Theranostics 2020; 10(24):11063-11079. doi:10.7150/thno.45674

Research Paper

CSRP2 suppresses colorectal cancer progression via p130Cas/Rac1 axis-meditated ERK, PAK, and HIPPO signaling pathways

Lixia Chen1,2, Xiaoli Long1,2, Shiyu Duan1,2, Xunhua Liu1,2, Jianxiong Chen1,2, Jiawen Lan1,2, Xuming Liu1, Wenqing Huang2, Jian Geng1,2✉, Jun Zhou1,2✉

1. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
2. Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.

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Citation:
Chen L, Long X, Duan S, Liu X, Chen J, Lan J, Liu X, Huang W, Geng J, Zhou J. CSRP2 suppresses colorectal cancer progression via p130Cas/Rac1 axis-meditated ERK, PAK, and HIPPO signaling pathways. Theranostics 2020; 10(24):11063-11079. doi:10.7150/thno.45674. Available from http://www.thno.org/v10p11063.htm

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Abstract

Metastasis is a major cause of death in patients with colorectal cancer (CRC). Cysteine-rich protein 2 (CSRP2) has been recently implicated in the progression and metastasis of a variety of cancers. However, the biological functions and underlying mechanisms of CSRP2 in the regulation of CRC progression are largely unknown.

Methods: Immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR) and Western blotting (WB) were used to detect the expression of CSRP2 in CRC tissues and paracancerous tissues. CSRP2 function in CRC was determined by a series of functional tests in vivo and in vitro. WB and immunofluorescence were used to determine the relation between CSRP2 and epithelial-mesenchymal transition (EMT). Co-immunoprecipitation and scanning electron microscopy were used to study the molecular mechanism of CSRP2 in CRC.

Results: The CSRP2 expression level in CRC tissues was lower than in adjacent normal tissues and indicated poor prognosis in CRC patients. Functionally, CSRP2 could suppress the proliferation, migration, and invasion of CRC cells in vitro and inhibit CRC tumorigenesis and metastasis in vivo. Mechanistic investigations revealed a physical interaction between CSRP2 and p130Cas. CSRP2 could inhibit the activation of Rac1 by preventing the phosphorylation of p130Cas, thus activating the Hippo signaling pathway, and simultaneously inhibiting the ERK and PAK/LIMK/cortactin signaling pathways, thereby inhibiting the EMT and metastasis of CRC. Rescue experiments showed that blocking the p130Cas and Rac1 activation could inhibit EMT induced by CSRP2 silencing.

Conclusion: Our results suggest that the CSRP2/p130Cas/Rac1 axis can inhibit CRC aggressiveness and metastasis through the Hippo, ERK, and PAK signaling pathways. Therefore, CSRP2 may be a potential therapeutic target for CRC.

Keywords: Colorectal cancer, CSRP2, Hippo, ERK, PAK