lactate. This leads to enhancement of immune-suppressive cells, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and dendritic cells (DCs); and inhibition of cytolytic cells, such as natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs). By promoting immune-suppression in the tumor microenvironment, LDH-A is able to promote resistance to chemo/radio/targeted therapy. Here we discuss the evidence that LDH is both a metabolic and an immune surveillance prognostic biomarker and its elevation is harbinger of negative outcome in both solid and hematologic neoplasms. Show more

Keywords: LDH (lactate dehydrogenase), cancer metabolism biomarker, cancer immune surveillance biomarker

DOI: 10.3233/CBM-160336

Citation: Cancer Biomarkers, vol. 19, no. 4, pp. 353-363, 2017

Authors: Shen, Hongyu | Li, Liangpeng | Wang, Dandan | Yang, Sujin | Chen, Xiu | Zhou, Siying | Zhong, Shanliang | Zhao, Jianhua | Tang, Jinhai

Article Type: Research Article

Abstract: BACKGROUND: Sal-like protein 4 (SALL4) is recognized as a potential biomarker for assessing cancer prognosis. Many experiments have been done to explore the aberrant expression of SALL4 in cancer patients. OBJECTIVE: To explore the association between SALL4 expression and cancer prognosis. METHODS: A systematically comprehensive search was performed through PubMed, Web of Science, and CNKI. The prognostic value of SALL4 expression in cancer patients was evaluated by pooled hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The overexpression of SALL4 was identified to be significantly associated with a poor …prognosis in cancer patients (pooled HR: 2.02, 95% CI: 1.67–2.46). This association was also detected in digestive system neoplasms subgroup (pooled HR: 1.91, 95% CI: 1.52–2.39) and reproductive system neoplasms subgroup (pooled HR: 1.95, 95% CI: 1.17–3.26). In the geography subgroup analysis, a statistical association was confirmed in the Chinese subgroup (pooled HR: 1.982, 95% CI: 1.526–2.576). In the respect of disease progression, there was a certain degree of relationship between higher expression of SALL4 and recurrence-free survival (RFS) (pooled HR: 1.617, 95% CI: 1.190–2.196). CONCLUSION: SALL4 is a promising prognostic biomarker for cancer, and is appropriate for the assessment of cancer prognosis in the Chinese people. Show more

Keywords: SALL4, cancer, biomarker, prognosis, meta-analysis

DOI: 10.3233/CBM-160052

Citation: Cancer Biomarkers, vol. 19, no. 4, pp. 365-373, 2017

Authors: Ahmad, Arif | Raish, Mohammad | Shahid, Mohammad | Batra, Swaraj | Batra, Vineeta | Husain, Syed Akhtar

Article Type: Research Article

Abstract: BACKGROUND: Cervical cancer is the most common cancer in Indian women. Infection with a high-risk human papillomavirus (HR-HPV) is the greatest risk factor for developing cervical cancer. The genetic and epigenetic changes in the tumor suppressor p16 gene is play an important role in the development of cervical cancer. OBJECTIVE: To evaluate the expression and promoter methylation of p16 gene in HR-HPV infected squamous cell carcinoma of the uterine cervix. METHODS: To find out p16 INK4a expression and methylation status 105 squamous cell carcinoma of the uterine cervix were …investigated by using immunohistochemistry and Methylation Specific PCR techniques. RESULTS: HPV16/18 was amplified in 83.8% cases of the cervix. 80% of them were positive for HPV type 16, while only 3.8% were positive for HPV type 18. Promoter CpG island hypermethylation of p16 gene was detected in 20.9% tissue samples of cervical carcinoma. Of these hypermethylated samples 90.9% cases showed nil/very low p16 INK4a expression (P = 0.001). Overexpression of p16 INK4a was observed in 73.3% cases of HR-HPV infected squamous cell carcinoma of the cervix. CONCLUSION: An association between p16 methylation, expression, and HR-HPV infection suggested the compliance of HPV infection and aberration of p16 gene have a synergic effect on initiation and progression of cervical carcinoma. Show more

Keywords: Cervical cancer, Human Papilloma Virus, expression, methylation, p16 gene

DOI: 10.3233/CBM-160060

Citation: Cancer Biomarkers, vol. 19, no. 4, pp. 375-381, 2017

Authors: Thein, Mya Sanda | Kohli, Anita | Ram, Rohit | Ingaramo, Maria Clara | Jain, Alka | Fedarko, Neal S.

