ABSTRACT
In order to understand the role of the p53 tumor suppressor gene in microRNA expression during osteoblast differentiation, we used a screen to identify microRNAs that were altered in a p53-dependent manner. MicroRNAs from MC3T3-E1 preosteoblasts were isolated from day 0 (undifferentiated) and day 4 (differentiating) and compared to a p53 deficient MC3T3-E1 line treated similarly. Overall, one fourth of all the microRNAs tested showed a reduction of 0.6 fold, and a similar number of them were increased 1.7 fold with differentiation. P53 deficiency caused 40% reduction in expression of microRNAs in differentiating cells, while a small percent (0.03%) showed an increase. Changes in microRNAs were validated using real-time PCR and two microRNAs were selected for further analysis (miR-34b and miR-140). These two microRNAs were increased significantly during differentiation but showed a dramatic reduction in expression in a p53 deficient state. Stable expression of miR-34b and miR-140 in MC3T3-E1 cells resulted in decreases in cell proliferation rates when compared to control cells. There was a 4-fold increase in p53 levels with miR-34b expression and a less dramatic increase with miR-140. Putative target binding sites for bone specific transcription factors, Runx2 and Osterix, were found for miR-34b, while Runx2, beta catenin and type 1 collagen were found to be miR-140 targets. Western blot analyses and functional assays for the transcription factors Runx2, Osterix and Beta-catenin confirmed microRNA specific interactions. These studies provide evidence that p53 mediated regulation of osteoblast differentiation can also occur through specific microRNAs such as miR-34b and miR-140 that also directly target important bone specific genes.
ABSTRACT
PURPOSE OF REVIEW: Cancer pain is often incapacitating and discouraging to patients; is demoralizing to family members and care takers; and is taxing and difficult to subdue for the pain specialists. The consequences of implementing suboptimal treatment are far-reaching; therefore, effective treatment methods are in a great demand. The face of cancer pain management has changed in considerable ways, and interventional procedures have become an integral part of providing multimodal analgesia in cancer pain treatment. The goals of this review are to draw attention to the critical role that regional anesthetic nerve blocks and interventional pain management techniques play in treating malignancy-related pain and emphasize the benefits provided by the aforementioned treatment strategies. RECENT FINDINGS: A large proportion of cancer patients continues to struggle with an inadequately treated pain despite a strict adherence to the WHO analgesic step ladder. The previous pain treatment algorithm has been modified to include peripheral neural blockade, neuro-destructive techniques, neuromodulatory device use, and intrathecal drug delivery systems. The accumulated evidence highlights the opioid-sparing qualities and other benefits afforded by these modalities: decreasing medication-induced side effects, reducing economic burden of poor analgesia, and overall improvement in quality of life of the patients afflicted with a painful neoplastic disease. The rising prevalence of cancer-related pain syndromes is paralleled by an unmatched growth of innovative treatment strategies. Modified WHO analgesic ladder represents one of the greatest paradigm shifts within the domain of oncologic pain treatment. The cancer patient population requires a prompt and liberal, albeit judicious, delivery of unorthodox pain treatment options freed from the rigid bonds of conventional guidelines and standard practices.
