TNFAIP6 can inhibit osteoblastic differentiation of human mesenchymal stem cells [23]. From this, we might conclude that this is one potential mechanism of SCLC-mediated osteoclasia through upregulation of TNFAIP6 gene expression by HIF-1 alpha. High expression of IL6 also is associated with malignant tumors and deep vein thrombosis disease [24]. This helps to explain why a hypercoagulable state is usually associated with SCLC and what causes the thrombosis. Another novel finding is that with the genes in the same family HIF-1 alpha upregulates the

expression of SOCS1 but downregulates the expression of SOCS2, upregulates the expression of IGFBP5 but downregulates the expression of IGFBP3. Clinical research has shown that SOCS2 is an independent predictor for good prognosis, negative lymph nodes and has increased expression in Belinostat molecular weight less malignant tumors [25]. From this the downregulation of SOCS2 by HIF-1 alpha maybe worsen the prognosis of SCLC. Besides these increased IGFBP-5 mRNA levels have been proved to be associated with a poor outcome for the patients who have positive lymph nodes[26] and high circulating concentrations

of IGFBP-3 is associated with a lower cancer risk from clinical trail[27]. Thus upregulation of IGFBP5 and downregulation of IGFBP3 by hypoxia or HIF-1 alpha cannot be considered as good predictors of prognosis. As for SOCS1 some scholars have demonstrated that SOCS1 plays an important role in degrading IFN resistance of neuroendocrine tumor LDE225 in vivo cells through negative regulation of Jak/STAT signaling pathway[28]. Our study demonstrates Phosphoribosylglycinamide formyltransferase that SOCS1 potentially induces the apoptosis and suppresses the growth of NCI-H446 cells and therefore we thought the upregulation of SOCS1 may be a good predictor for the prognosis of SCLC. As an upstream regulatory factor that plays a contrary effect on the apoptosis

and growth of SCLC cells, through which mechanism HIF-1 alpha upregulates the expression of.SOCS1, is a new problem to investigate. Previous study had demonstrated that the activation of STAT3 mediated by IL-6 could upregulate the expression of SOCS1 at mRNA and protein level [29]. From our study we can see that the expression of STAT3 and IL-6 are both upregulated at protein level. So we can primarily conclude that HIF-1 alpha can upregulate the expression of SOCS1 through mediation of STAT3 and IL-6. As for the signal transduction pathway involving in this pocess we will carry out some resrarch work in the future. Taken together, our data provide novel insights into the composition and function of differential gene expression regulated by HIF-1alpha in SCLC NCI-H446 cells. Improving the survival rate of patients with SCLC requires a better understanding of the function of genes associated with tumorigenesis and the subsequent development of novel gene therapeutic strategies including gene targeted therapy.