Showing papers in "Neoplasma in 2017"

Long non-coding RNA MALAT1 promotes cholangiocarcinoma cell proliferation and invasion by activating PI3K/Akt pathway.

Abstract: Increasing evidence indicated that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) acted as a key regulator in the proliferation and invasion of several cancers. However, the function of MALAT1 in the development of cholangiocarcinoma has not been experimentally established. In the present study, the expression levels of MALAT1 in cholangiocarcinoma cell lines were detected by quantitative real-time PCR. The effects of MALAT1 knockdown on the cell proliferation and invasion of cholangiocarcinoma cells were detected with Cell Counting Kit-8 (CCK-8), colony formation assay and Trans-well assay, respectively. The expressions of epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, Vimentin) were evaluated to discover whether the process of EMT was involved. We also evaluated the expression of phos-phatidylinositol-3-kinase/serine/threonine kinase (PI3K/Akt) signaling pathway proteins (PI3K, p-PI3K, Akt, p-Akt) to determine the associated molecular mechanism. And we discovered that MALAT1 was up-regulated in cholangiocarcinoma cancer cells. CCK-8, colony formation and trans-well assay showed that the proliferation and invasion of QBC-939 and RBE with MALAT1 knockdown were inhibited. Moreover, MALAT1 could promote EMT in cholangiocarcinoma cells. In addition, MALAT1 may activate PI3K/Akt pathway. These results indicated that MALAT1 promoted cholangiocarcinoma cell proliferation and invasion. The effects of MALAT1 on cholangiocarcinoma cells might be through activating the PI3K/Akt signaling pathway. These investigations may facilitate a better understanding of MALAT1 and it might be a potential therapeutic target for the treatment of cholangiocarcinoma.

miR-361-5p suppresses lung cancer cell lines progression by targeting FOXM1.

Abstract: Lung cancer is the most common type of cancer and the leading cause of death in worldwide. MicroRNAs are known to be key players in a variety of biological processes, including tumorigenesis. In present study, we investigated the effect of miR-361-5p on lung cancer progression. We found that miR-361-5p was down-regulated in lung cancer. Overexpression of miR-361-5p suppressed lung cancer proliferation and invasion. Mechanistically, FOXM1 was identified as a direct target of miR-361-5p. Furthermore, miR-361-5p inhibits EMT-like phenotype through down-regulation of FOXM1 expression in lung cancer cells. In conclusion, our results indicated that miR-361-5p acts as a tumor suppressor in lung cancer.

Detection and characterization of ciRS-7: a potential promoter of the development of cancer.

Abstract: Circular RNAs (circRNAs) are a class of newly-identified non-coding RNA molecules. CircRNAs are conserved across different species and display specific organization, sequence, and expression in disease. Moreover, circRNAs' closed ring structure, insensitivity to RNase, and stability are advantages over linear RNAs in terms of development and application as a new kind of clinical marker. In addition, according to recent studies, circular RNA-7 (ciRS-7) acts as a sponge of miR-7 and thus inhibits its activity. Numerous evidences have confirmed expression of miR-7 is dysregulated in cancer tissues, however, whether ciRS-7 invovled in oncogenesis by acting as sponge of miR-7 remains unclear. Most recently, a study reported ciRS-7 acted as an oncogene in hepatocellular carcinoma through targeting miR-7 expression. This suggest ciRS-7/ miR-7 axis affects oncogenesis, and it provides a new perspective on the mechanisms of decreased miR-7 expression in cancer tissues. Discovery of sponge role of circRNAs caused researchers to more closely explore the underlying mechanism of carcinogenesis and has significant clinical implications, and may open a new chapter in research on the pathology and treatment of cancers. This review summarizes the structure and function of circRNAs and provides evidence for the impact of ciRS-7 in promoting the development of cancer by acting as sponge of miR-7.

miR-215 promotes cell migration and invasion of gastric cancer cell lines by targeting FOXO1.

Abstract: Gastric cancer is one of the most common malignant tumor worldwide and has high morbidity and mortality. microRNAs are small, non-coding RNAs which play critical roles in the post-transcriptional regulation of gene expression. In this current study, we used qRT-PCR to detect miR-215 and FOXO1 expression level in 50 paired gastric cancer tissues and found that miR-215 was frequently overexpressed and FOXO1 was down-regulated in GC cancer tissues. Clinicopathological analysis showed that miR-215 expression level was correlated with the progression of tumor invasion and TNM stage. Additionally, transwell invasion assay showed that miR-215 promoted the migration and invasion of gastric cancer cells. We found that miR-215 decreased FOXO1 expression by directly binding to the 3'-untranslated region (UTR) of FOXO1. These results suggest that miR-215 promotes cell migration and invasion of gastric cancer by targeting FOXO1. Therefore, this study provides a promising therapeutic strategy for treating gastric cancer.

Sympathetic and parasympathetic innervation in hepatocellular carcinoma.

Abstract: Autonomic nervous system plays an important role in the development of multiple cancers via regulating cancer cell proliferation, differentiation, apoptosis, migration and invasion. However, no detailed studies have been performed to study the role of autonomic nerve fibers in hepatocellular carcinoma (HCC) as well as its correlation with the progression of HCC. Here, we examined the distribution of the autonomic nerve fibers and analyzed the correlation between autonomic nerve fibers and the pathological characteristics of HCC patients. The transcriptional expression of adrenergic and cholinergic receptors was evaluated in both hepatoma cell lines and primary hepatoma cells. In addition, we summarized the function of receptors for neurotransmitters in different cancers recently reported. Our findings indicate that tissue of liver cancer is innervated by both sympathetic and parasympathetic nerves and the density of the nerve fibers is associated with patients' poor prognosis. Additionally, we report that adrenergic receptors β2 and cholinergic receptors α7, M1 and M3 are high expressed in both hepatoma cell lines and primary hepatoma cells, indicating these receptors may play essential roles in the regulation of autonomic nervous system triggered HCC.

