Purpose To investigate the involvement of hsa-microRNA-195-5p (miR-195) in progression and prognosis of human prostate cancer (PCa). Experimental Design qRT-PCR was performed to detect miR-195 expression in both PCa cell lines and clinical tissue samples. Its clinical significance was statistically analyzed. The roles of miR-195 and its candidate target gene ribosomal protein S6 kinase, 70kDa, polypeptide 1 (RPS6KB1) in PCa progression were confirmed based on both in vitro and in vivo systems. Results MiR-195 downregulation in PCa tissues was significantly associated with high Gleason score (P=0.001), positive metastasis failure (P<0.001) and biochemical recurrence (BCR, P<0.001). Survival analysis identified miR-195 as an independent prognostic factor for BCR-free survival of PCa patients (P=0.022). Then, we confirmed the tumor suppressive role of miR-195 through PCa cell invasion, migration and apoptosis assays in vitro, along with tumor xenografts growth, angiogenesis and invasion in vivo according to both gain-of-function and loss-of-function experiments. Additionally, RPS6KB1 was identified as a novel direct target of miR-195 through proteomic expression profiling combined with bioinformatic target prediction and luciferase reporter assay. Moreover, the re-expression and knockdown of RPS6KB1 could respectively rescue and imitate the effects induced by miR-195. Importantly, RPS6KB1 expression was closely correlated with aggressive progression and poor prognosis in PCa patients as opposed to miR-195. Furthermore, we identified MMP-9, VEGF, BAD and E-cadherin as the downstream effectors of miR-195-RPS6KB1 axis. Conclusion The newly identified miR-195-RPS6KB1 axis partially illustrates the molecular mechanism of PCa progression and represents a novel potential therapeutic target for PCa treatment.
Our previous microarray data showed that microRNA-224 (miR-224) was downregulated in human prostate cancer (PCa) tissues compared with adjacent benign tissues. However, the underlying mechanisms by which miR-224 is involved in PCa remain unclear. In this study, we identified TRIB1 as a target gene of miR-224. Forced expression of miR-224 suppressed PCa cell proliferation, invasion and migration, and promoted cell apoptosis by downregulating TRIB1. Moreover, the expression level of miR-224 in PCa tissues was negatively correlated with that of TRIB1. miR-224 downregulation was frequently found in PCa tissues with metastasis, higher PSA level and clinical stage, whereas TRIB1 upregulation was significantly associated with metastasis. Both miR-224 downregulation and TRIB1 upregulation were significantly associated with poor biochemical recurrence-free survival of patients with PCa. In conclusion, these findings reveal that the aberrant expression of miR-224 and TRIB1 may promote PCa progression and have potentials to serve as novel biomarkers for PCa prognosis.
Dietary supplements are increasingly marketed to and consumed by the American public for a variety of purported health benefits. On 9 September 2013, the Hawaii Department of Health (HDOH) was notified of a cluster of acute hepatitis and fulminant hepatic failure among individuals with exposure to the dietary supplement OxyELITE Pro™ (OEP). HDOH conducted an outbreak investigation in collaboration with federal partners. Physicians were asked to report cases, defined as individuals with acute onset hepatitis of unknown etiology on or after 1 April 2013, a history of weight-loss/muscle-building dietary supplement use during the 60 days before illness onset, and residence in Hawaii during the period of exposure. Reported cases’ medical records were reviewed, questionnaires were administered, and a product investigation, including chemical analyses and trace back, was conducted. Of 76 reports, 44 (58%) met case definition; of these, 36 (82%) reported OEP exposure during the two months before illness. No other common supplements or exposures were observed. Within the OEP-exposed subset, two patients required liver transplantation, and a third patient died. Excessive product dosing was not reported. No unique lot numbers were identified; there were multiple mainland distribution points, and lot numbers common to cases in Hawaii were also identified in continental states. Product analysis found consumed products were consistent with labeled ingredients; the mechanism of hepatotoxicity was not identified. We report one of the largest statewide outbreaks of dietary supplement-associated hepatotoxicity. The implicated product was OEP. The increasing popularity of dietary supplements raises the potential for additional clusters of dietary supplement-related adverse events.
We have isolated a tiger frog virus (TFV) from diseased tiger frogs, Rana tigrina rugulosa. The genome was a linear double-stranded DNA of 105,057 basepairs in length with a base composition of 55.01% G+C. About 105 open reading frames were identified with coding capacities for polypeptides ranging from 40 to 1294 amino acids. Computer-assisted analyses of the deduced amino acid sequences revealed that 39 of 105 putative gene products showed significant homology to functionally characterized proteins of other species in the GenBank/EMBL/DDBJ databases. These proteins included enzymes and structural proteins involved in virus replication, transcription, modification, and virus--host interaction. The deduced amino acid sequences of TFV gene products showed more than 90% identity to FV3, but a low degree of similarity among TFV, ISKNV, and LCDV-1. The results from this study indicated that TFV may belong to the genus Ranavirus of the family Iridoviridae.
