Abstract
DDEFL1 is related to maintaining a limiting amount of ARF6 in GTP-loaded form by accelerating its GTP hydrolysis activity, which has been implicated in hepatocellular cancer pathogenesis and lung cancer development. We investigated DDEFL1 expression in breast cancer and paired normal breast tissues by immunohistochemistry and found that DDEFL1 expression was significantly associated with tumor size, lymph node metastasis, high content of elastosis and TNM stage but not with menopausal status or age. We detected the mRNA and protein expression of DDEFL1 in breast cancer cell lines by Western blotting and quantitative real-time PCR (qRT-PCR). DDEFL1 was obvious in MDA-MB-435s and MDA-MB-231 but very weak in ZR-75-1. Further experiments were conducted to evaluate the effect of DDEFL1 small interfering RNA (siRNA) transfection on the biological behavior of MDA-MB-231. After transfection, the effects of DDEFL1 inhibition on expression of mRNA and protein were also analyzed by Western blotting and qRT-PCR. Increased apoptosis and invasive ability, decreased cellular proliferation was found in MDA-MB-231 with successful DDEFL1 siRNA transient transfection (p < 0.05). Western blotting and qRT-PCR results showed that the DDEFL1 inhibition up-regulated Caspase-3, Apaf-1, cytochrome c, and Bax expression and down-regulated Bcl-2 expression. The DDEFL1 inhibition also down-regulated the mRNA and protein expression of Rho, CDC42 and Rac1. Our study provided a functional linkage through DDEFL1 with breast cancer biological behaviours by Rho GTPases. Possible implication of our main finding for the DDEFL1 role in breast cancer and the downstream signaling pathways for the treatment of breast cancer.
Highlights
DDEFL1, known as UPLC1, CENTB6, ACAP4 or ASAP3(ArfGAPs with SH3 domain, ankyrin repeat, and PH domain 3), is a 903-amino acid cytoplasmic protein belonging to the subfamily of ADPribosylation factor (Arf) GTPase-activating proteins (GAPs) [1,2,3], DDEFL1 controls cell migration at least in part by destabilizing cytoskeletal protein cytoskeletal γ-actin-1 (ACTG1) [4]
A previous research indicated that DDEFL1 is a focal adhesion-associated Arf GAP that functions in cell migration and invasion [1]
We found that increased DDEFL1 expression was related to lymph node metastasis and TNM stage but not with age, gender, histological subtype, tumor grade, and T stage (p < 0.05)
Summary
DDEFL1 (development and differentiationenhancing factor-like 1), known as UPLC1, CENTB6, ACAP4 or ASAP3(ArfGAPs with SH3 domain, ankyrin repeat, and PH domain 3), is a 903-amino acid cytoplasmic protein belonging to the subfamily of ADPribosylation factor (Arf) GTPase-activating proteins (GAPs) [1,2,3], DDEFL1 controls cell migration at least in part by destabilizing cytoskeletal protein cytoskeletal γ-actin-1 (ACTG1) [4]. A previous study indicated that it is related to maintaining a limiting amount of ARF6 in GTP-loaded form by accelerating its GTP hydrolysis activity [5, 6]. It has been implicated in hepatocellular cancer pathogenesis and lung cancer development [7, 8]. This study investigated DDEFL1 expression and its clinical relevance in breast cancer, further to analyze its role in breast cancer cells. Individual tumor cell can adopt a variety of different modes to reach their destination, all of which depend on Rho GTPases at some level. Whether DDEFL1 correlate with Rho GTPases in breast cancer cell migration?
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