MTA-1 expression is associated with metastasis and epithelial to mesenchymal transition in colorectal cancer cells

Abstract

Although metastasis associated protein 1 (MTA1) has been widely linked to tumor metastasis, the relevant mechanisms remain to be elucidated, especially in colorectal cancer (CRC). Here, we have investigated the link between MTA1, metastasis and epithelial-mesenchymal transition (EMT) in CRC. Eighteen normal colon tissues and 91 resected tumor samples were analyzed for MTA1 expression by immunohistochemistry (IHC). IHC indicated low or no nuclear MTA1 expression in the normal tissues and significantly higher expression in Grade II, Grade III and liver metastasis tumors. No statistically significant difference was observed in MTA1 expression between Grade III and liver metastatic tumors. To demonstrate the functional importance of MTA1 in vitro, the gene was silenced in HCT-116 cells and LoVo cells and overexpressed in HCT-116 cells. MTA1 overexpression in HCT-116 cells enhanced proliferation, adhesion to fibronectin, motility, migration, invasion through Matrigel, anchorage-independent growth, neoangiogenesis and induced a loss of apoptosis. Silencing of MTA1 resulted in a reversal of all of these features. Mechanistically, MTA1 silencing caused an increase in the epithelial markers E-cadherin and ZO-1 and a decrease in the mesenchymal marker vimentin while MTA1 overexpression caused an increase in vimentin expression. Moreover, MTA1 enhanced the expression of Snai1 and Slug; silencing of MTA1 reduced their recruitment to the promoter of E-cadherin, thereby leading to its expression. MTA1 is highly expressed in higher grade tumors and is important in the orchestration of various phenotypic changes in CRC, most likely by inducing EMT. This further corroborates its role as a master regulator in tumorigenesis.

MTA1 promotes epithelial to mesenchymal transition and metastasis in non-small-cell lung cancer

“…MTA1 reportedly promotes EMT [17–21]. We assessed whether MTA1-induced NSCLC cell migration and invasion was related to EMT.…”

“…MTA1 reportedly promotes cancer cell invasion and metastasis through E-cadherin expression regulation [17, 18, 27] and EMT [19–21]. However, the role of MTA1-induced EMT in NSCLC has not been thoroughly studied.…”

“…MTA1 is overexpressed in a variety of human cancers, including NSCLC [13–16], providing a new molecular target for anti-cancer therapeutics. MTA1 reportedly contributes to tumor metastasis by promoting EMT in some cancers [17–21]. However, no study has systematically investigated MTA1 functions in the NSCLC EMT and metastasis processes.…”

Expression and role of nuclear receptor coregulators in colorectal cancer

“…Similarly, MTA1 protein expression is significantly higher in moderately and poorly differentiated CRC specimens and liver metastatic tumors compared with normal colon tissues. Moreover, MTA1 overexpression in HCT116 cells enhances cell proliferation, migration and adhesion, while MTA1 silencing inhibits these functions[103]. …”

Corepressor metastasis-associated protein 3 modulates epithelial-to-mesenchymal transition and metastasis

“…Interestingly, data derived from studies on breast cancer showed that SRC-1, the first discovered and cloned coactivator, is exclusively responsible for promoting metastasis without accelerating tumor growth [90]. SRC-1 plays a vital role in cancer cell invasion through multiple mechanisms by modulating twist, polyoma enhancer activator 3 (PEA3), Snail, and Smad interacting protein 1 (SIP1) [91, 92]. Thus, it is possible that SCR-1 may fall into category of proteins that are defined as potent metastasis suppressors.…”