FBP1 modulates cell metabolism of breast cancer cells by inhibiting the expression of HIF-1α.

Abstract: This study aimed to investigate the function of fructose-1, 6-bisphosphatase 1 (FBP1) in regulating cell growth and metabolism through hypoxia-inducible factor 1α (HIF-1α)-dependent hypoxic response in breast cancer cells. Two human breast carcinoma cell lines, including luminal-like cell line MCF-7 and basal-like cell line MDA-MB-468, were cultured under hypoxia condition, then the expressions of FBP1 and HIF-1α were detected by western blotting. In addition, up-regulated FPB1 in MDA-MB-468 cells were induced by lentivirus. Next, cell growth, migration and glucose metabolism were evaluated by MTT assay, Transwell and commercial kits, as well as the expressions of HIF-1α target genes, including pyruvate dehydrogenase kinase 1 (PDK1), lactate dehydrogenase A (LDHA), glucose transporter 1 (GLUT1) and vascular endothelial growth factor (VEGF) were detected by RT-qPCR. Furthermore, chromatin immunoprecipitation was used to estimate whether the hypoxia response elements (HREs) of PDK1, LDHA, GLUT1 and VEGF promoters were incorporated with FBP1. FBP1 was downregulated in MDA-MB-468 cells compared with MCF-7 cells. Overexpression of FBP1 in MDA-MB-468 cells reduced cell growth (p < 0.05) and migration (p < 0.05) as well as glycose consumption (p < 0.05) and lactate production (p < 0.05). In addition, overexpressed FBP1 inhibited HIF-1α protein expression and the mRNA levels of PDK1, LDHA, GLUT1 and VEGF (p < 0.05) under hypoxia condition. Also, FBP1 was revealed to have a concrete connection with PDK1. This study reveal that overexpressed FBP1 may repress tumor growth, migration and glycolysis via targeting HIF-1α in BLBC.

Combination of LINE-1 hypomethylation and RASSF1A promoter hypermethylation in serum DNA is a non-invasion prognostic biomarker for early recurrence of hepatocellular carcinoma after curative resection

Abstract: Hepatocarcinogenesis, a multistep process, involves not only genetic mutations but also epigenetic alterations. Widespread of global DNA hypomethylation is accompanied with specific regional hypermethylation especially at tumor suppressor genes' promoters. The aim of this study is to determine the efficacy of combined DNA methylation analysis of a global DNA methylation marker - LINE-1 and a tumor suppressor gene highly associated with the malignancy of HCC- RASSF1A in serum as a novel prognostic marker for diagnosis of early recurrence after curative resection.LINE-1 was hypomethylated in 66.7% (70/105) and RASSF1A promoter was hypermethylated in 73.3% (77/105) of HCC serum DNA samples by methylation specific PCR, but in none of the healthy controls: LINE-1 hypometylation (0/50) and RASSF1A hypermethylation (0/50). A significant association was found between LINE-1 hypomethylation and clinical pathologic features including HBsAg positivity (p=0.009), tumor size (p=0.001) and AFP levels (p<0.001). Besides, significant correlation was detected between RASSF1A promoter hypermethylation and lymph nodes metastasis (p=0.045).The results of Kaplan-Meier estimates of survival suggested that LINE-1 hypomethylation was highly associated with poor survival of patients (disease-free survival p=0.002, overall survival p=0.0123). More importantly, co-evaluation of LINE-1 hypomethylation and RASSF1A promoter hypermethylation was found to be significantly correlated to early recurrence and poor prognosis (disease-free survival p=0.0001, overall survival p=0.05) in patients after curative resection.In conclusion, our study showed that the combined examination of LINE-1 hypomethylation and RASSF1A promoter hypermethylation was effective in predicting early recurrence of HCC after curative resection. Patients with dual positivity of LINE-1 hypomethylation and RASSF1A promoter hypermethylation should be supplied with more intensive care and close follow-up after they undergo tumor resection.

Preoperative mean platelet volume and platelet distribution associated with thyroid cancer.

Abstract: Thyroid cancer is the most frequent cancer of the endocrine glands and the fifth most frequent cancer in women. Activated platelets play a crucial role in thrombosis, inflammation, and cancer. Mean platelet volume (MPV) and platelet distribution width (PDW) are early index of platelet activation. The purpose of this study is to investigate platelet indices levels in thyroid cancer. The study enrolled 280 patients with thyroid cancer and 280 control subjects. Patients' characteristics and hematologic tests data were collected at the time of diagnosis. Correlations between platelet indices and clinical characteristics were analyzed. The odds ratios (ORs) and 95% confidence intervals (CIs) for thyroid cancer were calculated using multivariate logistic regression analyses across MPV and PDW quartiles. The patients with thyroid cancer had lower MPV and higher PDW compared with control subjects. MPV was correlated with tumor-nodus-metastases (TNM) stage and lymph node metastasis. Moreover, after adjusting for other risk factors, the prevalence risk of thyroid cancer for the lowest quartile of MPV was 7.242 (4.069-12.887) (P < 0.001) and for the highest quartile of PDW was 6.065 (3.321-11.076) (P < 0.001), respectively. The study showed that the patients with thyroid cancer have lower MPV and higher PDW compared to control subjects. Moreover, MPV and PDW were independently associated with the presence of thyroid cancer. Further studies are needed to evaluate the utility of MPV and PDW as novel diagnostic screening tools for thyroid cancer.

