Showing papers in "Oncology Letters in 2012"
TL;DR: This view is challenged by recent investigations which find that the function of mitochondrial OXPHOS in most cancers is intact.
Abstract: Metabolic activities in normal cells rely primarily on mitochondrial oxidative phosphorylation (OXPHOS) to generate ATP for energy. Unlike in normal cells, glycolysis is enhanced and OXPHOS capacity is reduced in various cancer cells. It has long been believed that the glycolytic phenotype in cancer is due to a permanent impairment of mitochondrial OXPHOS, as proposed by Otto Warburg. This view is challenged by recent investigations which find that the function of mitochondrial OXPHOS in most cancers is intact. Aerobic glycolysis in many cancers is the combined result of various factors such as oncogenes, tumor suppressors, a hypoxic microenvironment, mtDNA mutations, genetic background and others. Understanding the features and complexity of the cancer energy metabolism will help to develop new approaches in early diagnosis and effectively target therapy of cancer.
660 citations
TL;DR: The highest ratio was observed in retinoblastoma patients and the lowest in anaplastic ependymoma, and the results were able to distinguish between the diagnoses based on the results of the obtained GSH:GSSG ratio.
Abstract: Oxidative stress causes profound alterations of various biological structures, including cellular membranes, lipids, proteins and nucleic acids, and it is involved in numerous malignancies. Reduced glutathione (GSH) is considered to be one of the most important scavengers of reactive oxygen species (ROS), and its ratio with oxidised glutathione (GSSG) may be used as a marker of oxidative stress. The main aim of this study was to determine GSH:GSSG ratio in the blood serum of paediatric cancer patients to use this ratio as a potential marker of oxidative stress. The whole procedure was optimised and the recoveries for both substances were greater than 80% under the optimised conditions. We analysed a group of paediatric patients (n=116) with various types of cancer, including neuroblastoma, anaplastic ependymoma, germ cell tumour, genital tract tumour, lymphadenopathy, rhabdomyosarcoma, nephroblastoma, Ewing's sarcoma, osteosarcoma, Hodgkin's lymphoma, medulloblastoma and retinoblastoma. We simultaneously determined the levels of reduced and oxidised glutathione, and thus, its ratio in the blood serum of the patients. The highest ratio was observed in retinoblastoma patients and the lowest in anaplastic ependymoma. We were able to distinguish between the diagnoses based on the results of the obtained GSH:GSSG ratio.
457 citations
TL;DR: The results of preliminary studies suggest that let-7 is involved in the regulation of oncogenic pathways in numerous types of tumors and is, therefore, a potential molecular target for tumor therapy.
Abstract: MicroRNAs (miRNAs) are highly evolutionarily-conserved non-coding small RNAs, which were first identified in Caenorhabditis elegans. Let-7 miRNA is involved in the regulation of gene expression in cells. Several novel factors and feedback loops involved in the regulation of the synthesis of let-7 have been identified and additional let-7 target genes have been found. Let-7 has also been shown to be significantly correlated with the occurrence and development of cancer and the results of preliminary studies suggest that it is involved in the regulation of oncogenic pathways in numerous types of tumors. Let-7 is, therefore, a potential molecular target for tumor therapy. Thus, this review examined let-7 and the correlation between let-7 and oncogenic pathways in cancer.
169 citations
TL;DR: It was identified that liver, bone and brain metastasis as well as the presence of pleural and/or pericardial fluids were unfavorable prognostic factors, however, lung, adrenal gland and extrathoracic lymph node metastasis were not statistically significant prognostic factor.
Abstract: The aim of our retrospective study was to evaluate the clinicopathological features associated with distant metastasis from small cell lung cancer (SCLC). We reviewed patients diagnosed with SCLC metastasis at the time of presentation between 1999 and 2010. Among the consecutive 251 SCLC patients diagnosed, 152 (60.6%) patients had distant metastasis, of which 20.3, 18.3, 15.5, 10.0 and 6.0% of patients had liver, bone, brain, lung and adrenal gland metastasis, respectively. In a multivariate analysis using Cox’s proportional hazards model, we identified that liver, bone and brain metastasis as well as the presence of pleural and/or pericardial fluids were unfavorable prognostic factors. However, lung, adrenal gland and extrathoracic lymph node metastasis were not statistically significant prognostic factors. With regard to the treatment of SCLC patients, particularly those with liver, bone and brain metastasis or pleural and/or pericardial fluids, we should take the metastasizing organs into consideration.
120 citations
TL;DR: The results suggest thatmiR-21, miR-31, mi-96 and mi-135b may function in the process of CRC development and progression and miR -135b levels in particular may correlate with the degree of malignancy.
