Promotion of hepatocellular carcinoma metastasis through matrix metalloproteinase activation by epithelial-mesenchymal transition regulator Twist1

Abstract

E-cadherin loss is a key biological mechanism in tumour invasion. As a main regulator of epithelial-mesenchymal transition (EMT) mechanism-mediated invasion and metastasis, Twist1 plays an important role through its regulation of E-cadherin expression. However, whether or not Twist2 has the same function in tumour metastasis remains unclear. The purpose of this study is to investigate the expressions and different roles of Twist1 and Twist2 in human hepatocellular carcinoma (HCC). The expressions of Twist1 and Twist2 in HCC tissue were evaluated by immunohistochemical staining. The role of Twist1 and Twist2 in invasiveness was also evaluated in vitro by using HCC cell lines. Twist1 nuclear overexpression is found to be correlated with HCC metastasis, and its expression is negatively correlated with E-cadherin expression in human tissue. Twist2, a Twist1 homology protein, only expresses in the cytoplasm and shows no significant correlation with HCC metastasis. By ectopic transfection of Twist1 and Twist2 into the HCC cells, HepG2 and PLC, Twist1 is able to down-regulate E-cadherin expression and promote matrix metalloproteinase (MMP) activation, specifically in MMP2 and MMP9. In functional assays, Twist1 is found to promote invasion in HepG2 and PLC cells, but the invasion ability of the groups is not affected Twist2. Our findings indicate that Twist1 induces HCC invasion via increased activity in MMPs, leading to poor clinical prognoses. The results of this study also demonstrate a novel cogitation in Twist2, which has no effect on HCC invasion and metastasis. Twist1 may contribute to HCC invasion and metastasis and may be used as a novel therapeutic target for the inhibition of HCC metastasis.

Downregulation of discoidin domain receptor 2 in A375 human melanoma cells reduces its experimental liver metastasis ability

“…Our previous studies on hepatic stellate cells and skin fibroblasts during heptic and skin injury, respectively, revealed that DDR2 signaling regulates key aspects of wound-repair such as MMP2 synthesis, cell proliferation and chemotactic invasion (11,12,17). MMPs are the major protein source implicated in extracellular matrix degradation in healthy and diseased tissues (17,11,24). We used siDDR2 against DDR2 expression with in vitro MMP2/9 secretion, cell proliferation and cell migration (20,21) because they are also key prometastatic characteristics of tumor cells (22).…”

“…MMP2 together with MMP9 and MMP1 (24,25), are the main enzymes for extracellular matrix remodelling during tissue repair (23). MMPs have also been described in metastatic progression because their activity is required for cancer cell motility (24,25). MMPs are also involved in other cell-mediated events during metastatic progression.…”

“…MMPs are also involved in other cell-mediated events during metastatic progression. For example, the mitogenic response of some growth factors is regulated by MMPs, which control the availability of the receptor (24). In addition, MMP degradation of the extracellular matrix allows some signalling cascades to interconnect (22).…”

Probing the Bi-directional Interaction Between Microglia and Gliomas in a Tumor Microenvironment on a Microdevice

“…Nuclear staining was carried out using According to the manufacturer's instructions for the transcription kit, real-time PCR was performed with a Mx3000P qPCR system (Agilent Technologies, USA) with SYBR Premix Ex Taq (Takara). The oligonucleotide sequences for Twist1 and MMP-9, which are involved in tumor metastasis, were adapted from the literature [23]. The relative expression level of each gene was calculated using the comparative threshold cycle (C t ) method, and the housekeeping gene β-actin served as an internal standard.…”

Overexpression of peroxiredoxin 2 inhibits TGF-β1-induced epithelial-mesenchymal transition and cell migration in colorectal cancer

“…Twist1, like other EMT-inducing transcription factors, including Snail, Slug and SIP1, binds DNA through similar E-box sequence motifs and represses E-cadherin and other epithelial cell adhesion molecules. Further studies on different hepatic cellular cancer (HCC) cell lines revealed that Twist1 is able to downregulate E-cadherin expression and promote matrix metalloproteinase (MMP) activation, specifically in MMP2 and MMP9 (7). Transforming growth factor (TGF)-β1 is a multi-functional cytokine with diverse effects on cancer cells (8).…”