Abstract
Breast cancer is the first cause of cancer-related mortality among women worldwide, according to the most recent estimates. This mortality is mainly caused by the tumors’ ability to form metastases. Cancer cell migration and invasion are essential for metastasis and rely on the interplay between actin cytoskeleton remodeling and cell adhesion. Therefore, understanding the mechanisms by which cancer cell invasion is controlled may provide new strategies to impair cancer progression. We investigated the role of the ADP-ribosylation factor (Arf)-like (Arl) protein Arl13b in breast cancer cell migration and invasion in vitro, using breast cancer cell lines and in vivo, using mouse orthotopic models. We show that Arl13b silencing inhibits breast cancer cell migration and invasion in vitro, as well as cancer progression in vivo. We also observed that Arl13b is upregulated in breast cancer cell lines and patient tissue samples. Moreover, we found that Arl13b localizes to focal adhesions (FAs) and interacts with β3-integrin. Upon Arl13b silencing, β3-integrin cell surface levels and FA size are increased and integrin-mediated signaling is inhibited. Therefore, we uncover a role for Arl13b in breast cancer cell migration and invasion and provide a new mechanism for how ARL13B can function as an oncogene, through the modulation of integrin-mediated signaling.
Highlights
Cell migration plays a crucial role in physiological processes such as embryogenesis, immune responses and tissue repair
To investigate whether Arl13b could confer enhanced migratory and invasion capacities to breast cancer cells, we started by assessing the effect of Arl13b silencing in migration and invasion of a highly invasive breast cancer cell line (MDA-MB-231), by using two distinct short hairpin RNAs targeting Arl13b (E4 and E6)
These results suggest that the formation of larger focal adhesions (FAs) in Arl13b-depleted cells may result from an inhibition of integrin-mediated signaling, which regulates FA turnover
Summary
Cell migration plays a crucial role in physiological processes such as embryogenesis, immune responses and tissue repair. Cell migration dysregulation is implicated in various pathologies, like vascular disease, chronic inflammation and cancer [1]. Cancer cells subvert the machinery that regulates cell migration and invasion to escape the primary tumor site and form local and distant metastases, which are the leading cause of cancer–related deaths [2]. Targeting regulators of cell migration and invasion and understanding the mechanisms by which they control these processes may provide new strategies to delay cancer progression and impair metastasis. Cell migration is a multistep process that requires spatiotemporal coordination of actin cytoskeleton remodeling and cell adhesion [1,3]. Cell migration relies on the driving force generated by Cancers 2019, 11, 1461; doi:10.3390/cancers11101461 www.mdpi.com/journal/cancers
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