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Molecular Cancer
Published in: Molecular Cancer 1/2018

Open Access 01-12-2018 | Research

RASAL2 promotes tumor progression through LATS2/YAP1 axis of hippo signaling pathway in colorectal cancer

Authors: Yi Pan, Joanna Hung Man Tong, Raymond Wai Ming Lung, Wei Kang, Johnny Sheung Him Kwan, Wing Po Chak, Ka Yee Tin, Lau Ying Chung, Feng Wu, Simon Siu Man Ng, Tony Wing Chung Mak, Jun Yu, Kwok Wai Lo, Anthony Wing Hung Chan, Ka Fai To

Published in: Molecular Cancer | Issue 1/2018

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Abstract

Background

Patients with colorectal cancer (CRC) have a high incidence of regional and distant metastases. Although metastasis is the main cause of CRC-related death, its molecular mechanisms remain largely unknown.

Methods

Using array-CGH and expression microarray analyses, changes in DNA copy number and mRNA expression levels were investigated in human CRC samples. The mRNA expression level of RASAL2 was validated by qRT-PCR, and the protein expression was evaluated by western blot as well as immunohistochemistry in CRC cell lines and primary tumors. The functional role of RASAL2 in CRC was determined by MTT proliferation assay, monolayer and soft agar colony formation assays, cell cycle analysis, cell invasion and migration and in vivo study through siRNA/shRNA mediated knockdown and overexpression assays. Identification of RASAL2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays.

Results

Integrated genomic analysis identified copy number gains and upregulation of RASAL2 in metastatic CRC. RASAL2 encodes a RAS-GTPase-activating protein (RAS-GAP) and showed increased expression in CRC cell lines and clinical specimens. Higher RASAL2 expression was significantly correlated with lymph node involvement and distant metastasis in CRC patients. Moreover, we found that RASAL2 serves as an independent prognostic marker of overall survival in CRC patients. In vitro and in vivo functional studies revealed that RASAL2 promoted tumor progression in both KRAS/NRAS mutant and wild-type CRC cells. Knockdown of RASAL2 promoted YAP1 phosphorylation, cytoplasm retention and ubiquitination, therefore activating the hippo pathway through the LATS2/YAP1 axis.

Conclusions

Our findings demonstrated the roles of RASAL2 in CRC tumorigenesis as well as metastasis, and RASAL2 exerts its oncogenic property through LATS2/YAP1 axis of hippo signaling pathway in CRC.
Appendix
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Metadata
Title
RASAL2 promotes tumor progression through LATS2/YAP1 axis of hippo signaling pathway in colorectal cancer
Authors
Yi Pan
Joanna Hung Man Tong
Raymond Wai Ming Lung
Wei Kang
Johnny Sheung Him Kwan
Wing Po Chak
Ka Yee Tin
Lau Ying Chung
Feng Wu
Simon Siu Man Ng
Tony Wing Chung Mak
Jun Yu
Kwok Wai Lo
Anthony Wing Hung Chan
Ka Fai To
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2018
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-018-0853-6

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