BRAF inhibitors: efficacious and tolerable in BRAF-mutant acral and mucosal melanoma.

Abstract: BRAF inhibitors substantially have impressive clinical efficacy in cutaneous melanoma. However, their role in acral and mucosal melanoma remains unclear. Records were reviewed of patients with metastatic or unresectable BRAF-mutant acral and mucosal melanoma hospitalized and administrated BRAF inhibitors during January 2011 and March 2016. Clinical data were collected to determine PFS, ORR, DCR, OS, and safety. Among 28 acral and 12 mucosal melanoma patients treated with BRAF inhibitors, median PFS were 3.6 (95%CI 3.0-6.4) and 4.4 (95%CI 0.8-12.7) months, median OS were 6.2 (95%CI 6.1-12.1) and 8.2 (95%CI 6.6-19.9) months; ORRs were 38.1% and 20.0%, DCRs were 81.0% and 70.0% in acral and mucosal melanoma, respectively. BRAF inhibitors were well tolerated. The most common adverse effects (AEs) were cutaneous and hematological. Grade 3/4 AEs were relatively rare. In conclusion, BRAF inhibitors have acceptable efficacy and good tolerance in BRAF mutant acral and mucosal melanoma.

MiR-99a-5p regulates proliferation, migration and invasion abilities of human oral carcinoma cells by targeting NOX4.

Abstract: Previous research has showed that miR-99a-5p was a tumor suppressor. The aim of our study was to explore the effect of miR-99a-5p on the vitality and proliferation, migration together with the invasion of oral tumor cells via inhibiting the expression of NOX4. QRT-PCR and Western blot were applied to examine the expression level of miR-99a-5p and NOX4 in human oral tumorous and adjacent tissues. Dual luciferase reporter gene assay was applied to confirm that miR-99a-5p negatively regulated directly on NOX4 in TSCC1 cells. Cell transfection and lentiviral vectors were used to up-regulate expression of miR-99a-5p and NOX4, respectively. Cell proliferation, cell cycle, apoptosis and invasion along with the migration in different groups were assessed using MTT assay, colony formation assay, the flow cytometry, transwell assay and the wound healing assay, respectively. MiR-99a-5p was under-expressed in human oral tumor, while NOX4 was over-expressed. There was a negative relationship between miR-99a-5p and NOX4. Up-regulating miR-99a-5p or down-regulating NOX4 suppressed the vitality, proliferation, migration together with invasion of TSCC1 cells. MiR-99a-5p affected the vitality and proliferation, migration together with the invasion of oral tumor cells through targeting NOX4.

MicroRNA-1285 inhibits malignant biological behaviors of human pancreatic cancer cells by negative regulation of YAP1.

Abstract: Pancreatic ductal adenocarcinoma is a most deadly malignancy, with a 5-year survival rate of ~7%. Chemotherapy is the main treatment strategy of this disease. However, the high rate of resistance to chemotherapeutic agent contributes to poor prognosis. MicroRNAs are essential for the initiation, progression and chemoresistance of human malignancies. Previous studies have shown that miRNA-1285 participates in renal cell carcinoma and hepatocellular carcinoma. However, its roles in pancreatic ductal adenocarcinoma are poorly understood. In this study, we confirmed that miR-1285 was significantly down-regulated in gemcitabine-resistant pancreatic cancer cell lines by qRT-PCR. We found that miR-1285 suppressed cell proliferation as well as increased the sensitivity of PDAC cells to gemcitabine by CCK8 assays in vitro. Results from transwell assay indicated that miR-1285 inhibited pancreatic cancer cell migration and invasion. Experiments using different cell lines got identical results. All those results demonstrated that miR-1285 act as tumor suppressor of pancreatic cancer. To our knowledge, this study is the first to elucidate the function of miR-1285 in pancreatic cancer. Western blotting analysis verified that miR-1285 negatively regulated YAP1 protein level, together with EGFR and β-catenin. YAP1 is a known oncoprotein of pancreatic cancer. As silencing of YAP1 activity might be beneficial in cancer prevention and treatment, our results suggest that miR-1285 might serve as a novel therapeutic target for miRNA-based therapy in pancreatic cancer. Further research elucidating the exact mechanisms of miRNA-1285 function and the correlation between miR-1285 levels in tissues or serum and clinical characteristics of pancreatic cancer is needed later.

A microRNA expression signature as a predictor of survival for colon adenocarcinoma.