Abstract: The aim of this study was to determine the expression of miR-21, miR-31, miR-96 and miR-135b in 52 paired colorectal cancer (CRC) tissues and to analyze the correlation between microRNAs (miRNAs) and clinicopathological features. We developed a quantification method that relies on a standard plot, constructed from known concentrations of standards, in order to measure the number of miRNAs. In addition to this, we analyzed the expression levels of miR-21, miR-31, miR-96 and miR-135b in 52 cases of primary CRC and corresponding normal mucosal tissue using real-time PCR with SYBR-Green I. An independent sample t-test was used to compare the differential expression between tumor tissues and normal mucosal tissues. The Mann-Whitney U and Kruskall-Wallis tests were used to compare the correlation between miRNA expression levels and clinicopathological features. The expression of miR-21, miR-31, miR-96 and miR-135b was upregulated in the CRC tissues compared to normal mucosal tissues (P<0.05). Furthermore, miR-21 and miR-135b were positively correlated with the clinical stage (P=0.048 and P=0.029, respectively), while miR-96 and miR-135b were correlated with liver metastasis (P=0.006 and P=0.013, respectively). Our results suggest that miR-21, miR-31, miR-96 and miR-135b may function in the process of CRC development and progression. miR-135b levels in particular may correlate with the degree of malignancy.
116 citations
TL;DR: This study isolated kaempferol-3-O-rhamnoside as an active compound from the leaves of Schima wallichii Korth, a plant commonly consumed by non-human primates, and its anti-cancer activities, including its ability to induce apoptotic mechanisms, were investigated in MCF-7 breast cancer cells.
Abstract: Plants consumed by non-human primates represent potential drug sources for human disease management. In this study, we isolated kaempferol-3-O-rhamnoside as an active compound from the leaves of Schima wallichii Korth., a plant commonly consumed by non-human primates. Its anti-cancer activities, including its ability to induce apoptotic mechanisms, were investigated in MCF-7 breast cancer cells. Results showed that in MCF-7 cells, kaempferol-3-O-rhamnoside inhibits cell proliferation in a dose-dependent manner and promotes apoptosis via the activation of the caspase signaling cascade, which includes caspase-9, caspase-3 and PARP. Our results provide a basis for further exploration of kaempferol-3-O-rhamnoside as an active compound for potential anti-cancer therapeutics.
92 citations
TL;DR: It is demonstrated that the expression of PTEN protein, but not mRNA, was negatively directly regulated by miR-21 in the KLE cell line, which modulated EEC cell proliferation through the downregulation ofPTEN.
Abstract: The aim of this study was to investigate the role of microRNA-21 (miR-21) in the regulation of phosphatase and tensin homolog deleted from chromosome-10 (PTEN) expression and proliferation of endometrioid endometrial cancer (EEC) cells. We performed a qRT-PCR assay with miR-21 and PTEN in 16 paired EEC tumor tissues and adjacent non-tumor endometrium. To investigate the regulation of PTEN by miR-21, we designed gain- and loss-of-function of miR-21 experiments in the KLE cell line by transfection with a synthetic miR-21 mimic and inhibitor. To validate the putative binding site of miR-21 in the 3′ untranslated region (3′-UTR) of PTEN messenger RNA (mRNA), a dual-luciferase reporter assay was carried out. To evaluate the potential effect of miR-21 on EEC proliferation, we performed both overexpression experiments, using an miR-21 mimic, and inhibition assays, using an miR-21 inhibitor. miR-21 was overexpressed in EEC and was inversely correlated with PTEN protein expression (P<0.001). miR-21 regulated PTEN protein expression and cell proliferation in the KLE cell line and the direct binding of miR-21 to the PTEN 3′-UTR was confirmed using a dual-luciferase reporter assay. The upregulation of miR-21 led to a significant decrease in the PTEN protein expression level (P=0.007). The downregulation of miR-21 led to a significant increase in PTEN protein (P=0.002). The expression of luciferase in the wt-PTEN-3′-UTR-pGL3 group was downregulated in the presence of the miR-21 mimic (P=0.001). miR-21 was overexpressed in EEC. In conclusion, we demonstrated that the expression of PTEN protein, but not mRNA, was negatively directly regulated by miR-21 in the KLE cell line. The overexpression of miR-21 modulated EEC cell proliferation through the downregulation of PTEN.
82 citations
TL;DR: It is suggested that Notch-1 is potentially an effective target for treating castration-resistant prostate cancer because it downregulates the anti-apoptotic protein Bcl-2, and upregulate the pro-APoptoticprotein Bax, which ultimately results in increased sensitivity of PC-3 cells to docetaxel.
Abstract: Although docetaxel-based chemotherapy is therapeutically efficacious, drug resistance often leads to treatment failure in castration-resistant prostate cancer patients. The Notch signaling pathway plays a key role in prostate development and prostate cancer. We investigated whether silencing Notch-1 has therapeutic potential for the treatment of prostate cancer. To determine this, we performed cell and molecular analyses following the silencing of the Notch-1 gene in PC-3 castration-resistant prostate cancer cells using small interfering RNA. The results demonstrated that silencing the Notch-1 gene effectively inhibits proliferation and induces apoptosis in PC-3 cells. In addition, docetaxel treatment results in decreased proliferation and increased apoptosis in the Notch-1-silenced cells compared to the control PC-3 cells. Docetaxel treatment was also accompanied by an upregulation of Bax and a downregulation of Bcl-2. Thus, Notch-1 silencing downregulates the anti-apoptotic protein Bcl-2, and upregulates the pro-apoptotic protein Bax, which ultimately results in increased sensitivity of PC-3 cells to docetaxel. Taken together, these results suggest that Notch-1 is potentially an effective target for treating castration-resistant prostate cancer.
