Nuclear SIPA1 activates integrin β1 promoter and promotes invasion of breast cancer cells

Abstract

SIPA1 (signal-induced proliferation-associated protein 1) is a GTPase activation protein that can catalyze the hydrolysis of Rap1 bound GTP to GDP. Recently attention has been paid to a potential role for SIPA1 in cancer metastasis; however, the underlying mechanism of how changes in SIPA1 levels may lead to increased metastasis remains poorly understood. In this study, we showed that SIPA1 was mainly localized to the nuclei in highly invasive breast cancer tumor tissue and MDA-MB-231 cells. Knockdown of SIPA1 in MDA-MB-231 altered cell morphology and cell proliferation ability. Furthermore, this study is the first to establish that nuclear SIPA1 can interact with the integrin β1 promoter and activate its transcription; this interaction appears to be important for SIPA1-dependent MDA-MB-231 cell adhesion and invasion. We also demonstrated that the phosphorylation of FAK, Akt and the expression of MMP9, downstream signaling molecules of integrin β1, were decreased upon SIPA1 knockdown, and MDA-MB-231 cell invasion was impaired. Taken together, these results suggest nuclear SIPA1 contributes to breast cancer cell invasion through the regulation of integrin β1 signaling.

Suppression of SIPA-1 expression may reduce bladder cancer invasion and metastasis via the downregulation of E-cadherin and ZO-1

“…Previous studies have suggested that SIPA-1 is involved in certain types of cancer activity, including mutation (23,24), apoptosis (12,25), proliferation (4,15), invasion (15,16) and metastasis (13,26,27). In the present study, it was observed that SIPA-1 additionally regulates bladder cancer cell metastasis and invasion (Figs.…”

“…Recent studies have indicated that SIPA-1 is associated with the motility of cancer cells (14)(15)(16). In addition, nuclear SIPA-1 activates the integrin β1 promoter and promotes the invasion of breast cancer cells (15). SIPA-1 serves a variety of functions during disease progression and exerts contrasting effects on growth and motility of colorectal cancer cells (13).…”

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

“…SIPA1 (Takahara et al ., 2017; Zhang et al ., 2017) and RAB3D (Yang et al ., 2003; Zhang et al ., 2015) are both involved in proliferation, invasion, and metastasis in multiple cancers, exhibiting similar functions to APE1. All four genes showing significantly reduced expression in a dose‐dependent manner (Fig.…”

Association of four new candidate genetic variants with Parkinson's disease in a Han Chinese population

“…A majority of studies showed that rare GCH1 coding variants were considered as a risk factor for Parkinson's disease Hjermind et al, 2006;Cobb et al, 2009;Mencacci et al, 2014]. Moreover, previous studies have focused on the association of SIPA1 with carcinogenesis of many cancers, such as breast cancer, lung cancer, colorectal cancer, cervical cancer and so on [Minato and Hattori, 2009;Brooks et al, 2010;Ji et al, 2012;Xie et al, 2013;Zhang et al, 2015]. Therefore, the role of these genes (VPS13C, MIR4697, GCH1, and SIPA1L2) awaits discovery in the pathophysiologic pathway of PD.…”