Article Type: Research Article

Abstract: BACKGROUND: Cancer progression has been associated with altered immune cell function and activation. Neopterin, which is secreted by interferon-γ stimulated macrophages, exhibits an association with multiple cancer types and metastatic disease. Chitotriosidase, which is secreted by chronically activated macrophages and granulocyte-macrophage colony-stimulating factor stimulated neutrophils has not been studied in the setting of cancer. OBJECTIVE: The goal of this discovery study was to screen chitotriosidase for diagnostic capacity in detecting cancer and compare its operating characteristics with those of neopterin. METHODS: Serum from subjects with breast (n = …66) or prostate (n = 70) cancer, and from 204 subjects free of malignant disease were studied. Chitotriosidase was measured by enzyme activity assay, while neopterin was measured by a competitive enzyme immunoassay. Statistical analyses included group comparisons by Mann Whitney U test, diagnostic capacity by receiver operating characteristics (ROC) curve analysis and biomarker associations with physiologic and clinical measures by Spearman correlation. RESULTS: Chitotriosidase activity was significantly higher in both cancer types compared with gender matched controls, though only in breast cancer was the diagnostic capacity significant (area under the ROC curve of 0.97 ± 0.01). In contrast, neopterin was significantly elevated in prostate cancer and exhibited discriminatory capacity (area under the ROC curve of 0.76 ± 0.05). Age, BMI, % body fat and metastasis were variables that correlated with neopterin, but not chitotriosidase levels. CONCLUSIONS: The operating characteristics of serum chitotriosidase were different from neopterin and further analysis of chitotriosidase as a biomarker for breast cancer is warranted. Show more

Keywords: Neopterin, chitotriosidase, macrophages, cancer

DOI: 10.3233/CBM-160101

Citation: Cancer Biomarkers, vol. 19, no. 4, pp. 383-391, 2017

Authors: Bellampalli, Ravishankara | Vohra, Manik | Sharma, Kashish | Bhaskaranand, Nalini | Bhat, Kamalakshi G. | Prasad, Krishna | Sharma, Anu R. | Satyamoorthy, Kapaettu | Rai, Padmalatha S.

Article Type: Research Article

Abstract: BACKGROUND: Remethylation of homocysteine is catalyzed by B12 dependent methionine synthase (MTR) in all types of cells and by B12 non-dependent betaine homocysteine methyltransferase (BHMT) in liver and kidney cells. Of many etiologies of cancer, an unexplored area is the variations of genes implicated in methylation reaction. OBJECTIVE: The study evaluated the association of BHMT (rs3733890) with acute lymphoblastic leukemia (ALL), followed by in-silico characterization of variations in BHMT gene. METHODS: BHMT [rs3733890; c.742G > A, which substitutes an arginine by a glutamine at codon 239 (R239Q)] …was screened by Tetra-primer Amplification Refractory Mutation System PCR (T-ARMS-PCR) and confirmed using DNA sequencing. In-silico analysis was conducted using bioinformatics tools. RESULTS: BHMT (rs3733890) showed an insignificant association with both childhood and adult ALL. Bioinformatics analysis showed that 18 nsSNPs are deleterious, 3 SNPs in 3 ′ -UTR (rs59109725, rs116634518 and rs138578732) alter the miRNA-binding site, and 11 CNVs are present in the BHMT gene. As consequence of BHMT (rs3733890) polymorphism the free energy changes from - 101210.1 kJ/mol to - 200021.8 kJ/mol. CONCLUSIONS: BHMT (rs3733890) polymorphism showed no association with ALL. Hence this investigation needs further evaluation in larger sample size and effect of other SNPs, CNVs and miRNA’s is required to elucidate the role of BHMT gene in ALL development. Show more

Keywords: Acute lymphoblastic leukemia, BHMT gene, T-ARMS-PCR, SNPs

DOI: 10.3233/CBM-160186

Citation: Cancer Biomarkers, vol. 19, no. 4, pp. 393-401, 2017

Authors: Li, Lu | Gao, Qilong | Xu, Guolin | Shi, Bian | Ma, Xuhui | Liu, Huaimin | Li, Qiujian | Tian, Tongde | Tang, Jingwen | Niu, Hong