78 citations
TL;DR: Findings provide evidence that miR-195 plays a key role in inhibiting osteosarcoma cell migration and invasion through targeting FASN, and strongly suggest that exogenous mi R-195 may have therapeutic value in treating osteosARcoma.
Abstract: microRNAs are involved in different cancer-related processes. miR-195, one of the miR-16/15/195/424/497 family members, has been shown to act as a tumor suppressor during tumorigenesis. However, the function of miR-195 in osteosarcoma is still unclear. In our study, the miR-195 expression level was upregulated in osteosarcoma cells, by transfection with miR-195, and the fatty acid synthase (FASN) mRNA and protein expression levels were measured by RT-PCR and western blotting. Cell migration and invasion was measured using wound healing migration and Transwell invasion assays. We found that the upregulation of miR-195 greatly decreased cell invasion and the migration of U2OS. We also identified that FASN may be a direct target of miR-195 by the luciferase activity assay. These findings provide evidence that miR-195 plays a key role in inhibiting osteosarcoma cell migration and invasion through targeting FASN, and strongly suggest that exogenous miR-195 may have therapeutic value in treating osteosarcoma.
77 citations
TL;DR: The data suggest that miR-224 plays a significant role in HCC, possibly through the activation of the AKT signaling pathway by targeting PPP2R1B.
Abstract: microRNAs (miRNAs) are a class of small non-coding RNAs that post-transcriptionally regulate gene expression. Increasing evidence has shown that the deregulation of miRNAs is linked to cancer. The overexpression of miR-224 has been reported in several human cancers. The aim of the present study was to investigate the function of miR-224 in the pathogenetic process of hepatocellular carcinoma (HCC), and the precise mechanism underlying its function. Both gain-of-function and loss-of function assays were conducted through transfection with miR-224 mimics and miR-224 inhibitors in the HepG2 liver carcinoma cell line. The data revealed that miR-224 exerts a significant role in promoting cell proliferation, migration and invasion. Western blot analysis showed that the phosphorylation levels of AKT positively correlated with endogenous levels of miR-224. In addition, results from a dual luciferase reporter assay showed that the expression of the serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A β isoform (PPP2R1B) is inhibited by miR-224; thus, it appears that PPP2R1B is a candidate target of miR-224 in HCC. These data suggest that miR-224 plays a significant role in HCC, possibly through the activation of the AKT signaling pathway by targeting PPP2R1B.
73 citations
TL;DR: The expression of Oct3/4, Nanog and Sox2 in 3 human breast cancer cell lines, MCF7, T-47D and MDA-MB-231, was determined by reverse transcription polymerase chain reaction (RT-PCR) and protein expression was detected by immunocytohistochemistry.
Abstract: Previous studies have demonstrated that pluripotency-associated transcription factors, such as Oct3/4, Nanog and Sox2, play a crucial role in the development and malignant progression of various types of tumors. Breast cancer is the most frequent cancer among females, being a heterogeneous disease, with distinct morphologies, metastatic behavior and therapeutic responses. The expression of Oct3/4, Nanog and Sox2 in 3 human breast cancer cell lines, MCF7, T-47D and MDA-MB-231, was determined. The expression of Oct3/4, Nanog and Sox2 mRNA was determined by reverse transcription polymerase chain reaction (RT-PCR) and protein expression was detected by immunocytohistochemistry. RT-PCR revealed that all three human breast cancer cell lines tested expressed evident Oct3/4, Nanog and Sox-2 mRNA at various levels. Higher levels of Oct3/4 were identified in MCF7 and MDA-MB-231 cells compared with T-47D cells. Higher levels of Nanog were observed in MCF7 and T-47D cells compared with MDA-MB-231 cells and the highest expression of Sox-2 was detected in MCF7 cells. The nuclear localization of Oct3/4, Nanog and Sox-2 was confirmed by immunostaining. Oct3/4, Nanog and Sox2 were expressed in human breast cancer cell lines. Further studies are required to characterize the role of Oct3/4, Nanog and Sox2 in human breast cancer.
TL;DR: The results indicate that the expression of many known as well as novel miRNAs was altered in patients with the hepatitis C virus infection compared with those with the Hepatitis B virus and without any virus infection.
Abstract: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the liver. Since postoperative recurrence and intrahepatic metastases occur frequently, the postoperative 5-year survival rate is low. To investigate the molecular mechanisms of HCC progression, mRNA as well as microRNA (miRNA) expression levels have been profiled in various studies. However, no previous study has comprehensively compared the expression of miRNAs in HCC patients with various clinical features using the tumor and surrounding non-tumor tissues and normal liver samples. In this study, we profiled the expression of miRNAs in tumor and non-tumor tissues from 40 HCC patients with heterogeneous pathogenesis and 6 surrounding non-tumor tissues from patients with metastatic liver cancer. To identify miRNAs specific to each disease state, we comprehensively compared the expression of miRNAs in various combinations. The results indicate that the expression of many known as well as novel miRNAs was altered in patients with the hepatitis C virus infection compared with those with the hepatitis B virus and without any virus infection. The following miRNAs were downregulated in the tumor and non-tumor tissues, and thus could serve as novel biomarkers for chronic liver diseases: miR-18b*, miR-296-5p, miR-557, miR-581, miR-625*, miR-1228, miR-1249 and miR-2116*. Similarly, miR-129*, miR-146b-3p and miR-448 are novel candidates for HCC biomarkers regardless of virus infection.
