Polymorphism in the hypoxia-inducible factor 1alpha gene may confer susceptibility to LDD in Chinese cohort.

OBJECTIVE: This study aimed to investigate whether or not hypoxia-inducible factor-1α (HIF-1α) gene variants are associated with the susceptibility and clinical characteristics of lumbar disc degeneration (LDD). METHODS: We examined 320 patients with LDD and 447 gender- and age-matched control subjects. We also determined the HIF-1α gene variants, including C1772T (P582S) and G1790A (A588T) polymorphisms. RESULTS: Significant differences were observed in allelic and genotypic distributions of 1790 A > G polymorphisms between LDD cases and control subjects. Logistic regression revealed that 1790 AA genotypes indicated a protective effect against the development of LDD. The HIF-1α 1790 A > G polymorphisms also affected the severity of LDD as evaluated based on the modified Japanese Orthopedic Association (mJOA) scores. The 1790 AA genotype carriers exhibited significantly lower mJOA scores than AG and GG carriers. C1772T did not show any association with the risk and severity of LDD. CONCLUSION: Our study suggested that HIF-1α 1790 A > G polymorphisms may be used as a molecular marker to determine the susceptibility and severity of LDD.

FIM-A, a phosphorus-containing sirolimus, inhibits the angiogenesis and proliferation of osteosarcomas.

The mTOR pathway is a central control of cell growth, proliferation, metabolism, and survival, and is deregulated in most cancers. Cancer cells are addicted to increased activity of mTOR kinase-mediated signaling pathways, leading to numerous inhibitors of mTOR signaling in preclinic and clinical trials for cancer therapy. Phosphorus-containing sirolimus (FIM-A), which targets mTOR signaling, inhibits cancer cell growth in vitro. Here we report that FIM-A reduces the angiogenesis and proliferation of osteosarcoma both in vitro and in vivo. In cultured osteosarcoma cell lines, FIM-A inhibited cell proliferation and arrested cells in the G1 phase of the cell cycle, accompanied with reduction of VEGF and HIF-1alpha. With in vivo mouse osteosarcoma xenografts, FIM-A treatment resulted in the inhibition of mTORC1 signaling as demonstrated by the decreased phosphorylation of p70S6K1 and 4E-BP1. Consistent with this finding, FIM-A significantly decreased the average tumor volume, nuclei staining of PCNA, and the number of intratumoral microvessels. Our data demonstrated that targeting mTORC1 by FIM-A inhibited the growth of osteosarcoma in vitro and in vivo, providing the basis for further development of FIM-A as a therapy for osteosarcoma patients.

KISS1 expression in osteosarcoma: high in chinese clinical cases, but lower in cell lines.

PURPOSE: Osteosarcoma is the most common primary bone malignancy with a notorious feature of high metastasis. KISS1 has been identified as a putative human metastasis suppressor gene in numerous types of cancer. This study was aimed to evaluate the relationship between expression of KISS1 and invasion ability in osteosarcoma cell lines, and the relationships between KISS1 expression levels and prognosis of clinical cases. METHODS: Expression levels of KISS1 in 3 types of osteosarcoma cell lines (MG-63, Saos-2 and U-2 OS) and a normal osteoblast cell line (hF-OB 1.19) were examined using semi-quantitative RT-PCR and immunochemistry staining. Transwell assays were used to detect the cell invasion ability. The osteosarcoma cell lines and specimen sections of osteosarcoma together with control were immuno-stained with KISS1 antibody. The relationship between the clinical data and the expression of KISS1 was evaluated. RESULTS: KISS1 mRNA expression was moderate in U-2 OS, weak in Saos-2 and lost in MG-63. Transwell assays displayed a gradually increased aggressive phenomenon in osteosarcoma cell lines U-2 OS, Saos-2 and MG-63. However, a contrary conclusion was obtained with clinical specimen, a higher positive rate of KISS1 expression being displayed in osteosarcoma patients, especially in metastastic cases, compared to the benign osteochondroma patients. Furthermore, significant earlier distant metastasis was observed in KISS1 positive than negative cases. CONCLUSION: KISS1 expression levels were found to be decreased with the increasing aggressive ability in osteosarcoma cell lines. However, expression of KISS1 positively correlated with metastasis in osteosarcoma patients.