Human tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 suppresses hepatocellular carcinoma metastasis through inhibiting Rac1

Abstract

BackgroundTumor invasion and metastasis are the major reasons for leading death of patients with hepatocellular carcinoma (HCC). Therefore, to identify molecules that can suppress invasion and metastasis of tumor will provide novel targets for HCC therapies. Tumor necrosis factor (TNF)-alpha-induced protein 8-like 2, TIPE2, is a novel immune negative molecule and an inhibitor of the oncogenic Ras in mice but its function in human is unclear. Our previous research has shown that TIPE2 is downregulated in human primary HCC compared with the paired adjacent non-tumor tissues.ResultsIn present study, we provide evidence that TIPE2 inhibits effectively human hepatocellular carcinoma metastasis. The forced expression of TIPE2 in HCC-derived cell lines markedly inhibits tumor cell growth, migration and invasion in vitro and suppresses growth and metastasis of HCC in vivo. Clinical information from a cohort of 112 patients reveals that loss or reduced expression of TIPE2 in primary HCC tissues is significantly associated with tumor metastasis. Mechanically, TIPE2 inhibits the migration and invasion through targeting Rac1 and then reduces F-actin polymerization and expression of matrix metallopeptidase 9 (MMP9) and urokinase plasminogen activator (uPA).ConclusionOur results indicate that human TIPE2 is endogenous inhibitor of Rac1 in HCC by which it attenuates invasion and metastasis of HCC. The data suggest that TIPE2 will be a new target for HCC therapy.

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

“…54 Moreover, reduced TIPE2 expression is associated with metastasis of hepatic cancer. 56 In contrast, TIPE2 expression was increased in the tumor tissues of patients with renal cell carcinoma and positively correlated with TNM staging. 57 Similarly, TIPE2 expression is increased in colon cancer tissues and is associated with lymph node metastases and the Duke stage of the cancer.…”

“…23 In HCC, TIPE2 reduces Rac-mediated F-actin polymerization and the expression of MMP-9 and urokinase plasminogen activator, and a loss of TIPE2 in this setting is associated with metastasis. 56 It also inhibits the TNFmediated activation of Erk1/2 and NF-κB in an HCC cell line. 68 In contrast, TIPE2 overexpression induced cell death and inhibited Ras-mediated tumorigenesis in mice.…”

Bergamottin, a natural furanocoumarin abundantly present in grapefruit juice, suppresses the invasiveness of human glioma cells via inactivation of Rac1 signaling

“…C6 glioma cells with high Rac1 activity possess increased invasiveness compared with those with low Rac1 activity (19), indicating a favorable role for Rac1 in glioma invasion. Targeting Rac1 abrogates cancer progression and metastasis (20,21). Rac1 small-molecule inhibitors (ZINC69391 and 1A-116) have been documented to decrease cell proliferation, trigger apoptotic death and inhibit cell migration and invasion in malignant glioma cells (9).…”

TIPE2 Mediates the Suppressive Effects of Shikonin on MMP13 in Osteosarcoma Cells

“…The dysregulation of TIPE2 has also been found to mediate diverse immunological diseases [37][38][39][40][41]. Recently, involvement of loss of TIPE2 has been suggested in the carcinogenesis of different cancer, including Non-small cell lung cancer [42], hepatocellular carcinoma [43,44], renal cell carcinoma [45], etc. However, whether TIPE2 may be involved in the pathogenesis of OS has not been reported.…”