Abstract
Ectopic expression of Swiprosin-1, an actin-binding protein (also known as EF hand domain containing 2; EFHD2), enhanced motile protrusions associated with actin, such as lamellipodia and membrane ruffles. Swiprosin-1 levels were increased in various human cancer tissues, particularly at highly invasive stages of malignant melanoma. Expression of Swiprosin-1 was correlated with that of epidermal growth factor receptor (EGFR) and induced by EGF. In a mouse metastasis model, Swiprosin-1 overexpression induced pulmonary metastasis whereas its knockdown led to marked inhibition of metastasis of highly invasive melanoma cells. Swiprosin-1 at the lamellipodia and membrane ruffles controlled the direction of cell protrusion and enhanced migration velocity through activating the Rho family of small GTPases, including Rac1, Cdc42 and RhoA. Our collective findings support the potential utility of Swiprosin-1 as a therapeutic target to prevent cancer invasion and metastasis.
Highlights
Invasion and metastasis remain the leading causes of cancer-related mortality
Swiprosin-1 at the lamellipodia and membrane ruffles controlled the direction of cell protrusion and enhanced migration velocity through activating the Rho family of small guanosine triphosphatases (GTPase), including Rac1, Cdc42 and RhoA
In tissue microarray containing 30 normal and 29 human cancer tissue sections, significant Swiprosin-1 expression was observed in the majority of carcinomas, including adenocarcinoma and squamous cell carcinoma
Summary
Invasion and metastasis remain the leading causes of cancer-related mortality. Elucidation of the mechanisms underlying acquisition of metastatic potential by cancer cells is critical for diagnosis and development of effective treatment regimes. Various regulators of the actin cytoskeleton are involved in the acquisition of invasive and metastatic phenotypes. Expression levels of actin-binding proteins, such as components of the Arp2/3 complex, N-WASP, WAVE, and Fascin, are abnormally up- or downregulated in a variety of cancer tissues and cell lines [2]. An actin bundling protein, is upregulated in several cancer types, including thymic [3], endometrial [4], pancreatic [5], and hepatocellular [6] carcinoma, and regulates migration, invasion and MMP expression of pancreatic ductal adenocarcinoma [7]. Depletion of Fascin in melanoma CHL1 or MDA-MB-231 breast adenocarcinoma cell lines leads to significant reduction in invadopodia [10] with specialized actin-rich membrane structures [11], which initiates tumor invasion
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