Abstract: Colon cancer is a major cause of cancer mortality worldwide and most colon cancers are adenocarcinoma. MicroRNA (miRNA) expression signature has been shown to be able to predict progression and prognosis of various cancers. The aim of our study was to explore a novel signature of microRNA expression for predicting survival of colon adenocarcinoma patients. By analyzing the miRNA expression profiles and clinical information of 329 colon adenocarcinoma patients derived from The Cancer Genome Atlas database. 129 miRNAs were identified to be expressed differentially between the cancer and adjacent tissues. Among them, 27 miRNAs were found to be associated with the corresponding clinical characteristics of the patients. Furthermore, 7 miRNAs (let-7a-2, mir-32, mir-181a-1, mir-197, mir-328, mir-505 and mir-652) were found to be significantly correlated with the patient survival. The risk established by the 7-miRNA signature we built was proved be an independent prognostic factor (Hazard ratio [HR] = 2.048; 95% CI = 1.144-3.664; p, 0.016). In summary, our study identified miRNAs correlated with progression and prognosis of colon adenocarcinoma and built a 7-microRNA expression signature for prediction of the survival of the patients with colon adenocarcinoma.

miR-33a expression sensitizes Lgr5+ HCC-CSCs to doxorubicin via ABCA1.

Abstract: Cancer stem cells (CSCs) are responsible for the unrestrained cell growth and chemo-resistance of malignant tumors. Reports about miR-33a in different type of cancer are limited, and it remains elusive whether there is a link between miR-33a and chemo-resistance of CSCs. Here we report that Lgr5+ hepatocellular carcinoma (HCC) cells from primary tissues and cell lines behave similarly to CSCs and are chemo-resistant to doxorubicin. Significantly, reduced miR-33a expression is associated with the chemo-resistance of Lgr5+ HCC-CSCs, accompanied by an overexpression of ABCA1 which is identified as target of miR-33a by mainly using miRNA luciferase assay and western-blotting. We demonstrate that down-regulation of miR-33a expression directly contributes to chemo-resistance of Lgr5+ HCC-CSCs, and restoring miR-33a expression sensitizes them to doxorubicin via apoptosis by mainly using TUNEL assay, soft agar colony formation assay and xenograft assay. Additionally, reduced miR-33a expression in HCC tissues is associated with chemo-response and poor patient survival, which suggests the therapeutic potential of miR-33a. In conclusion, our work indicates that ectopic miR-33a expression sensitizes Lgr5+ HCC-CSCs to doxorubicin via direct targeting ABCA1, which sheds new light on understanding the mechanism of chemo-resistance in HCC-CSCs and contributes to development of potential therapeutics against HCC.

Long noncoding RNA ASAP1-IT1 promotes cancer stemness and predicts a poor prognosis in patients with bladder cancer.

Abstract: Urinary bladder cancer (UBC) is one of the most common urogenital malignancies. Cancer stem-like cells (CSCs) play a vital role in tumor development and recurrence. Long noncoding RNAs (lncRNAs) are reported to influence cancer progression via transcriptional, posttranscriptional or epigenetic regulation. Dysregulation of several lncRNAs has been implicated in UBC. In our study, we found that an uncharacterized lncRNA, ASAP1-IT1, was overexpressed in UBC tissues compared with adjacent non-malignant tissues. High ASAP1-IT1 expression levels in UBC specimens were correlated with advanced tumor stage, higher clinical stage, poor pathological differentiation and bad overall survival. We further found that depletion of ASAP1-IT1 in T24 cells by RNA interference reduced the stemness of bladder cancer, whereas forced overexpression of ASAP1-IT1 in J82 cells enhanced cancer cell stemness by sphere assay, ALDEFLUOR and flow cytometry assay on CD44+ population. Our data suggest that ASAP1-IT1 plays an oncogenic role in bladder cancer and can be used as a potential prognostic and therapeutic target.

miR-508-5p acts as an anti-oncogene by targeting MESDC1 in hepatocellular carcinoma.

Abstract: Hepatocellular carcinoma (HCC) is the third leading cause of cancer associated mortality. Accumulating evidence has shown that microRNAs (miRNAs) act as critical factors for tumor recurrence and metastasis. MiR-508-5p has been reported as a down-regulated miRNA in the primary gastric cancer tissues. However, the role of miR-508-5p on HCC has not been well elucidated. In this study, we observed that miR-508-5p was downregulated in HCC tissues when compared to the non-tumorous tissues. We then demonstrated that overexpression of miR-508-5p attenuated HepG2 cells proliferation and invasion and induced cell apoptosis in vitro. Furthermore, our further investigations revealed that mesoderm development candidate 1 (MESDC1) is a potential target of miR-508-5p, as well as miR-508-5p overexpression downregulated MESDC1 expression. Overexpression of MESDC1 promoted HepG2 cells migration, invasion and proliferation in vitro. In addition, miR-508-5p markedly suppressed the tumor growth in xenograft model, while MESDC1 promoted the tumor growth in xenograft model. This study provides new insight into molecular mechanisms that miR-508-5p acts as a tumor suppressor by targeting MESDC1 in HCC progression.

Predicative values of serum microRNA-22 and microRNA-126 levels for non-small cell lung cancer development and metastasis: a case-control study.