TL;DR: Findings indicate that BER sensitizes cells to the anticancer effects of DOX, and generates synergistic effects in A549 and HeLa cells.
Abstract: The clinical use of doxorubicin (DOX), a potent antineoplastic agent, is limited by its serious side-effects, which include acute and chronic cumulative dose-related cardiotoxicity. Berberine (BER), a botanical alkaloid, has been reported to possess cardioprotective and antitumor effects. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-tetrazolium bromide (MTT) assay was used to detect the cell viability of A549, HeLa and HepG2 cells after each cell line was treated with DOX, BER or a combination of DOX and BER for 24 h. Apoptosis was evaluated by acridine orange staining. The results showed that BER and DOX exhibited dose-dependent inhibitory effects on A549 and HeLa cells which were likely mediated by inducing apoptosis. The same result was found in the combination group. Isobologram illustration and combination index (CI) analyses revealed that the combination of DOX and BER generates synergistic effects in A549 (CI=0.61) and HeLa (CI=0.73) cells. These findings indicate that BER sensitizes cells to the anticancer effects of DOX.
TL;DR: This study demonstrates that the miR-96 targeting of FOXO1 is upregulated in TCC; in addition, TCC tumorigenesis may be partly due to the ability of miR -96 to promote FoxO1 repression, thereby bypassing cell apoptosis controls.
Abstract: Transitional cell carcinoma (TCC) is one of the most common types of malignancies and a leading cause of genitourinary system cancer mortality worldwide. The tumor suppressor gene FOXO1, a member of the forkhead box O (FOXO) subfamily of transcription factors, is downregulated in a number of cancers, including TCC; however, the underlying mechanisms are poorly understood. In the present study, we used microRNA (miRNA) target prediction algorithms to identify a conserved potential miR-96 binding site in the 3′-untranslated region (3′-UTR) of FOXO1. Using quantitative real-time PCR (qRT-PCR) and northern blot analysis, we identified that miR-96 was downregulated in TCC tissues compared to normal bladder tissues (NB), suggesting that the loss of FOXO1 expression in TCC may be mediated by miR-96. To confirm this, we transfected pre-miR-96/anti-miR-96 into the T24 TCC cell line and revealed that miR-96 expression was sufficient to significantly reduce FOXO1 expression. Conversely, FOXO1 expression was not completely restored by the inhibition of miR-96 in T24 cells. Moreover, RNA silencing of FOXO1 significantly reduced miR-96 inhibitor-mediated T24 cell apoptosis. In conclusion, our study demonstrates that the miR-96 targeting of FOXO1 is upregulated in TCC; in addition, TCC tumorigenesis may be partly due to the ability of miR-96 to promote FOXO1 repression, thereby bypassing cell apoptosis controls.
TL;DR: The results of the study suggest that Alu81-qPCR is a more reliable method than other techniques, such as the PicoGreen assay, for quantifying cfDNA in human blood, demonstrating the potential to complement current diagnostic procedures for the management of gastric cancer patients.
Abstract: In the present study, an accurate and reproducible method for quantifying cell-free DNA (cfDNA) in human blood was established and tested for its ability to predict gastric cancer in patients. Using 'Alu81-qPCR' to amplify 81-bp Alu DNA sequences, we first estimated the amount of cfDNA in the serum or plasma of 130 patients with gastric cancer to identify which source of cfDNA is more suitable for the biomarker screening of these patients. The results of Alu81-qPCR revealed that the amount of cfDNA in the plasma was low compared with that in the serum, but was found at similar levels among the samples, indicating that the plasma may be a more suitable source of cfDNA for biomarker screening. For the 54 patients with gastric cancer and the 59 age-matched healthy controls, the mean levels of plasma cfDNA were 2.4-fold higher in the patient group compared with the control group, indicating that plasma cfDNA levels may be useful for predicting patients with gastric cancer. The results of our study suggest that Alu81-qPCR is a more reliable method than other techniques, such as the PicoGreen assay, for quantifying cfDNA in human blood, demonstrating the potential to complement current diagnostic procedures for the management of gastric cancer patients.
TL;DR: Differential expression profiles of miRNAs between OS and osteoblast cell lines were investigated and bioinformatic research suggests that they are able to regulate the biological behaviors of OS in a complex and effective manner.
