SOCS3 blocks HIF-1 expression to inhibit proliferation and angiogenesis of human small cell lung cancer by downregulating activation of Akt, but not STAT3

Suppressor of cytokine signaling 3 (SOCS3) is a major negative regulator of signal transducer and activator of transcription 3 (STAT3) during tumorigenesis. Previous studies have indicated that SOCS3 also regulates other signaling pathways, such as PI3K/Akt. However, little is known about the specific molecular mechanisms by which SOCS3 regulates the proliferation and angiogenesis of small cell lung cancer (SCLC) cells. The present study investigated the effect of SOCS3 upregulation on the expression of hypoxia-inducible factor-1 (HIF-1) and how this affects the proliferation and angiogenesis of SCLC cells. It was investigated whether this interaction is associated with STAT3 or the Akt signaling pathway. The results of the present study revealed that SOCS3 negatively regulates proliferation and angiogenesis of NCI-H446 cells and that HIF-1 is required in this process. The results also suggested a suppressive role of SOCS3 in Akt signaling, but not STAT3 signaling to block HIF-1 expression and a previously unidentified regulatory mechanism for Akt function. In conclusion, the present study suggested that SOCS3 targets the Akt signaling pathway to inhibit HIF-1 expression and affect the growth and angio-genesis of SCLC cells, and may therefore be considered as a potential novel therapeutic for the treatment of SCLC.