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ASPP1 deficiency promotes epithelial-mesenchymal transition, invasion and metastasis in colorectal cancer

ASPP1 deficiency promotes epithelial-mesenchymal transition, invasion and metastasis in colorectal cancer
ASPP1 deficiency promotes epithelial-mesenchymal transition, invasion and metastasis in colorectal cancer
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.
2041-4889
Liu, Dian
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Ertay, Ayse
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Hill, Charlotte
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Zhou, Yilu
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Li, Juanjuan
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Zou, Yanmei
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Qiu, Hong
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Yuan, Xianglin
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Ewing, Robert
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Lu, Xin
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Xiong, Hua
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Wang, Yihua
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Liu, Dian
d8f5cd4b-9fbe-4475-ba94-4c4fe6fb4127
Ertay, Ayse
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Hill, Charlotte
6d1cfed3-11b1-48af-b171-b8726ab673eb
Zhou, Yilu
1878565d-39e6-467d-a027-7320bf4cdaf2
Li, Juanjuan
7888cf96-2102-4b8c-b719-5dd71f4c359d
Zou, Yanmei
70f6fe01-220c-43c8-8047-ece8d8dc49d9
Qiu, Hong
e7cb953a-c410-4ecc-ad66-d988ce34020b
Yuan, Xianglin
b250cf57-48ce-4f76-9f61-f058badbab92
Ewing, Robert
022c5b04-da20-4e55-8088-44d0dc9935ae
Lu, Xin
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Xiong, Hua
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Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e

Liu, Dian, Ertay, Ayse, Hill, Charlotte, Zhou, Yilu, Li, Juanjuan, Zou, Yanmei, Qiu, Hong, Yuan, Xianglin, Ewing, Robert, Lu, Xin, Xiong, Hua and Wang, Yihua (2020) ASPP1 deficiency promotes epithelial-mesenchymal transition, invasion and metastasis in colorectal cancer. Cell Death and Disease, 11 (4), [224]. (doi:10.1038/s41419-020-2415-2).

Record type: Article

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.

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ASPP1 in CRC-min - Accepted Manuscript
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Accepted/In Press date: 18 March 2020
e-pub ahead of print date: 8 April 2020
Published date: 8 April 2020
Additional Information: Funding Information: This project was supported by the National Natural Science Foundation of China [81772827], an Academy of Medical Sciences/the Wellcome Trust Springboard Award [SBF002\1038] and Medical Research Council [MR/ S025480/1]. A.E. was supported by the Wessex Medical Trust. C.H. was supported by Gerald Kerkut Charitable Trust and University of Southampton Central VC Scholarship Scheme. Yilu Zhou was supported by an Institute for Life Sciences PhD Studentship. Yanmei Zou was supported by the Natural Science Foundation of Hubei Province [2018CFB611]. X.L. was supported by the Ludwig Institute for Cancer Research Ltd and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). We thank Senji Shirasawa for providing HKe3 cells and Julian Downward for providing HKe3 ER:HRAS V12 and MCF10A ER:HRAS V12 cells. Publisher Copyright: © 2020, The Author(s).

Identifiers

Local EPrints ID: 438882
URI: http://eprints.soton.ac.uk/id/eprint/438882
ISSN: 2041-4889
PURE UUID: b925f3b5-91b5-4d63-9efb-f291b302a4ee
ORCID for Juanjuan Li: ORCID iD orcid.org/0000-0003-2164-094X
ORCID for Robert Ewing: ORCID iD orcid.org/0000-0001-6510-4001
ORCID for Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648

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Date deposited: 26 Mar 2020 17:30
Last modified: 23 Jul 2022 02:18

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Contributors

Author: Dian Liu
Author: Ayse Ertay
Author: Charlotte Hill
Author: Yilu Zhou
Author: Juanjuan Li ORCID iD
Author: Yanmei Zou
Author: Hong Qiu
Author: Xianglin Yuan
Author: Robert Ewing ORCID iD
Author: Xin Lu
Author: Hua Xiong
Author: Yihua Wang ORCID iD

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