Abstract
The apoptosis-stimulating protein of p53 (ASPP) family of proteins can regulate apoptosis by interacting with the p53 family and have been identified to play an important role in cancer progression. Previously, we have demonstrated that ASPP2 downregulation can promote invasion and migration by controlling β-catenin-dependent regulation of ZEB1, however, the role of ASPP1 in colorectal cancer (CRC) remains unclear. We analyzed data from The Cancer Genome Atlas (TCGA) and coupled this to in vitro experiments in CRC cell lines as well as to experimental pulmonary metastasis in vivo. Tissue microarrays of CRC patients with information of clinical-pathological parameters were also used to investigate the expression and function of ASPP1 in CRC. Here, we report that loss of ASPP1 is capable of enhancing migration and invasion in CRC, both in vivo and in vitro. We demonstrate that depletion of ASPP1 could activate expression of Snail2 via the NF-κB pathway and in turn, induce EMT; and this process is further exacerbated in RAS-mutated CRC. ASPP1 could be a prognostic factor in CRC, and the use of NF-κB inhibitors may provide new strategies for therapy against metastasis in ASPP1-depleted CRC patients.
Highlights
Introduction The Apoptosis StimulatingProteins of p53 (ASPP)family consists of three members (ASPP1, ASPP2 and iASPP), which have similar sequences in the C-termini including Ankyrin repeats, SH3 domain and Proline-rich region[1,2,3,4]
We demonstrated that ASPP1 is expressed in the nucleus and cytoplasm, both in normal and colorectal cancer (CRC) tissue
We analyzed the correlation between ASPP1 expressions (Fig. 1a) and clinical–pathological factors by categorizing tissues into high and low expression groups according to both clinical stage and lymph node stage
Summary
Family consists of three members (ASPP1, ASPP2 and iASPP), which have similar sequences in the C-termini including Ankyrin repeats, SH3 domain and Proline-rich region[1,2,3,4]. They bind with apoptosis regulating proteins, including p53, p63 and p73, to regulate cell apoptosis[4]. EMT is a cell plasticity program where epithelial cells lose their cell polarity and cell–cell adhesion to gain migratory and invasive properties in turn becoming mesenchymal cells[12,13] It is widely regarded as being crucial for cancer progression[14]. EMT-Transcription Factors (EMT-TFs) including Snail1/2 (SNAI1/2), Twist-related protein 1/2 (TWIST1/2) and zinc-finger E-box-binding homeobox 1/2 (ZEB1/2) are able to activate the EMT program[15,16]
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