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.