Abstract: Presented study aims to explore the predictive values of serum microRNA-22 (miR-22) and miR-126 levels for non-small cell lung cancer (NSCLC) development and metastasis.A total of 127 NSCLC patients who were admitted in the First People's Hospital of Yancheng City from May, 2013 to May, 2015 were selected as the case group, including 71 cases of adenocarcinoma and 56 cases of squamous cell carcinoma. There were 112 healthy individuals selected as the control group. The qRT-PCR was performed to testify the serum miR-22 and miR-126 levels. Logistic regression analysis was conducted to analyze independent factors influencing NSCLC metastasis and receiver operating characteristic (ROC) curve was drawn to analyze the sensitivity and specificity of serum miR-22 and miR-126 levels in predicting NSCLC developments and metastasis.The serum miR-22 level was significantly higher in the case group than that in the control group, while the serum miR-126 level was lower in the case group as compared with that in the control group. Compared with squamous cell carcinoma patients, serum miR-22 level significantly increased, while serum miR-126 level decreased in patients with adenocarcinoma. Patients at III + IV stage showed increased serum miR-22 level and relatively decreased serum miR-126 level as compared to patients at I + II stage. Serum miR-22 level elevated in patients with metastasis; in contrast serum miR-126 level reduced in comparison to those without metastasis. In patients with familial inheritance, serum miR-22 level increased but serum miR-126 level decreased as compared to those without familial inheritance. The specificity and sensitivity of serum miR-22 and miR-126 levels in predicting NSCLC development were 99.11%, 84.30%, 82.68% and 96.40%, respectively. The specificity and sensitivity of serum miR-22 and miR-126 levels in predicting NSCLC metastasis were 59.74%, 96.00%, 84.00% and 62.30%, respectively.Results indicated that serum miR-22 and miR-126 levels may be used as the predicative biomarkers for NSCLC development and metastasis.

Hyaluronic acid/ Hyaluronidase as biomarkers for bladder cancer: a diagnostic meta-analysis.

Abstract: This study aimed to determine the value of HA/HAase for detecting bladder cancer on the basis of preceding statistical performance. PubMed, Springer Link, Web of Science and Cochrane Library were systematically searched to identify potentially relevant published articles by using the key words: "bladder cancer or bladder tumor or bladder carcinoma", "hyaluronic acid or hyaluronan", "hyaluronidase or HAase". The methodological quality of each study was assessed by QUADAS-2. According to the inclusive and exclusive criteria, 8 articles were identified and methodologically analyzed by STATA 12.0 software package.The results showed that the pooled sensitivity of HA and HAase was 0.832 (95% confidence interval [CI]: 0.798, 0.861) and 0.834 (95% CI: 0.756, 0.891) respectively, the pooled specificity was 0.886 (95% CI: 0.852, 0.913) and 0.860 (95% CI: 0.801, 0.904), and the area under the summary ROC cure (AUC) was 0.90 (95% CI: 0.87, 0.92) and 0.91 (95% CI: 0.88, 0.93), respectively. Simultaneously the diagnostic accuracy of the combination of HA and HAase showed that the pooled sensitivity was 0.908 (95% CI: 0.879, 0.931), the pooled specificity was 0.825 (95% CI: 0.789, 0.856) and AUC was 0.94 (95% CI: 0.91, 0.95), indicating a relatively higher accuracy than HA and HAase alone. This meta-analysis strongly suggests that HA/HAase could be used as biomarkers for the diagnosis of bladder cancer.

MiR-34a suppresses HNSCC growth through modulating cell cycle arrest and senescence.

Abstract: MiR-34a acts as a tumor suppressor in various malignancies. In HNSCC, the role of miR-34a in proliferation has not been fully elaborated and the target genes are still bind. Here, we addressed that forced miR-34a expression induced cell cycle arrest and senescence. Hypoxia/HIF1α was found to negatively correlate to the expression of miR-34a in HNSCC tissues and partially reverse miR-34a-imposed cell senescence through suppressing miR-34a expression. In order to screen the possible target genes of miR-34a in HNSCC, the differential genes mediated by miR-34a were screened by mRNA microarray. There were 91 genes co-down regulated in two cell lines, which were closely associated with MAPK, ErbB and p53 pathways. Genes, including FUT1, AXL, and MAP2K1 were finally identified as the novel targets of miR-34a by qPCR and luciferase assay. These findings indicate that miR-34a plays an essential role in suppressing HNSCC growth through inducing cell cycle arrest and senescence, by targeting proliferation-associated genes.

Expression of orphan GPR56 correlates with tumor progression in human epithelial ovarian cancer.

Abstract: G protein-coupled receptor 56 (GPR56) has been demonstrated to be a significant prognostic predictor in several types of malignances, including melanoma, glioblastoma, breast cancer, colon cancer, and pancreatic cancer. GPR56 has a putative mucin-like extracellular domain, indicating functions for this receptor in the cell-cell interactions and triggering different downstream signaling pathways responsible for regulating cell survival, proliferation, adhesion, and migration. But the expression and clinical significance of GPR56 has not been elucidated in epithelial ovarian cancer (EOC). We detected GPR56 expression by immunohistochemistry in 110 samples of ovarian serous carcinoma to explore the correlation between its expression and clinicopathologic characteristics and overall survival. As the result, we found that GPR56 expression is significantly associated with advanced FIGO stage (P = 0.01) and positive lymph node invasion (P = 0.016), and it serves as an independent unfavorable prognostic factor through univariate and multivariate analysis. GPR56 knockdown could dramatically decrease the proliferation and invasion of epithelial ovarian cancer cells through down-regulating the RhoA-GTP level and up-regulating the E-cadherin level, which indicates GPR56 could promote the progression and invasion of EOC. In conclusion, GPR56 expression was demonstrated as an independent prognostic factor in EOC, suggesting that GPR56 may play an oncogenic role through the Rho and E-cadherin pathway and GPR56 could be a novel potential drug target in EOC.

MicroRNA-584-3p reduces the vasculogenic mimicry of human glioma cells by regulating hypoxia-induced ROCK1 dependent stress fiber formation.

