Sonic hedgehog signaling pathway induces cell migration and invasion through focal adhesion kinase/AKT signaling-mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9 in liver cancer

Abstract

The aberrant activation of sonic hedgehog (SHH) pathway contributes to initiation and progression of various malignancies. However, the roles and underlying mechanisms of SHH signaling pathway in invasion and metastasis of liver cancer have not been well understood. In this study, we found that SHH signaling was activated and correlated with invasion and metastasis in hepatocellular carcinoma (HCC). Enhanced SHH signaling by recombinant human SHH N-terminal peptide (rSHH-N) promoted hepatoma cell adhesion, migration and invasion, whereas blockade of SHH signaling with SHH neutralizing antibody or cyclopamine suppressed hepatoma cell adhesion, migration and invasion. Furthermore, matrix metalloproteinase (MMP)-2 and MMP-9 expressions and activities were upregulated and downregulated by rSHH-N and SHH signaling inhibitor, respectively. The rSHH-N-mediated hepatoma cell migration and invasion was blocked by MMP-specific inhibitors or neutralizing antibodies to MMP-2 and MMP-9. In addition, phosphorylations of AKT and focal adhesion kinase (FAK) were increased and decreased by rSHH-N and SHH signaling inhibitor, respectively. Further investigations showed that activation of AKT and FAK were required for rSHH-N-mediated upregulation of MMP-2 and MMP-9, cell migration and invasion. Finally, we found that SHH protein expression was positively correlated with phosphorylatd FAK Tyr397, phosphorylatd AKT Ser473, MMP-2 and MMP-9 protein expressions in HCC samples. Taken together, our findings suggest that SHH pathway induces cell migration and invasion through FAK/AKT signaling-mediated MMP-2 and MMP-9 production and activation in liver cancer.

miR-141 Is a Key Regulator of Renal Cell Carcinoma Proliferation and Metastasis by Controlling EphA2 Expression

“…In contrast, inhibition of miR-141 led to increased phosphorylation of FAK and AKT. Additional downstream mediators of FAK/AKT such as MMPs (MMP-2/9) that have been implicated in the aggressiveness of RCC (37,38) are known to contribute to FAK/AKTmediated cell proliferation and progression (47)(48)(49)(50), which is further supported by our study on the functional activities of miR-141 and EphA2. However, further investigation of EphA2/p-FAK/p-AKT/MMP pathway regulation in RCC is mandatory.…”

Baicalein inhibits the migration and invasion of colorectal cancer cells via suppression of the AKT signaling pathway

“…For example, the AKT signaling pathway is associated with the expression of MMP-2/-9 in healthy and cancerous tissues (24,25). Furthermore, the antitumor effects of baicalein treatment are associated with the AKT signaling pathway (26).…”

Association between FOXM1 and hedgehog signaling pathway in human cervical carcinoma by tissue microarray analysis

“…Previous studies have reported that the inhibition of the Hh signaling pathway in glioma (53) and liver cancer (54) suppressed the expression of MMP-2, MMP-9 and VEGF. FOXM1 may act as the downstream element of the Hh signaling pathway, and both FOXM1 and the Hh signaling pathway may modulate the expression and activity of MMP-2, MMP-9 and VEGF (18,(54)(55)(56). Thus, it is possible to hypothesize that the Hh signaling pathway may regulate the expression and activity of MMP-2, MMP-9 and VEGF through FOXM1.…”