Novel MIG-7 expression increases tumor cell invasion and tumor progression

Aaron Petty

Tumor cell spread by invasion and metastasis is a primary cause of death and post-treatment disease recurrence in cancer and requires complex interactions with the surrounding tumor microenvironment. Therefore, in order to better target cancer spread and mortality, factors specific to these interactions and tumor cell invasion must be identified. We have identified a novel gene expression, Mig-7, which results from the cross-talk between interaction of Hepatocyte growth factor (HGF), a microenvironment growth factor, with c-Met receptor and [alpha]v[beta]5 integrin signaling. Importantly, Mig-7 expression is specific to cancer cells and tissues in studies to date. The only normal cells to date that express Mig-7 are fetal cytotrophoblast cells (CTBs), which behave similarly to invasive cancer cells. Based on this link, the present studies were undertaken to determine whether Mig-7 expression plays a role in tumor cell invasion, as well as in vasculogenic mimicry and primary tumor growth, processes linked to invasion. Our studies demonstrate that reduction of Mig-7 expression and function by siRNA knockdown in RL95 endometrial carcinoma cells and by antibody treatment in HEC1A endometrial carcinoma cells, respectively, resulted in decreased invasion, as well as decreased activation of the membrane type-1 matrix metalloproteinase (MT1- MMP). Mig-7 expression knockdown by siRNA also decreased initial primary tumor growth and activation of ERK1/2, Akt, and S6K signaling kinase. In addition, Mig-7 expression, in response to the microenvironment, resulted in increased cleavage of laminin 5 [gamma]2 chain promigratory fragments, important for invasion, as well as in decreased tumor cell adhesion to laminins of the basement membrane. Mig-7 expression in melanoma cells was limited to aggressive cells capable of vasculogenic mimicry, and overexpression in human HT29 colon carcinoma cells resulted in formation of vessel-like structures in 3D cultures. Mouse models revealed that Mig-7 expression colocalized with endothelial cell markers to small, abnormal vessel-like structures in lymph nodes of nude mice injected with human RL95 and HEC1A cell lines. Taken together, these results suggest that Mig-7 expression plays an important role in tumor cell invasion in a tumor microenvironment-dependent manner, and may be involved in primary tumor growth and the process of vasculogenic mimicry.

Novel MIG-7 expression increases tumor cell invasion and tumor progression

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