Abstract: We report in this study that microRNA-584-3p (miR-584-3p) is related to the vasculogenic mimicry (VM) of human glioma cells. Unsurprisingly, the postoperative survival time was significantly prolonged in those glioma patients without VM phenomena compared with those with positive VM. miR-584-3p may function as a potent tumor suppressor by inhibiting VM of malignant glioma. However, the molecular mechanisms underlying these properties remain poorly understood. Our preliminary mechanistic studies revealed that miR-584-3p suppressed the VM by disturbing hypoxia-induced stress fiber formation and migration of glioma cells. Specifically, we defined ROCK1 as a potential functionally relevant target of miR-584-3p involved in this process in glioma cells. Our results demonstrate a tumor suppressor function for miR-584-3p in glioma, where it inhibits the VM of tumor cells by antagonizing hypoxia-induced ROCK1-dependent stress fiber formation. Our findings have potential implications for glioma gene therapy by targeting miR-584-3p and suggest that VM could represent a prognostic indicator for gliomas.

Inhibition of JMJD6 expression reduces the proliferation, migration and invasion of neuroglioma stem cells.

Abstract: Neuroglioma is the most common form of human primary malignant brain tumor, more and more studies recently showed only a small subpopulation of glioma cells which called glioma stem cells have true tumorigenic potential. Meanwhile, it was reported the overexpression of JMJD6 protein is closely involvement with the occurrence and development of multiple tumors, and JMJD6 is required for the differentiation of multiple organ, tissues and cells during embryogenesis. However, the influence of JMJD6 overexpression on neuroglioma development is unclear now. Hence, to explore the effects of JMJD6 expression on neuroglioma, we firstly isolated glioma stem cells by using CD133 MicroBead Kit, and identified via neurosphere-forming assay and Immunofluorescence staining. At the same time, we investigated the effects and mechanism of JMJD6 on the proliferation, migration and invasion of glioma stem cells through MTT, transwell assays and the Cignal finder cancer 10-pathway reporter array. The results demonstrated that the glioma neurosphere cells positively expressed stem cell marker SOX2, neuroectodermal stem cell marker Nestin, and also expressed astrocytes marker GFAP and neurons marker β-tubulin III fter FBS-induced differentiation for a week, which proved the glioma neurosphere cells have the self-renewal and multipotential differentiation capacity. Moreover, shRNA lentiviral vector mediated knockdown of JMJD6 in glioma stem cells led to decreased proliferation, migration and invasion, the underlying molecular mechanism is related to the weaken of Wnt signaling pathway and strengthen of p53 signaling pathway.

Radionuclides in radiation-induced bystander effect; may it share in radionuclide therapy?

Abstract: For many years in radiobiology and radiotherapy predominated the conviction that cellular DNA is the main target for ionizing radiation, however, the view has changed in the past 20 years. Nowadays, it is assumed that not only directed (targeted) radiation effect, but also an indirect (non-targeted) effect may contribute to the result of radiation treatment. Non-targeted effect is relatively well recognized after external beam irradiation in vitro and in vivo, and comprises such phenomena like radiation-induced bystander effect (RIBE), genomic instability, adaptive response and abscopal (out of field) effect. These stress-induced and molecular signaling mediated phenomena appear in non-targeted cells as variety responses resembling that observed in directly hit cells. Bystander effects can be both detrimental and beneficial in dependence on dose, dose-rate, cell type, genetic status and experimental condition. Less is known about radionuclide-induced non-targeted effects in radionuclide therapy, although, based on characteristics of the radionuclide radiation, on experiments in vitro utilizing classical and 3-D cell cultures, and preclinical study on animals it seems obvious that exposure to radionuclide is accompanied by various bystander effects, mostly damaging, less often protective. This review summarizes existing data on radionuclide induced bystander effects comprising radionuclides emitting beta- and alpha-particles and Auger electrons used in tumor radiotherapy and diagnostics. So far, separation of the direct effect of radionuclide decay from crossfire and bystander effects in clinical targeted radionuclide therapy is impossible because of the lack of methods to assess whether, and to what extent bystander effect is involved in human organism. Considerations on this topic are also included.

High Farnesoid X Receptor (FXR) expression is a strong and independent prognosticator in invasive breast carcinoma.

Abstract: Farnesoid X Receptor (FXR), a nuclear receptor superfamily member, is related with bile acids, glucose and lipids metabolism and recently with cancer. In the present study the clinical significance of FXR expression in invasive breast carcinoma was evaluated. FXR protein expression was assessed immunohistochemically on paraffin-embedded breast cancer tissues obtained from 115 breast cancer patients and was statistically analyzed with clinicopathological parameters, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression, as well as with tumor cells' proliferative capacity and overall and disease-free patients' survival. FXR positivity was noted in 91 (79.1%) and high FXR expression in 51 (44.3%) out of 115 invasive breast carcinoma cases. High FXR expression was significantly associated with smaller tumor size (p=0.0318) and increased tumor cells' proliferative rate (p=0.0375). Invasive breast carcinoma patients presenting high FXR expression showed significantly longer overall and disease-free survival times compared to those with low FXR expression (log-rank test, p=0.0052 and p=0.0058). In multivariate analysis, FXR expression was identified as independent prognostic factor of overall and disease-free patients' survival (Cox-regression analysis, p=0.0023 and p=0.0049, respectively). The present data support evidence that FXR may be implicated at the earlier stage of breast malignant disease progression, being a strong and independent prognosticator of favorable overall and disease-free survival in invasive breast carcinoma.

Knockdown of CFTR enhances sensitivity of prostate cancer cells to cisplatin via inhibition of autophagy.