Abstract: Osteosarcoma (OS) is the most common primary malignant bone tumor, particularly in adolescents and young adults. Early diagnosis remains a significant problem in the clinical treatment of OS as we remain far from a comprehensive understanding of the molecular genetic mechanisms and the biology involved. In addition, microRNAs (miRNAs or miRs), a large family of small non-coding RNAs, may provide a greater understanding of OS as they play a complex role in gene expression regulation in vitro and in vivo. In the current study, the differential expression profiles of miRNAs between OS and osteoblast cell lines were investigated by miRNA microarrays and real-time quantitative PCR (RT-qPCR). A total of 268 miRNAs were identified that were significantly dysregulated in OS compared with the osteoblast cell line, including miR-9, miR-99, miR-195, miR-148a and miR-181a, which had been validated as overexpressed, and miR-143, miR-145, miR-335 and miR-539, which were confirmed to be downregulated. This differential expression may aid future OS diagnosis and prognosis prediction and illustration of the potential mechanisms in the oncogenesis, development and metastasis of OS. Bioinformatic research on these differentially expressed miRNAs suggests that they are able to regulate the biological behaviors of OS in a complex and effective manner. Further study on the function of these miRNAs is likely to provide new insights into OS biology and treatment.
TL;DR: It is demonstrated for the first time that AML ND patients have increased plasma concentrations of IL-35, suggesting that this cytokine is involved in the pathophysiological process of the disease, and that further research is required to address this issue.
Abstract: Acute myeloid leukemia (AML) is the most common hematological malignancy in adults, characterized by distorted proliferation and the development of myeloid cells and their precursors in the blood and bone marrow. Interleukin 35 (IL-35), a novel inhibitory cytokine secreted by regulatory T (Treg) cells is a novel potential target used for the therapeutic manipulation of Treg activity in order to treat cancer and autoimmune diseases. To investigate the role and imbalance of Treg-related cytokines in the pathogenesis of AML, we measured the plasma concentration of three Treg-associated cytokines [IL-35, IL-10 and transforming growth factor-β (TGF-β)] and evaluated their clinical relevance. The concentration of IL-35, IL-10 and TGF-β in plasma specimens from 55 patients with AML [27 newly diagnosed (ND) patients and 28 in complete remission (CR)] and 24 controls was analyzed using the enzyme-linked immunosorbent assay method. Significantly higher levels of plasma IL-35 and IL-10 were observed in AML ND patients compared with healthy controls or AML CR patients. IL-10 concentrations were positively correlated with TGF-β, whereas no correlations were found between the other cytokines. IL-10 levels were positively correlated with white blood cell (WBC) and neutrophil (NEU) count but there were no correlations between IL-35 and TGF-β with WBC and NEU count. In conclusion, we demonstrated for the first time that AML ND patients have increased plasma concentrations of IL-35, suggesting that this cytokine is involved in the pathophysiological process of the disease, and that further research is required to address this issue.
TL;DR: The results indicate that the inactivation of CRISP3 is an early event in OSCC, since the T1/T2 classification is correlated with DNA copy number loss of CRisP3, whereas T3/T4 classification is not.
Abstract: The aim of this study was to identify tumor suppressor genes (TSGs) in oral squamous cell carcinoma (OSCC) using whole-genome analysis of microarray technology and real-time quantitative polymerase chain reaction (QPCR). We applied whole-genome analysis of TSGs in the specimens from 3 patients of OSCC by microarray technology. A total of 11 genes, CRISP3, SCGB3A1, AGR2, PIP, C20orf114, TFF1, STATH, AZGP1, MUC7, DMBT1 and LOC389429, were found to be down-regulated, and 2, matrix metallopeptidase (MMP) 1 and MMP3, were found to be up-regulated in the 3 OSCC patients using microarray technology. In this study, we selected the CRISP3 gene. CRISP3 belongs to the cystein-rich secretary protein gene family in chromosome 6p12.3. CRISP3 has been found in the salivary gland, spleen and prostate gland and is a prominent biomarker in the gene expression of prostate cancer. Down-regulation of this gene was previously observed in OSCC. No studies examining the DNA copy number of CRISP3 in detail exist. We analyzed the DNA copy number of CRISP3 in 5 OSCC-derived cell lines (SAS, Ca9-22, KON, HSC2 and HSC4) and 60 OSCC tissues by real-time QPCR. The DNA copy number loss of CRISP3 was observed in 2 of the 5 OSCC-derived cell lines (SAS, HSC2) and in 24 of 60 patients (40.0%) using real-time QPCR. A significant statistical correlation between the copy number loss and gender and T classification was observed. These results indicate that the inactivation of CRISP3 is an early event in OSCC, since the T1/T2 classification is correlated with DNA copy number loss of CRISP3, whereas T3/T4 classification is not. We conclude that CRISP3 may be involved in the carcinogenesis of OSCC.
TL;DR: The results revealed that high expression levels of MACC1 were correlated with lymph node metastasis, distant metastasis and a later TNM stage, and the downregulation ofMACC1 sensitized pancreatic cancer cells to gemcitabine treatment through the inhibition of the Ras/ERK signaling pathway.
Abstract: It has been suggested that the newly identified metastasis-associated in colon cancer-1 (MACC1) oncogene is involved in the progression and metastasis of cancer. Several studies have indicated that MACC1 has potential as a novel biomarker. In this study, we aimed to investigate the functions and serum expression levels of MACC1 in pancreatic cancer patients. Blood serum samples from 60 cancer patients and 49 controls were analyzed for serum MACC1 by ELISA. The results revealed that high expression levels of MACC1 were correlated with lymph node metastasis, distant metastasis and a later TNM stage. Inhibition of MACC1 by siRNAs significantly suppressed pancreatic cancer cell proliferation and migration. Furthermore, it was found that the downregulation of MACC1 sensitized pancreatic cancer cells to gemcitabine treatment through the inhibition of the Ras/ERK signaling pathway. Our findings suggest that MACC1 may aid in the diagnosis of pancreatic cancer and serve as a potential therapeutic target.
