TIPE-2 suppresses growth and aggressiveness of hepatocellular carcinoma cells through downregulation of the phosphoinositide 3-kinase/AKT signaling pathway

Rapid proliferation and migration are the main features of hepatocellular carcinoma (HCC) cells, which serve an essential role in carcinogenesis and are a hallmark of cancer therapy resistance. Previous studies have reported that tumor necrosis factor-α-induced protein-8 like-2 (TIPE-2) is involved in cancer initiation and the progression of HCC. The present study aimed to clarify the role of TIPE-2 in HCC carcinogenesis, growth and aggressiveness. The effects of TIPE-2 on HCC were determined using colony forming and cell cycle analyses. Cell apoptosis, and growth and aggressiveness of HCC cells, were investigated following TIPE-2 treatment. Treatment with TIPE-2 markedly suppressed HCC cell proliferation and increased the number of cells in S phase of the cell cycle. The results demonstrated that TIPE-2 significantly inhibited growth, migration and invasion of HCC cells via the downregulation of tumor metastasis-associated genes. Flow cytometric analysis indicated that TIPE-2 promoted apoptosis of HCC cells via regulation of apoptosis-associated gene transcription. In addition, TIPE-2 administration downregulated the expression of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) in HCC cells. In addition, TIPE-2 selectively decreased neuroblastoma Ras viral oncogene and p27 expression in HCC cells. In vivo assays revealed that TIPE-2 significantly inhibited tumor growth and prolonged animal survival by promoting apoptosis of tumor cells. The results of the present study indicated that TIPE-2 acts as an inhibitor of HCC cell growth and aggressiveness, and promotes apoptosis, thus suggesting that TIPE-2 may inhibit the metastasis-associated PI3K/AKT signaling cascade and may arrest the tumor cell cycle. These findings provide a potential molecular mechanism by which TIPE-2 promotes apoptosis of HCC cells.