Abstract: Prostate cancer is one of the most lethal diseases in men worldwide. Although the survival rate of men diagnosed with prostate cancer has increased with the improvement of treatments, drug resistance still remains a big challenge for improving overall survival. Cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated anion channel, has been reported to have a pivotal role in the pathogenesis of various cancers, but its role in chemoresistance of prostate cancer cells is poorly understood. In our study, we found that CFTR expression was significantly increased in prostate cancer tissues associated the chemoresistance, and in the cisplatin-resistant cell line LNCaP/CP compared with their respective parental cells. Cisplatin treatment inhibited CFTR expression in a concentration-dependent manner, which was correlated with a decrease in cell viability. Moreover, inhibition of CFTR by transfection of small interfering RNA enhanced cisplatin-induced the decrease of cell viability. Autophagy was dramatically increased in LNCaP/CP cells, as evidenced by autopaphgic markers as well as fluorescence microscopy analysis of GFP-LC3, MDC and AO staining. Of note, inhibiting autophagy by 3MA induced LNCaP/CP cell apoptosis, showed by MTT assay and Hoechst 33258 staining. In addition, blockade of CFTR also inhibited LNCaP/CP cell viability and autophagy. Furthermore, the dephosphorylation of AKT and mTOR was reversed by CFTR inhibition, indicating the knockdown of CFTR might inhibit autophagy in LNCaP/CP cells via activation of AKT/mTOR signaling. Altogether, these results provide a novel understanding of the mechanism for acquired cisplatin. Inhibition of CFTR may be a useful strategy to increase the efficacy of cisplatin to treat prostate cancer by preventing the protective response of autophagy.

Identification of chemokine CXCL10 in tumor microenvironment by antibody array as a prognostic marker in hepatocellular carcinoma.

Abstract: Immunological microenvironment is not only composed of multiple immune cells, but also deposited various inflammation factors that regulate immune response to tumor cells. To ascertain the crucial immune factors presented in hepatocellular carcinoma microenvironment (HCM), tumor tissue culture supernatant (TCS) and the corresponding non-tumor tissue culture supernatant (NCS) from patient with hepatocellular carcinoma (HCC) were analyzed by antibody array technology. Among the inflammation-associated cytokines assayed, high level of chemokines CXCL8/IL-8 (6.82-fold increase) and CXCL10/IP-10 (16.45-fold increase) in TCS than that in paired NCS were evidently identified. And low expression of IL-16 (0.14-fold decrease) and RANTES/CCL5 (0.17-fold decrease) in TCS were also uncovered. Especially, overexpression of CXCL10 in primary HCC compared with their non-tumor counterparts was significantly associated with serum AFP level (P = 0.004), tumor size (P = 0.021), tumor number (P < 0.001) and TNM stage (P = 0.027). In addition, Kaplan-Meier curves demonstrated that patients with higher CXCL10 expression levels had significantly poorer overall survival (P = 0.016) and disease-free survival (P = 0.022) than those with lower CXCL10 expression levels. Univariate and multivariate analyses revealed that the level of CXCL10 expression was an independent prognostic factor for overall survival in HCC patients. In summary, high concentration of CXCL10 is deposited in HCM identified by antibody array, which may contribute to the prediction of clinical outcome of HCC patients.

Epigallocatechin gallate inhibits the growth of salivary adenoid cystic carcinoma cells via the EGFR/Erk signal transduction pathway and the mitochondria apoptosis pathway.

Abstract: ACC is one of the most malignant tumors in salivary gland, and of poor prognosis. A critical role in ACC development and progression is played by EGFR family members including EGFR. EGCG, a low molecular weight polyphenol contained in green tea, has broad anticancer properties, but whether EGCG regulates activity of ACC is unknown. In the present study, the effects of EGCG were investigated in vitro with particular attention to the pathway of EGFR/Erk and mitochondria apoptosis in SACC-83 cell lines. The results of MTS assay and flow cytometry demonstrated that EGCG (20-80 μM) could inhibit proliferation and promote apoptosis of SACC-83 cells. Furthermore, by Western blotting with antibodies specific for EGFR, Erk 1/2 (p-Erk 1/2), Mek (p-Mek), Bcl-2, and Bax, it was demonstrated that EGCG could reduce the expression of EGFR, inhibit phosphorylation of Erk 1/2 and Mek, downregulate Bcl-2, and upregulate Bax. In addition, it was also shown that EGCG could inhibit mRNA expression of P90 RSK by RT-PCR. In conclusion, the results suggest that EGCG might be a potential therapeutic or adjuvant strategy for the treatment of patients with ACC, by inhibiting proliferation and inducing the apoptosis of the tumor cells.

Mechanisms regulating radiosensitivity of glioma stem cells.

Abstract: Malignant glioblastoma (GBM) has become a very common and difficult brain tumor given its low cure rate and high recurrence rate. GBMs are resistant to treatments because glioma stem cells (GSCs)/glioma-initiating cells (GICs), a specific subpopulation of GBM, possess properties of tumor stem cells, such as unlimited proficiency, self-renewal, differentiation and resistance to chemotherapy and radiotherapy, and exhibit a very strong DNA repair capability. Radiotherapy has become a preponderant treatment, and researchers have found many significant tumor microenvironmental factors and valuable signaling pathways regulating the GSC radioresistance, including NOTCH, Wnt/β-catenin, Hedgehog, STAT3, and PI3K/AKT/mTOR. Therefore, we seek to boost GSC radiosensitivity through activating or inactivating pathways alone or together to eliminate the likely source of glioma and prolong survival of patients.