Article Type: Research Article

Abstract: BACKGROUND: Breast cancer is a common gynecological malignant tumor and currently its clinical diagnosis mainly depends on methods of iconography and measurement of serum level. OBJECTIVE: To analyze correlation between serum index levels and prognosis of patients with breast cancer in one week and six months after operation, and to establish support vector machine (SVM) model to evaluate its effectiveness. METHODS: One hundred sixty eight patients diagnosed with breast cancer at Affiliated Cancer Hospital of Zhengzhou University were collected, 46 of which did palindromia while other 122 didn’t six months after operation. Serum …CA153, CA125 and CEA levels of different periods in two groups were analyzed from their differences. Through receiver operating characteristic (ROC) curve analysis, their diagnostic threshold values were calculated, at the same time, SVM model was built. RESULTS: There was a significant difference between serum index levels of recurrence group and non-recurrence group in one week and six months after operation (P < 0.05); SVM model was established with an accuracy of 96.67% (29/30), a sensitivity of 90% (9/10) and a specificity of 100% (20/20). CONCLUSIONS: Serum CAl53, CEA and CA125 levels after operation have certain instructional significance for prognosis of breast cancer patients, and the established SVM model has high clinical application value. Show more

Keywords: Breast cancer, serum marker, prognosis, diagnostic threshold value, SVM

DOI: 10.3233/CBM-160322

Citation: Cancer Biomarkers, vol. 19, no. 4, pp. 403-409, 2017

Authors: Maimaiti, Yusufu | Dong, Lingling | Aili, Aikebaier | Maimaitiaili, Maimaitiaili | Huang, Tao | Abudureyimu, Kelimu

Article Type: Research Article

Abstract: BACKGROUND: Bcl-2 interacting mediator of cell death (Bim) appears to have contradictory roles in cancer. It is uncertain whether Bim show prognostic significance in patients with breast cancer. OBJECTIVE: To investigate the correlation between Bim expression and clinicopathological characteristics of breast cancer and to evaluate Bim’s effect on overall survival (OS). METHODS: We used immunohistochemistry (IHC) technique to detect the expression of Bim via tissue microarray in 275 breast cancer samples, Kaplan-Meier analysis to perform survival analysis, and Cox proportional hazards regression model to explore the risk factors of breast cancer. …RESULTS: The results revealed that Bim expression was significantly correlated with age, estrogen receptor (ER) and/or progesterone receptor (PR), human epidermal growth factor receptor (HER2) and Ki67 expression (P < 0.05). Bim expression was significantly different in the four molecular subtypes (P = 0.000). Survival analysis showed that Bim positive expression contributed to a shorter OS (P = 0.034), especially in patients with luminal A tumors (P = 0.039). Univariate and multivariate regression analysis showed that Bim was an independent prognostic factor for breast cancer (P < 0.05). CONCLUSION: Bim may serve as an effective predictive factor for lower OS in breast cancer patients, especially in those with luminal A tumors. Show more

Keywords: Bim, breast cancer, biomarker, prognosis, luminal A

DOI: 10.3233/CBM-160377

Citation: Cancer Biomarkers, vol. 19, no. 4, pp. 411-418, 2017

Authors: Chen, Xiaoxi | Lai, Xiangwen | Wu, Caixia | Tian, Qingxin | Lei, Tingting | Pan, Jingye | Huang, Guoyu

Article Type: Research Article

Abstract: BACKGROUND: Members of the SIRT family are a highly conserved family of NAD + -dependent enzymes, many of which (SIRT1-7) play an important role in tumor formation. Recently, several studies have suggested that SIRT4 not only regulates glutamine metabolism, but also serves as a tumor suppressor. There are no studies have assessed its clinical significance in endometrioid adenocarcinoma. METHODS: We investigated SIRT4 protein levels in endometrioid adenocarcinoma and its possible association with selected clinico-pathological parameters by immunohistochemical staining of a tissue microarray that included 65 endometrioid adenocarcinoma patients. RESULTS: SIRT4 …protein levels in endometrioid adenocarcinoma were markedly lower than its non-neoplastic tissue counterpart (P < 0.001). Moreover, lower SIRT4 expression levels were observed in advanced AJCC stages of development (P = 0.002). CONCLUSIONS: Our results indicated that SIRT4 may be involved in the development of endometrioid adenocarcinoma and is a promising target for both the diagnosis and potential therapy of endometrioid adenocarcinoma. Show more