TL;DR: The present study conducted miRNA expression profiling of 3 primary colorectal cancers and 3 brain-metastatic carcinomas using Agilent Human miRNA Microarrays to identify microRNA expression profiles associated with brain metastases of coloreCTal cancers.
Abstract: The present study aimed to identify microRNA (miRNA) expression profiles associated with brain metastases of colorectal cancers. We conducted miRNA expression profiling of 3 primary colorectal cancers and 3 brain-metastatic carcinomas using Agilent Human miRNA Microarrays. Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) was employed to validate the results obtained from the miRNA microarray analysis. Overexpression of miR-145, miR-1, miR-146a, miR-576-5p, miR-126*, HS287, miR-28-5p, miR-143, miR-199b-5p, miR-199a-5p, miR-10b, miR-22, miR-133b, miR-145*, miR-199a, miR-133a, miR-125b and downregulation of miR-31 and HS170 were observed in brain-metastatic carcinomas. Quantitative RT-PCR experiments with miR-125b confirmed the expression patterns we found in our microarray experiments. miRNAs are differentially expressed between colorectal cancers and matched brain-metastatic carcinomas. The miRNA variation trend is quite different in the process of metastasis compared to that of carcinogenesis. These miRNAs may therefore serve as potential diagnostic markers and therapeutic targets for colorectal cancers with brain metastases.
TL;DR: FEV1.0%, serum CRP and smoking history are reliable predictors of the risk of respiratory complications following esophageal cancer resection, according to multiple logistic regression analyses.
Abstract: The development of surgical and postoperative management techniques has improved the treatment outcomes of esophageal cancer resection. However, respiratory morbidity is still the most frequent complication after esophagectomy. The objective of the present study was to identify risk factors for respiratory complications following resection for esophageal cancer. This study included 96 patients with esophageal cancer who had undergone esophagectomy with lymph node dissection. The patients were divided into 2 groups according to the presence (20 patients, 17 had pneumonia and 3 had acute respiratory distress syndrome) or absence (76 patients) of postoperative respiratory complications (PRC). The two groups were compared with respect to their preoperative clinical variables, such as age, body mass index, smoking history, serum albumin, serum C-reactive protein (CRP), number of lymphocytes, %VC, FEV1.0% and FEV1.0. Furthermore, multiple logistic regression analyses were used to estimate relative risk factors for respiratory complications. Results of the univariate analysis showed that smoking history (+/-, patients with PRC, 19/1 and without PRC, 53/23), serum CRP (≥1.0 mg/dl/<1.0 mg/dl, patients with PRC, 6/14 and without PRC, 6/70) and FEV1.0% (≥60%/<60%, patients with PRC, 16/4 and without PRC, 73/3) were significantly different between the two groups. Multiple logistic regression analysis showed that FEV1.0% was the strongest predictor of PRC. FEV1.0%, serum CRP and smoking history are reliable predictors of the risk of respiratory complications following esophageal cancer resection. For patients with these factors, perioperative management for the prevention of postoperative respiratory complications should be considered.
TL;DR: FN1 protein expression in RCC is associated with a higher disease-related mortality rate, indicating a possible role in R CC progression, and results of the multivariate Cox regression analysis showed that FN1 expression was not an independent marker of either overall or tumor-specific survival.
Abstract: Fibronectin 1 (FN1) is a glycoprotein that is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defenses and metastasis The aim of this study was to elucidate the FN1 protein expression in renal cell carcinoma (RCC) and to determine its potential prognostic relevance A total of 270 clear cell RCC tissue specimens were collected from patients undergoing surgery for renal tumors Biomarker expression was determined by immunohistochemistry and correlated with clinical variables Survival analysis was carried out for 153 patients with complete follow-up data and pathologically proven clear cell carcinoma of the kidney The follow-up group had a mean follow-up period of 838 months (IQR 262-1362 months) The calculated median 5-year overall and tumor-specific survival rate of all 153 evaluable patients was 666 and 710%, respectively A higher disease-related mortality rate was observed among patients with cytoplasmic FN1 expression (413 vs 247%, p=0039, Fisher's exact test) No significant correlation was found between FN1 staining and patient characteristics such as age, gender, tumor differentiation and visceral metastasis However, there was a trend for FN1 expression and correlation with tumor stage and lymph node metastasis (p=0085 and p=0203; respectively) The Kaplan-Meier analysis revealed significant differences in the 5-year tumor-specific survival for patients with and without cytoplasmic FN1 expression (648 vs 777%; p=0035, log-rank test) However, results of the multivariate Cox regression analysis showed that FN1 expression was not an independent marker of either overall or tumor-specific survival In conclusion, FN1 protein expression in RCC is associated with a higher disease-related mortality rate, indicating a possible role in RCC progression Therefore, our data on FN1 encourage further investigations to determine the role of FN1 in RCC
TL;DR: Neo-CT is effective and well-tolerated in MIBC and this split-dose cisplatin regimen facilitates treatment in an outpatient setting and allows inclusion of patients with compromised GFR.
