Saikosaponin‑d suppresses the expression of cyclooxygenase‑2 through 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.