Keywords: Endometrioid adenocarcinoma, endometrium, sirtuin, SIRT4

DOI: 10.3233/CBM-160419

Citation: Cancer Biomarkers, vol. 19, no. 4, pp. 419-424, 2017

Authors: Yang, Deying | Zhao, Deqin | Chen, Xinrui

Article Type: Research Article

Abstract: We aimed to investigate the influence of miR-133b/fibrillin 1 (FBN1 ) on proliferation and invasion of human gastric cancer (GC) cells. Carcinomatous and adjacent tissues of 43 GC patients, normal gastric mucosa cell line GES-1 and GC cell lines including AGS, HGC-27, KATO III, NCI-N87, SGC-7901, MKN-45 and MGC-803 were collected. Then, the expressions of miR-133b and FBN1 were detected by qRT-PCR. The dual luciferase reporter gene assay was conducted to determine the targeting relationship between miR-133b and FBN1 .The protein expression levels of FBN1, β -catenin, Cyclin D1, C-myc and MMP-7 were detected by Western …Blot. Furthermore, the cell viability, proliferation, migration and invasion ability were measured by CCK-8, colony formation assay, wound healing assay and Transwell assay, respectively. MiR-133b was down-regulated in GC tissues and cells compared with adjacent tissues and normal cells. Conversely, FBN1 was up-regulated in GC tissues and cells in contrast with adjacent tissues and normal cells. MGC-803 and MKN-45 cell lines were chosen to conduct the following assays. The luciferase reporter assay proved that miR-133b directly targeted FBN1 . The overexpression of miR-133b and silence of FBN1 could inhibit the cell proliferative, migratory and invasive abilities of GC cells, while the influence of down-regulated miR-133b expression and up-regulated FBN1 expression were quite the contrary. Compared with NC group, in the miR-133b mimics group, the expression of β -catenin, N-cadherin and Wnt1 of Wnt/β -catenin signal pathway increased, while the expressions of E-cadherin decreased. MiR-133b inhibits the proliferative, migratory and invasive abilities of GC cells by increasing FBN1 expression. Show more

Keywords: Gastric cancer, miR-133b, FBN1

DOI: 10.3233/CBM-160421

Citation: Cancer Biomarkers, vol. 19, no. 4, pp. 425-436, 2017

Authors: Zhang, Meifeng | Wu, Wei | Gao, Ming | Fei, Zhewei

Article Type: Research Article

Abstract: BACKGROUND AND OBJECTIVE: To investigate the diagnostic potentials of microRNA-451(miR-451) in papillary thyroid carcinoma (PTC) diagnosis and lymph node (LN) metastasis, formalin-fixed, paraffin-embedded (FFPE) tissue specimens corresponding to PTC tumors (n = 60) and their normal counterparts (N ormal tissues A djacent to T umor, NAT, n = 60), along with sera from PTC patients with malignant tumors (n = 70) and benign lesions (n = 70) were analyzed for the expression of miR-451 by real-time PCR. …METHODS: The usefulness of miR-451 expression as a prognostic marker for diagnosis of PTC malignancies was evaluated by Receiver Operating Curve (ROC). We reported that when compared to those in NAT, the levels of miR-451 in FFPE tissues from various stages of PTC patients (n = 60) were significantly lower (Mean ± SEM; 12.62 ± 1.73 vs 38.8 ± 3.51, p < 0.0001). Receiver operating curve (ROC) analysis revealed that the a rea u nder c urve (AUC) was 0.808; suggesting miR-451 expression was a reliable tissue biomarker for PTC malignancies. Further in depth analyses of these specimens revealed that miR-451 levels were significantly lower in PTC patients with lymph node (LN) metastasis than those without LN metastasis (3.96 ± 1.67 vs. 14.15 ± 1.95, p = 0.006) with calculated AUC of 0.792, supporting the notion that miR-451 expression was also a good indicator for PTC lymph node involvements. Analyses sera from the cohorts of PTC patients indicated that miR-451 levels in patients with malignant lesions (n = 70) were significantly lower (10.72 ± 1.52 vs. 19.28 ± 2.73, p = 0.010) than those with benign ones (n = 70). Parallel analyses of serum miR-451 levels in patients with LN metastasis also showed that they were significantly lower when compared to those without LN metastasis (6.79 ± 2.29 vs. 12.08 ± 1.86, p = 0.017). RESULTS: ROC analyses revealed that AUC was 0.626 for malignancies and was 0.690 for lymph node involvement, respectively, suggesting that miR-451was a modest blood based biomarker for PTC malignancies and lymph node metastasis. CONCLUSIONS: We concluded that miR-451 expression is a reliable FFPE tissue biomarker for PTC malignancies and it may have potentials to become a noninvasive, blood-based biomarker for PTC diagnosis and evaluation of LN status. Show more

Keywords: microRNA-451, papillary thyroid carcinoma, diagnosis, lymph node metastasis