BackgroundEven though aberrant expression of microRNA (miR)-30d has been reported in prostate cancer (PCa), its associations with cancer progression remain contradictory. The aim of this study was to investigate clinical significance, biological functions and underlying mechanisms of miR-30d deregulation in PCa.MethodsInvolvement of miR-30d deregulation in malignant phenotypes of PCa was demonstrated by clinical sample evaluation, and in vitro and in vivo experiments. The mechanisms underlying its regulatory effect on tumor angiogenesis were determined.ResultsmiR-30d over-expression was observed in both PCa cells and clinical specimens. High-miR-30d was distinctly associated with high pre-operative PSA and Gleason score, advanced clinical and pathological stages, positive metastasis and biochemical recurrence (BCR), and reduced overall survival of PCa patients. Through gain- and loss-of-function experiments, we found that miR-30d promoted PCa cell proliferation, migration, invasion, and capillary tube formation of endothelial cells, as well as in vivo tumor growth and angiogenesis in a mouse model. Simulation of myosin phosphatase targeting subunit 1 (MYPT1), acting as a direct target of miR-30d, antagonized the effects induced by miR-30d up-regulation in PCa cells. Notably, miR-30d/MYPT1 combination was identified as an independent factor to predict BCR of PCa patients. Furthermore, miR-30d exerted its pro-angiogenesis function, at least in part, by inhibiting MYPT1, which in turn, increased phosphorylation levels of c-JUN and activated VEGFA-induced signaling cascade in endothelial cells.ConclusionsmiR-30d and/or its target gene MYPT1 may serve as novel prognostic markers of PCa. miR-30d promotes tumor angiogenesis of PCa through MYPT1/c-JUN/VEGFA pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0615-x) contains supplementary material, which is available to authorized users.
Aim: CD147 and MMPs have been demonstrated to be involved in tumor invasion and angiogenesis. The aim of this study was to analyze the clinicopathological significance of CD147, MMP-1, MMP-2 and MMP-9 expression in human prostate cancer (PCa) and to evaluate their involvement in the progression of PCa. Methods: CD147, MMP-1, MMP-2 and MMP-9 expression was assessed in paraffin-embedded specimens collected from 62 cases of PCa and 15 cases of benign prostatic hyperplasia (BPH) by immunohistochemistry. Spearman’s correlation was applied to determine possible relationships between CD147, MMP-1, MMP-2 and MMP-9 expression and PCa. The association of CD147 and MMP-2 protein expression with the clinicopathological characteristics and the prognosis of PCa was subsequently assessed. Results: CD147was expressed in 51/62 (82.3%) PCa patients and in 2/15 (13.3%) BPH cases. MMP-1, MMP-2 and MMP-9 expression was significantly higher in PCa tissue than in BPH tissue. Using Spearman analysis, a significant positive correlation between CD147 and MMP-1, MMP-2 and MMP-9 expression was found (p <0.05). CD147 and MMP-2 expression was correlated with TMN grade and Gleason score. Patients with concurrent expression of CD147+ and MMP-2+ had the lowest survival (p <0.01). Conclusion: The results suggest that concurrent expression of CD147 and MMP may be an important characteristic of PCa which may help in the prediction of PCa progression.
MAP1S (originally named C19ORF5) is a widely distributed homolog of neuronal-specific MAP1A and MAP1B, and bridges autophagic components with microtubules and mitochondria to affect autophagosomal biogenesis and degradation. Mitochondrion-associated protein LRPPRC functions as an inhibitor for autophagy initiation to protect mitochondria from autophagy degradation. MAP1S and LRPPRC interact with each other and may collaboratively regulate autophagy although the underlying mechanism is yet unknown. Previously, we have reported that LRPPRC levels serve as a prognosis marker of patients with prostate adenocarcinomas (PCA), and that patients with high LRPPRC levels survive a shorter period after surgery than those with low levels of LRPPRC. MAP1S levels are elevated in diethylnitrosamine-induced hepatocelular carcinomas in wildtype mice and the exposed MAP1S-deficient mice develop more malignant hepatocellular carcinomas. We performed immunochemical analysis to evaluate the co-relationship among the levels of MAP1S, LRPPRC, P62, and γ-H2AX. Samples were collected from wildtype and prostate-specific PTEN-deficient mice, 111 patients with PCA who had been followed up for 10 years and 38 patients with benign prostate hyperplasia enrolled in hospitals in Guangzhou, China. The levels of MAP1S were generally elevated so the MAP1S-mediated autophagy was activated in PCA developed in either PTEN-deficient mice or patients than their respective benign tumors. The MAP1S levels among patients with PCA vary dramatically, and patients with low MAP1S levels survive a shorter period than those with high MAP1S levels. Levels of MAP1S in collaboration with levels of LRPPRC can serve as markers for prognosis of prostate cancer patients.
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