ODAM inhibits RhoA‐dependent invasion in breast cancer

Abstract

Odontogenic ameloblast-associated protein (ODAM) contributes to cell adhesion. In human cancer, ODAM is down-regulated, and the overexpression of ODAM results in a favourable prognosis; however, the molecular mechanisms underlying ODAM-mediated inhibition of cancer invasion and metastasis remain unclear. Here, we identify a critical role for ODAM in inducing cancer cell adhesion. ODAM induced RhoA activity and the expression of downstream factors, including Rho-associated kinase (ROCK). ODAM-mediated RhoA signalling resulted in actin filament rearrangement by activating PTEN and inhibiting the phosphorylation of AKT. When ODAM is overexpressed in MCF7 breast cancer cells and AGS gastric cancer cells that activate RhoA at high levels, it decreases motility, increases adhesion and inhibits the metastasis of MCF7 cells. Conversely, depletion of ODAM in cancer cells inhibits Rho GTPase activation, resulting in increased cancer migration and invasion. These results suggest that ODAM expression in cells maintains their adhesion, resulting in the prevention of their metastasis via the regulation of RhoA signalling in breast cancer cells. SIGNIFICANCE Breast cancer represents the first most frequent cancer, and the ratio of mortality is high in women. Of utmost importance for reducing risk by breast cancer are their anti-invasion mechanisms, particularly in the non-invasive cancer cells because metastasis is the principal cause of death among cancer patients. ODAM induced RhoA activity. ODAM-mediated RhoA signalling resulted in actin filament rearrangement, increased cell adhesion and inhibited the migration/invasion of MCF7 cells. These results suggest that ODAM expression maintains their adhesion, resulting in the prevention of their metastasis via the regulation of RhoA signalling in breast cancer cells.

CHG: A Systematically Integrated Database of Cancer Hallmark Genes

“…These results also confirm the accuracy of our results. For other genes that are not included in the Sanger database, we also confirm their important role in cancer-related biological processes through literature verification, such as ETS1 (Watabe et al, 1998;Fujimoto et al, 2004;Zhang et al, 2014;Li et al, 2015) and RHOA (Lee et al, 2015;Zeng et al, 2015;Sun et al, 2016) in hallmark "Activating Invasion and Metastasis".…”

Identification of odontogenic ameloblast associated as a novel target gene of the Wnt/β‐catenin signaling pathway

“…It was reported that ODAM expression induced PTEN expression and inactivated the PI3K/AKT pathway in melanoma 47 and CRC cells 42 . Another group reported that ODAM suppressed migration and invasion through an increase in RhoA expression in breast cancer cells 48 . These reports suggested the tumor‐suppressive role of ODAM in human carcinogenesis.…”

“… 42 Another group reported that ODAM suppressed migration and invasion through an increase in RhoA expression in breast cancer cells. 48 These reports suggested the tumor‐suppressive role of ODAM in human carcinogenesis. However, this view raised a discrepancy between its growth‐suppressive role and its elevated expression in cancer because cancer cells expressing abundant ODAM should not be selected in tumor evolution.…”

Identification of Triple-Negative Breast Cancer Genes and a Novel High-Risk Breast Cancer Prediction Model Development Based on PPI Data and Support Vector Machines

“…RHOA is the target of miR-146a to prevent cell invasion and metastasis in breast cancer (Liu et al, 2016). Lee et al showed that ODAM expression maintains breast cancer cell adhesion and thus prevents breast cancer cell metastasis by modulating RhoA signaling in breast cancer cells (Lee et al, 2015). The study by Kwon et al showed that SMURF1 acts in EGF-induced migration and invasion of breast cancer cells (Kwon et al, 2013).…”