Saikosaponin-d suppresses the expression of cyclooxygenase-2through the phospho-signal transducer and activator of transcription 3/hypoxia-inducible factor-1α pathway in hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is one of the most common malignancies and accounts for ~6% of all types of human cancer worldwide, particularly in Asia. The incidence and mortality rates in the USA have also rapidly increased. Saikosaponin-d (SSD), a saponin derivative extracted from several species of Bupleurum (Umbelliferae), possesses unique biological activities, including anti-inflammatory, antihepatitic and immunomodulatory effects. Our previous studies have demonstrated that SSD inhibits the proliferation and induces the apoptosis of HCC SMMC-7721 cells by downregulating the expression of cyclooxygenase (COX)-2 and decreasing the production of prostaglandin E2. However, the specific mechanism underlying how SSD controls the expression of COX-2 remains to be elucidated. In the present study, it was demonstrated that hypoxia inducible factor-1α (HIF-1α) was responsible for the expression of COX-2 under hypoxic conditions in HCC cells, and the activation of signal transducer and activator of transcription 3 (STAT3) was required for the expression of HIF-1α. SSD treatment inhibited STAT3 activation [phosphorylation of STAT3 (p-STAT3)], reduced the protein level of HIF-1α and decreased the expression of COX-2. These results suggested that SSD may target HCC cells by suppressing the expression of COX-2 through the p-STAT3/HIF-1α pathway.