DOI: 10.3233/CBM-170059

Citation: Cancer Biomarkers, vol. 19, no. 4, pp. 437-445, 2017

Authors: Dou, Chunqing | Jin, Xin | Sun, Liyuan | Zhang, Bao | Han, Mingming | Li, Tao

Article Type: Research Article

Abstract: OBJECTIVE: The transcription factor FOXF2 is reported to be down-regulated in HCC. Its deficiency is correlated with shorter disease-free survival and overall survival of HCC patients; however, the mechanism remains to be elucidated. MATERIALS AND METHODS: In this study, we performed qRT-PCR and western blotting to confirm the down-regulated FOXF2 in HCC tissue and cell lines. Then the HCC cell line Huh7 transduced with FOXF2 shRNA was adopted in a series of in vitro and in vivo assays to evaluate the cell phenotype change, migration, invasion, proliferation, colonization of circulating cell and the formation of …metastatic nodules. RESULTS: We found that FOXF2 was down-regulated in HCC tissues and cell lines. FOXF2 deficiency in Huh7 cells increased E-cadherin and decreased Vimentin. The down-regulation of FOXF2 impeded HCC cell migration and invasion capacity, but promoted the proliferation of HCC cells and the growth of subcutaneous tumors in nude mice, which indicated a mesenchymal-to-epithelial phenotypic change in Huh7 cells. FOXF2 deficiency enhanced the colonization of circulating HCC cell, thus promoted the formation of metastatic nodules. CONCLUSIONS: FOXF2 deficiency induced mesenchymal-epithelial transition (MET) in Huh7 cell which might facilitate the colonization of circulating tumor cells and the formation of metastasis. Show more

Keywords: Hepatocellular carcinoma (HCC), metastasis, forkhead box F2 (FOXF2), mesenchymal-epithelial transition (MET)

DOI: 10.3233/CBM-170139

Citation: Cancer Biomarkers, vol. 19, no. 4, pp. 447-454, 2017

Authors: Zhao, Qing | Cui, Zheng | Zheng, Yan | Li, Qun | Xu, Changyuan | Sheng, Xueqi | Tao, Mei | Xu, HuiXin

Article Type: Research Article

Abstract: BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor-α (PPAR-α ) activation has been reported to reduce myocardial ischemia-reperfusion (I/R) injury by inhibiting cell apoptosis. However, the antiapoptotic mechanism of PPAR-α is still unknown. Fenofibrate is a PPAR-α agonist In the present study, we investigate the effects and relevant mechanism of fenofibrate on experimental myocardial ischemia-reperfusion (I/R) injury in rats. METHODS: Adult male Wistar rats were pretreated with fenofibrate (80 mg/kg) daily for a period of 7 days. After the treatment period, myocardial I/R injury model was made …by left anterior descending coronary artery ligation for 45 min and reperfusion for 120 min. Myocardial infarct size, malondialdehyde (MDA) cleaved-caspase-9 protein expression, PPARα and uncoupling protein 2 (UCP2) mRNA levels in myocardial tissue were detected Cell apoptosis was detected by Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Serum lactate dehydrogenase and creatine kinase activities were measured in rats pretreated with fenofibrate The ultrastructure of myocardial tissues was observed. RESULTS: Significant increases in myocardial cell apoptosis, malondialdehyde (MDA) level and cleaved-caspase-9 protein expression level in myocardial tissue were observed, along with reductions of PPARα and uncoupling protein 2 (UCP2) mRNA levels in myocardial tissue of the experimental myocardial ischemia-reperfusion (I/R) injury in rats. Impaired mitochondria were also observed under electron microscopic. However, pretreatment of ischemia/reperfusion rats with fenofibrate brought the biochemical parameters and related genes expression levels to near normalcy, indicating the protective effect of fenofibrate against myocardial ischemia/reperfusion injury in rats. CONCLUSIONS: The PPAR-α activator fenofibrate conferred cytoprotective effect against myocardial ischemia-reperfusion (I/R) injury in rats. Associated mechanisms involved decreased cleaved-caspase-9 expression and decreased cell apoptosis. Show more

Keywords: Acute myocardial ischemia/reperfusion injury, apoptosis, PPARα, caspase-9

DOI: 10.3233/CBM-170572

Citation: Cancer Biomarkers, vol. 19, no. 4, pp. 455-463, 2017

Article Type: Other

Citation: Cancer Biomarkers, vol. 19, no. 4, pp. 465-470, 2017