Abstract: The aim of this study was to investigate the outcome of patients with muscle-invasive bladder cancer (MIBC) receiving neo-adjuvant chemotherapy (neo-CT) using a cisplatin-based regimen fractionated on days 1 and 8 of a 21-day cycle prior to organ-preservation (chemoradiation) or cystectomy. Patients with stage T2-T4, N0, M0, transitional cell carcinoma (TCC) of the bladder with a calculated glomerular filtration rate (GFR) ≥40 ml/min were eligible for inclusion in the study. Neo-CT comprised of gemcitabine (1,000 mg/m2 d1, d8, q21) plus cisplatin (35 mg/m2 d1, d8, q21) for four cycles. Following the administration of neo-CT, patients underwent surgery or radiotherapy (RT) with or without concurrent chemotherapy (CRT), based on the response to neo-CT and clinician and patient preference. A total of 23 patients were recruited: 21 males and 2 females; median age, 69 years (range, 49-85); stage T2=11, T3A=7, T3B=5, grade 2=1, grade 3=22. One patient progressed prior to neo-CT. In total, 75 cycles of neo-CT were administered. Treatment was well-tolerated with only one episode of neutropenic sepsis. Three of 22 patients developed early progression and did not receive radical treatment. For the remaining 19 patients, choice of definitive treatment (surgery vs. RT/CRT) was based on response to neo-CT. Eight patients had residual disease at cystoscopy following the completion of neo-CT; six patients underwent surgery and two underwent RT/CRT. A total of 11 patients had a complete response (CR) to neo-CT, nine of whom were treated by RT/CRT, with the remaining two declining radical treatment. Median follow-up for alive patients was 57 months (range, 4.4-68.5). Three-year survival was 37% (95% CI 17-58%) and 5-year survival was 31% (95% CI 15-52%). Neo-CT is effective and well-tolerated in MIBC. This split-dose cisplatin regimen facilitates treatment in an outpatient setting and allows inclusion of patients with compromised GFR.
TL;DR: Results suggest thatmiR-155 and miR-31 are differentially expressed in breast cancer patients, and their correlation with the clinicopathological characteristics may aid the diagnosis and treatment of invasive intraductal breast cancer.
Abstract: The purpose of the present study was to determine the tissue and plasma levels of microRNA (miR)-155 and miR-31 in 67 patients with invasive intraductal breast cancer and their correlation with the clinicopathological characteristics. Using a quantitative real-time-PCR (qRT-PCR) assay, it was demonstrated that the plasma levels of miR-155 and miR-31 in patients were 6- and 5-fold higher than those in healthy individuals, respectively (P 0.05). The expression levels of miR-155, but not miR-31, were inversely correlated with estrogen receptor (ER) and progesterone receptor (PR) expression (ER, r=-0.353, P=0.003; PR, r=-0.357, P=0.003). The tissue and plasma levels of miR-155 and miR-31 were not correlated with epidermal growth factor receptor-2 (HER-2) expression levels. Furthermore, high levels of plasma miR-155 and miR-31 were identified in the tumors of TNM stage II, lymph node metastasis 0-3 and tumor sizes of 2-5 cm in patients who were aged over 52 years. miR-155 was mainly expressed in patients with a pathology score of 3 for ER or PR expression; miR-31 expression was higher in patients with a pathology score of 2. These results suggest that miR-155 and miR-31 are differentially expressed in breast cancer patients. Their correlation with the clinicopathological characteristics may aid the diagnosis and treatment of invasive intraductal breast cancer.
TL;DR: The malignant transformation of endometriosis has multiple pathways of development and may share a common pathogenic mechanism; iron-induced oxidative stress derived from repeated hemorrhage.
Abstract: The association between endometriosis and malignant transformation has often been described in the medical literature. A search was conducted between 1966 and 2010 through the English language literature (online Medline PubMed database) using the keywords endometriosis combined with malignant transformation. The search revealed an increase in reports describing endometriosis and malignancy. Approximately 1.0% of women with endometriosis have lesions that undergo malignant transformation. The malignant processes that are associated with endometriosis may be classified into three groups: i) epithelial ovarian cancers (endometrioid adenocarcinoma and clear cell carcinoma), ii) other Mullerian-type tumors, including Mullerian-type mucinous borderline tumor and serous borderline tumor and iii) sarcomas such as adenosarcoma and endometrial stromal sarcoma in the female pelvic cavity. Persistent oxidative stress induced by endometriosis-dependent hemorrhage may be associated with carcinogenesis. In conclusion, the malignant transformation of endometriosis has multiple pathways of development and may share a common pathogenic mechanism; iron-induced oxidative stress derived from repeated hemorrhage.
TL;DR: Experimental and clinical evidence is evaluated to support a mechanistic role for circulation patterns and microvessels in liver, metastasis-related genes, chemokines and their receptors, and cellular adhesion molecules in the process of CRC liver metastasis.