Late cardiac effect of anthracycline therapy in physically active breast cancer survivors - a prospective study.

Abstract: The late-onset cardiotoxic effect of anthracycline is known, however the early detection and prevention of subclinical myocardial damage has not been fully understood yet. Besides medical therapy regular physical activities may also play a role in the prevention and reduction of side effects of chemotherapy. The aim of our present study was to detect the effect of regular physical activities on the diastolic function and on the symptoms of late heart failure in case of anthracycline chemotherapy. The prospective study included 55 female patients (age 31-65 year, average 49.5 years) with breast cancer and no cardiovascular risk factors. Proper cardiologic checkup included physical examination (blood pressure, pulse, etc.), ECG, standard echocardiography parameters (EF, LV dimensions etc.) and specific tissue Doppler (TDI) measurements. Symptoms of heart failure were also recorded. After five years of follow-up, symptoms of heart failure were evaluated again. Patients were assigned into two groups depending on their physical activity: 36 patients did perform regular physical activities (mean age 49.2 years) and 19 patients did not (average age 50.1 years). There was no significant difference between the two groups in basic physiological or standard echocardiography parameters neither at the baseline nor at the later time points. Diastolic dysfunction (decreased E/A) was detected 6 months after the beginning of the treatment (T2 time point) in both groups. In the inactive group this value fell below one however there was no significant difference (1.1±0.25 vs. 0.95±0.22). One year after the beginning of the treatment (T3) a significant difference could be detected between the two groups (1.05±0.28 vs. 0.86±0.25. P=0.038). Consistent change in diastolic function (Ea/Aa) could be detected with the more sensitive TDI (Tissue Doppler Imaging) measurements after treatments in both groups, especially in the septal segment (in the non active group the Ea/Aa decreased markedly but not significantly at T2 - 1.1±0.55 vs. 0.81±0.44, and this difference became significant at T3 and 2 years after treatment (T4), p=0.007 and p=0.065). The filling pressure (E/Ea) rose above 10 (p=0.09) in the non active group at T2; and it kept rising in both groups and became significant at T3 (p=0.012). Five years after the onset of the treatment symptoms of heart failure were less frequently reported in the physically active group than in the inactive one (19.45% vs. 68.42%). The data of our study show that the diastolic dysfunction of the left ventricle related to the anthracycline therapy became evident in the physically active group later and the symptoms of heart failure were less frequent than in the non active group after five years period. Enrollment in sport activities could be a good means for partial prevention in this group of patients. Cardiologic checkup at proper intervals plays a pivotal role in detection of possible cardiotoxicity. This is a strong indication for changes in the lifestyle of the patient and the treatment protocol alike.

The miR-93 promotes proliferation by directly targeting PDCD4 in hepatocellular carcinoma.

Abstract: Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide. Although advances have made in treatment of HCC, the overall survival rate remains low and the molecular pathogenesis of HCC is still poorly understood. The purpose of this study was to explore the molecular pathogenesis of HCC. A total of 89 patients were involved in the study. MicroRNA-93 (miR-93) was aberrantly up-regulated in HCC tissues as determined by qRT-PCR. The high level of miR-93 was closely associated with larger tumor size (p < 0.05) and poor overall survival (p < 0.05). In in vitro and in vivo assays, we demonstrated that high miR-93 levels enhanced cell growth of HCC. The luciferase activity assay showed that PDCD4 was a direct target of miR-93 and its expression was down-regulated by miR-93. Re-expression of PDCD4 inversely correlated with the level of miR-93 and attenuated the miR-93-induced promotion of cell growth in HCC. Taken together, our data indicate that miR-93 may function as an oncogenic factor in HCC, and promotes HCC cell proliferation by targeting PDCD4.

Methylation of SOX1 and VIM promoters in serum as potential biomarkers for hepatocellular carcinoma

Abstract: Aberrant methylation of tumor-related genes has been identified as a promising biomarker for hepatocellular carcinoma (HCC). This study aimed to investigate the diagnostic value of SRY (sex determining region Y)-box 1 (SOX1) and Vimentin (VIM) promoter methylation for HCC. The study included 360 subjects, 240 patients with HCC, 29 with liver cirrhosis (LC), 66 with chronic hepatitis B (CHB) and 25 healthy controls (HCs). The methylation status of SOX1 and VIM promoters in the serum was detected by methylation-specific polymerase chain reaction (MSP). The methylation frequencies of SOX1 and VIM promoters in HCC patients were significantly higher than those in LC (p<0.001 and p<0.001), CHB (p<0.001 and p<0.001) and HC (p<0.001 and p<0.001) subjects. Furthermore, hypermethylation of SOX1 and VIM promoters were found in patients with advanced TNM stage (III-IV) and larger tumor size (≥5 cm) compared with early stage (I-II) (p<0.001 and p=0.004) patients with smaller tumor size (<3 cm) (p=0.018 and p=0.001). Moreover, the VIM promoter methylation frequency was higher in patients with portal vein tumor thrombosis (PVTT) (p=0.006) and vascular invasion (p=0.003). In addition, the combination of α-fetoprotein (≥20 ng/ml) with SOX1 and VIM promoter methylation significantly improved their diagnostic value. In conclusions, aberrant methylation of SOX1 and VIM promoters may be potential biomarkers for noninvasive detection of HCC and HCC metastasis.