BackgroundPrevious work has shown reduced expression levels of let-7 in lung tumors. But little is known about the expression or mechanisms of let-7a in prostate cancer. In this study, we used in vitro and in vivo approaches to investigate whether E2F2 and CCND2 are direct targets of let-7a, and if let-7a acts as a tumor suppressor in prostate cancer by down-regulating E2F2 and CCND2.Methodology/PrincipalFindings Real-time RT-PCR demonstrated that decreased levels of let-7a are present in resected prostate cancer samples and prostate cancer cell lines. Cellular proliferation was inhibited in PC3 cells and LNCaP cells after transfection with let-7a. Cell cycle analysis showed that let-7a induced cell cycle arrest at the G1/S phase. A dual-luciferase reporter assay demonstrated that the 3′UTR of E2F2 and CCND2 were directly bound to let-7a and western blotting analysis further indicated that let-7a down-regulated the expression of E2F2 and CCND2. Our xenograft models of prostate cancer confirmed the capability of let-7a to inhibit prostate tumor development in vivo.Conclusions/SignificanceThese findings help to unravel the anti-proliferative mechanisms of let-7a in prostate cancer. Let-7a may also be novel therapeutic candidate for prostate cancer given its ability to induce cell-cycle arrest and inhibit cell growth, especially in hormone-refractory prostate cancer.
Hypoxia-inducible factor 1-α (HIF-1α) plays a critical role in angiogenesis-osteogenesis coupling during bone development and bone regeneration. Previous studies have shown that 17β-estradiol activates the HIF-1α signaling pathway and that mice with conditional activation of the HIF-1α signaling pathway in osteoblasts are protected from ovariectomy (OVX)-induced bone loss. In addition, it has been shown that hypoxia facilitates the osteogenic differentiation of mesenchymal stem cells (MSCs) and modulates Wnt/β-catenin signaling. Therefore, we hypothesized that activation of the HIF-1α signaling pathway by hypoxia-mimicking agents would prevent bone loss due to estrogen deficiency. In this study, we confirmed the effect of dimethyloxalylglycine (DMOG), a hypoxia-mimicking agent, on the HIF-1α signaling pathway and investigated the effect of DMOG on MSC osteogenic differentiation and the Wnt/β-catenin signaling pathway. We then investigated the effect of DMOG treatment on OVX-induced bone loss. Female C57BL/6J mice were divided into sham, OVX, OVX+L-DMOG (5 mg/kg/day), and OVX+H-DMOG (20 mg/kg/day) groups. At sacrifice, static and dynamic bone histomorphometry were performed with micro computed tomography (micro-CT) and undecalcified sections, respectively. Bone strength was assessed with the three-point bending test, and femur vessels were reconstructed and analyzed by micro-CT. Serum vascular endothelial growth factor (VEGF), osteocalcin, and C-terminal telopeptides of collagen type(CTX) were measured by ELISA. Tartrate-resistant acid phosphatase staining was used to assess osteoclast formation. Alterations in the HIF-1α and Wnt/β-catenin signaling pathways in the bone were detected by western blot. Our results showed that DMOG activated the HIF-1α signaling pathway, which further activated the Wnt/β-catenin signaling pathway and enhanced MSC osteogenic differentiation. The micro-CT results showed that DMOG treatment improved trabecular bone density and restored the bone microarchitecture and blood vessels in OVX mice. Bone strength was also partly restored in DMOG-treated OVX mice. Dynamic bone histomorphometric analysis of the femur metaphysic revealed that DMOG increased the mineralizing surface, mineral apposition rate, and bone formation rate. The serum levels of VEGF and osteocalcin were higher in DMOG-treated OVX mice. However, there were no significant differences in serum CTX or in the number of tartrate-resistant acid phosphatase-stained cells between DMOG-treated OVX mice and OVX mice. Western blot results showed that DMOG administration partly rescued the decrease in HIF-1α and β-catenin expression following ovariectomy. Collectively, these results indicate that DMOG prevents bone loss due to ovariectomy in C57BL/6J mice by enhancing angiogenesis and osteogenesis, which are associated with activated HIF-1α and Wnt/β-catenin signaling pathways.
We studied the prevalence, awareness, treatment and control of hypertension in an elderly Chinese population. The study subjects (age ≥60 years) were recruited from a suburban town of Shanghai from 2006 to 2008. We administered a standardized questionnaire to collect information on medical history, the use of medications and lifestyle. We measured blood pressure three times consecutively using a validated Omron 7051 oscillometric device (Kyoto, Japan) after the subjects had rested for at least 5 min in the sitting position. We defined hypertension as a blood pressure of at least 140 mm Hg systolic or 90 mm Hg diastolic or as the use of antihypertensive drugs. The 3949 participants (mean age of 68.3 years) included 2185 (55.3%) women, 182 (4.6%) obese subjects (body mass index ≥30 kg m(-2)) and 366 (9.3%) diabetic patients. The prevalence of hypertension was 59.4%. In the 2345 hypertensive patients, the awareness, treatment and control (<140/90 mm Hg) rates were 72.5%, 65.8% and 24.4%, respectively. In the 1542 treated hypertensive patients, 1196 (77.6%) used fixed-dose combinations of thiazide and reserpine or clonidine (n=1157, 75.0%) or of an angiotensin receptor blocker and hydrochlorothiazide (n=1) or free combinations (n=38, 2.5%), and 346 (22.4%) used a monotherapy of short-acting calcium channel blockers (n=217, 14.1%) or other classes of antihypertensive drugs (n=129, 8.3%). The corresponding control rates were 37.3% and 36.4%, respectively. In a stepwise logistic regression, the risk of uncontrolled hypertension was higher with older age (+10 years, odds ratio (OR) 1.19, P=0.03), female sex (OR 1.40, P=0.01), obesity (OR 2.35, P=0.0002) and heavy drinking (≥300 g per week, OR 2.18, P=0.0007). In conclusion, in elderly Chinese, the prevalence of hypertension is high. In spite of reasonably high awareness and treatment rates, the control rate remains low, most likely due to an unhealthy lifestyle and the underuse and/or underdose of antihypertensive drugs.
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