Analysis showed that miRNAs are dysregulated in clear cell renal cell carcinoma and may contribute to kidney cancer pathogenesis by targeting more than 1 key molecule. We identified mechanisms that may contribute to miRNA dysregulation in clear cell renal cell carcinoma. Dysregulated miRNAs represent potential biomarkers for kidney cancer.

Personalized medicine (PM) is defined as "a form of medicine that uses information about a person's genes, proteins, and environment to prevent, diagnose, and treat disease." The promise of PM has been on us for years. The suite of clinical applications of PM in cancer is broad, encompassing screening, diagnosis, prognosis, prediction of treatment efficacy, patient follow-up after surgery for early detection of recurrence, and the stratification of patients into cancer subgroup categories, allowing for individualized therapy. PM aims to eliminate the "one size fits all" model of medicine, which has centered on reaction to disease based on average responses to care. By dividing patients into unique cancer subgroups, treatment and follow-up can be tailored for each individual according to disease aggressiveness and the ability to respond to a certain treatment. PM is also shifting the emphasis of patient management from primary patient care to prevention and early intervention for high-risk individuals. In addition to classic single molecular markers, high-throughput approaches can be used for PM including whole genome sequencing, single-nucleotide polymorphism analysis, microarray analysis, and mass spectrometry. A common trend among these tools is their ability to analyze many targets simultaneously, thus increasing the sensitivity, specificity, and accuracy of biomarker discovery. Certain challenges need to be addressed in our transition to PM including assessment of cost, test standardization, and ethical issues. It is clear that PM will gradually continue to be incorporated into cancer patient management and will have a significant impact on our health care in the future. Mol Cancer Res; 8(9); 1175-87. ©2010 AACR.

BACKGROUND: Kallikrein-related peptidases (KLKs) are a family of serine proteases that have been shown to be dysregulated in several malignancies including ovarian cancer. The control of kallikrein genes and their physiological function in cancer is not well understood. We hypothesized that microRNAs (miRNAs) represent a novel mechanism for post-transcriptional control of KLK expression in cancer. METHODS: We first analysed miRNA expression in ovarian cancer in silico. A total of 98 miRNAs were reported to have altered expression in ovarian cancer. Three of these miRNAs were predicted to target KLK10. We experimentally verified the predicted miR -KLK10 interaction using two independent techniques, a luciferase assay with a construct containing the KLK10 3 0 untranslated region (UTR), pMIR -KLK10, and measuring KLK10 protein levels after transfection with miRNA. RESULTS: When we co-transfected cells with pMIR -KLK10 and either let-7f, miR-224, or mR-516a, we saw decreased luciferase signal, suggesting that these miRNAs can target KLK10. We then examined the effect of these three miRNAs on KLK10 protein expression and cell growth. Transfection of all miRNAs, let-7f, miR-224, and miR-516a led to a decrease in protein expression and cellular growth. This effect was shown to be dose dependent. The KLK10 protein levels were partially restored by co-transfecting let-7f and its inhibitor. In addition, there was a slight decrease in KLK10 mRNA expression after transfection with let-7f. CONCLUSIONS: Our results confirm that KLKs can be targeted by more than one miRNA. Increased expression of certain miRNAs in ovarian cancer can lead to decreased KLK protein expression and subsequently have a negative effect on cell proliferation. This dose-dependent effect suggests that a 'tweaking' or 'fine-tuning' mechanism exists in which the expression of one KLK can be controlled by multiple miRNAs. These data together suggest that miRNA may be used as potential therapeutic options and further studies are required.

Quebec platelet disorder (QPD) is an inherited bleeding disorder associated with increased urokinase plasminogen activator (uPA) in platelets but not in plasma, intraplatelet plasmin generation, and ␣-granule protein degradation. These abnormalities led us to investigate uPA expression by QPD CD34 ؉ progenitors, cultured megakaryocytes, and platelets, and whether uPA was stored in QPD ␣-granules. Although QPD CD34 ؉ progenitors expressed normal amounts of uPA, their differentiation into megakaryocytes abnormally increased expression of the uPA gene but not the flanking genes for vinculin or calcium/calmodulindependent protein kinase II␥ on chromosome 10. The increased uPA production by cultured QPD megakaryocytes mirrored their production of ␣-granule proteins, which was normal. uPA was localized to QPD ␣-granules and it showed extensive colocalization with ␣-granule proteins in both cultured QPD megakaryocytes and platelets, and with plasminogen in QPD platelets. In QPD megakaryocytes, cultured without or with plasma as a source of plasminogen, ␣-granule proteins were stored undegraded and this was associated with much less uPAplasminogen colocalization than in QPD platelets. Our studies indicate that the overexpression of uPA in QPD emerges with megakaryocyte differentiation, without altering the expression of flanking genes, and that uPA is costored with ␣-granule proteins prior to their proteolysis in QPD. (Blood. 2009;113:1535-1542)