The activation of PI3K/Akt and the overexpression of fatty acid synthase (FASN) are frequently observed in human osteosarcoma (OS). In the present study, in order to investigate the possible association between the phosphorylation of Akt and FASN expression, immunohistochemical staining was conducted on 24 OS specimens from patients with pulmonary metastasis, which revealed a significant positive correlation between phosphorylated Akt (p-Akt) and the expression of FASN (R=0.469, P=0.04). To investigate the association between p-Akt and FASN in vitro, human U2-OS OS cells were treated with FASN-specific RNAi plasmid or LY294002 (an inhibitor of PI3k/Akt). The mRNA levels of Akt and FASN were measured by real-time PCR. Western blot analysis was also performed to detect the protein experession of PI3K, Akt, p-Akt and FASN. The results demonstrated that the PI3K/Akt signaling pathway modulates FASN expression; the inhibition of FASN resulted in the downregulation of p-Akt in the U2-OS cells. Furthermore, the effects induced by the inhibition of the activity of p-Akt or FASN on the malignant phenotype of U2-OS cells were investigated, demonstrating that the malignant phenotype was inhibited by suppressing the activity of PI3K/Akt or FASN in the U2-OS cells. The findings from our study suggest the existence of a positive feedback regulation between Akt phosphorylation and FASN expression and that this loop may play an important role in the malignant phenotype of OS cells.

Our previous study indicated that Aurora-B is involved in osteosarcoma (OS) cell invasion and metastasis; however, the mechanism underlying Aurora-B overexpression in OS remains unknown. In the present study, significantly downregulated let-7i expression in OS tissues and OS cells was observed compared with that in normal adjacent tumorous tissues and human osteoblast cell lines. Bioinformatic predictions have revealed a conserved binding site in a microRNA locus on Aurora‑B, suggesting the potential of let‑7i targeting the Aurora‑B gene. To validate this, a luciferase reporter assay was performed on OS cells. The results indicated that Aurora‑B is a likely to be a direct target negatively regulated by let‑7i. The expression of let‑7i in OS cells was restored by infection with let‑7i mimics. Results revealed that Aurora‑B mRNA and protein expression levels were significantly decreased. Furthermore, the proliferation, migration and invasion abilities of OS cells were significantly suppressed by infection with let‑7i mimics. Notably, the inhibitory effect of silencing Aurora‑B by LV‑shAurora‑B on cell proliferation, migratory and invasive ability was significantly lower than that by let‑7i mimics, which indicated that let‑7i inhibits cell malignant phenotypes partially by targeting Aurora‑B in OS cells. All data suggested that let‑7i may be a novel potential target for OS treatment.

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Abstract.Pirarubicin is frequently used in chemotherapy against tumors. However, clinical use is severely limited by the development of progressive dose-dependent cardiomyopathy and acquired drug resistance. LY294002 is a commonly used pharmacologic inhibitor, which selectively inhibits the phosphoinositide 3-kinase-AKT nexus. The aim of this study was to investigate the combined inhibitory effect of LY294002 and pirarubicin on human osteosarcoma (OS) cells in vitro. The inhibitory effect of LY294002 plus pirarubicin on U2-OS and MG-63 OS cell proliferation, apoptosis, migration and invasion was investigated by cell proliferation, wound healing and Transwell invasion assays. The results revealed that LY294002 and pirarubicin synergistically induced apoptosis, and inhibited the growth, migration and invasion of OS cells. This indicates that LY294002 enhanced the effects of pirarubicin on OS in vitro. LY294002 combined with pirarubicin may thus be a future therapeutic strategy in OS. IntroductionOsteosarcoma (OS) is the most common type of malignant tumor of the bone. Due to the rapid and aggressive nature of the disease, the standard treatment for OS was previously amputation of the affected limb; however, the cure rate associated with this method was <10% and almost all patients succumbed to their disease within one year from initial diagnosis. Over the past three decades, with the development of effective chemotherapeutic agents, the five-year cumulative survival rate of primary OS patients has significantly improved to 60-90% (1-7). Chemotherapy is, thus, an important treatment for OS.Pirarubicin, a member of the anthracycline family, is widely applied in the treatment of OS (8-12). However, its clinical use is severely limited by the development of progressive dose-dependent cardiomyopathy and acquired drug resistance (13). Adjunctive drug therapies occasionally reduce adverse reactions and drug resistance. Therefore, drugs that enhance the effect of pirarubicin against OS are being investigated.The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway is important in tumor cell differentiation, cell cycle, apoptosis, growth and metastasis (8,9). Recent studies have shown that the PI3K/AKT signaling pathway is crucially involved in the resistance of cancer cells to chemotherapy (14,15). Therefore, inhibition of the PI3K/AKT signaling pathway is under investigation as a potential target for cancer therapy. LY294002 is a commonly used pharmacological PI3K inhibitor, which acts on the ATP-binding site of the PI3K enzyme and thus selectively inhibits the PI3K-AKT nexus. Numerous studies have demonstrated that LY294002 enhances the chemosensitivity of various cancer types to a wide variety of drugs (16)(17)(18)(19). However, whether LY294002 enhances the effects of pirarubicin on OS remains unclear.In the present study, the effect of LY294002 on the sensitivity of OS cell lines to pirarubicin chemotherapy was investigated, in addition to the possible mechanisms underlying any such effect. Materials and methodsCel...

Partial interference alignment (PIA) strategies for the K-user interference channel are considered. Two schemes are proposed to align the partial interference for the downlink interference channel in the case ofK>3. In the first scheme, strong interferences are limited as much as possible by aligning the two strongest interferers into a same subspace at the receiver. While the second scheme is to design its precoding matrix (or vector) by selecting the precoder pair which maximizes the chordal distance between designed signal subspace and interference signal subspace in the set of pecoding matrices (or vectors) at each transmitter. Simulation results show that compared with the existing schemes which don’t optimize the precoder, such as Fixed-PIA, the proposed schemes can improve the sum rates significantly by selecting IA forms in multi-input multi-output (MIMO) systems.