Abstract: The metastatic spread of tumor cells is one of the most common causes of mortality in cancer patients. The elucidation of the molecular mechanisms that underlie the formation of metastatic colonies has been one of the major objectives of cancer research. Organ-specific colonization of cancer cells is a significant and noteworthy feature of metastasis. Colorectal cancer (CRC) is one of the most common causes of cancer-related mortality. The liver is commonly the sole site of metastasis for CRC and represents a major cause of mortality in CRC patients. However, what regulates CRC cell metastasis into liver and the reasons for the liver-specific metastasis of CRC have yet to be adequately elucidated. Recent progress provides indications and a conceptual framework with which to investigate this issue. This review evaluated experimental and clinical evidence to support a mechanistic role for circulation patterns and microvessels in liver, metastasis-related genes, chemokines and their receptors, and cellular adhesion molecules in the process of CRC liver metastasis.
TL;DR: It is demonstrated that the glyceollins, previously described as anti-estrogenic agents, also exert antitumor activity in triple-negative breast carcinoma cell systems and this activity correlates with the Glyceollin alteration of microRNA and proteomic expression profiles.
Abstract: The purpose of this study was to investigate the effects of glyceollins on the suppression of tumorigenesis in triple-negative breast carcinoma cell lines. We further explored the effects of glyceollins on microRNA and protein expression in MDA-MB-231 cells. Triple-negative (ER-, PgR- and Her2/neu-) breast carcinoma cells were used to test the effects of glyceollins on tumorigenesis in vivo. Following this procedure, unbiased microarray analysis of microRNA expression was performed. Additionally, we examined the changes in the proteome induced by glyceollins in the MDA-MB-231 cells. Tumorigenesis studies revealed a modest suppression of MDA-MB-231 and MDA-MB-468 cell tumor growth in vivo. In response to glyceollins we observed a distinct change in microRNA expression profiles and proteomes of the triple-negative breast carcinoma cell line, MDA-MB-231. Our results demonstrated that the glyceollins, previously described as anti-estrogenic agents, also exert antitumor activity in triple-negative breast carcinoma cell systems. This activity correlates with the glyceollin alteration of microRNA and proteomic expression profiles.
TL;DR: It is indicated that increased Cdk6 expression contributes to bladder cancer development and may serve as a biomarker for bladder cancer.
Abstract: Cyclin-dependent kinase 6 (Cdk6) controls the cell cycle and aberrant expression of Cdk6 is involved in cancer progression. The aim of this study was to investigate the role of Cdk6 in bladder cancer development. Cdk6 expression was examined in 31 cases of bladder cancer and 29 tissues adjacent to bladder transitional cell carcinoma (TCC) using an immunohistochemistry assay. The correlation between Cdk6 expression and clinical characteristics was also analyzed. Compared with the adjacent tissues, cytoplasmic and nuclear Cdk6 expression levels were significantly increased in the invasive bladder cancer cases (P=0.005 and P 0.05 for both). Cytoplasmic and nuclear Cdk6 expression levels were correlated with bladder cancer stage (superficial vs. invasive, P=0.026 and P=0.006, respectively). The results therefore indicate that increased Cdk6 expression contributes to bladder cancer development and may serve as a biomarker for bladder cancer.
TL;DR: It was found that terpinolene, a common component of sage and rosemary, markedly reduced the protein expression of AKT1 in K562 cells and inhibited cell proliferation.
Abstract: Protein kinase AKT mediates cell proliferation and survival signals, and also contributes to cancer progression Increased expression and/or activation of AKT is involved in a variety of human cancers In cells treated with sage or rosemary extract, mRNA and protein expression levels of AKT1 were reduced compared with those of the control cells 48 h after the herbal treatments We found that terpinolene, a common component of sage and rosemary, markedly reduced the protein expression of AKT1 in K562 cells and inhibited cell proliferation
TL;DR: RANKL was found to increase the migration of breast cancer cells by activating the c-Src-Akt and c- Src-ERK signaling pathways.
Abstract: The receptor activator for nuclear factor κB ligand/receptor activator for nuclear factor κB (RANKL/RANK) pathway is critical for RANK-expressing cancer cells to home to bones, and c-Src is critical for cancer progression. The objective of this study was to explore the effect of c-Src in the RANKL/RANK pathway and migration activity in human breast cancer cells. Breast cancer cell lines MCF-7, MDA-MB-231 and BT-474 were obtained and cultured. Flow cytometry was used to examine RANK expression. The results showed that RANK was expressed in breast cancer cell lines MCF-7, MDA-MB-231 and BT-474, and soluble RANKL (sRANKL)-triggered migration of breast cancer cells by activating ERK1/2, Akt and c-Src. The sRANKL-induced migration was blocked with RANKL inhibitor osteoprotegerin (OPG), MEK inhibitor PD98059, PI3K inhibitor LY294002 and Src inhibitor PP2. Inhibition of c-Src function with PP2 blocked the activation of Akt and ERK1/2, resulting in the inhibition of RANKL-induced migration. In conclusion, RANKL was found to increase the migration of breast cancer cells by activating the c-Src-Akt and c-Src-ERK signaling pathways.