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LIMD1 is a survival prognostic marker of gastric cancer and hinders tumor progression by suppressing activation of YAP1

Authors Zhang D, Li S, Yu W, Chen C, Liu T, Sun Y, Zhao Z, Liu L

Received 24 May 2018

Accepted for publication 8 August 2018

Published 9 October 2018 Volume 2018:10 Pages 4349—4361

DOI https://doi.org/10.2147/CMAR.S174856

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Dr Antonella D'Anneo


Di Zhang,1,* Song Li,1,* Wenbin Yu,2,* Cheng Chen,2 Teng Liu,2 Yiting Sun,1 Zeyi Zhao,1 Lian Liu1

1Department of Chemotherapy, Cancer Center, Qilu Hospital of Shandong University, Jinan, Shandong, China; 2Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China

*These authors contributed equally to this work

Purpose: The purpose of this study was to investigate the clinical significance of LIMD1 and its biological roles in gastric cancer (GC).
Materials and methods: The prognostic value of LIMD1 in GC patients was determined by the online tool Kaplan–Meier Plotter. The biological functions of LIMD1 in GC were examined by in vitro assays, including proliferation, anchorage-independent growth, migration, invasion, and epithelial to mesenchymal transition (EMT) assays. The levels of downstream YAP1 regulated by LIMD1 were measured by Western blot analysis, and the sub-localization of YAP1 in GC cells was visualized by immunofluorescence staining. Differential expression levels and copy number levels of LIMD1 between GC and normal tissues were compared using the Oncomine database. A correlation of LIMD1 mRNA level and the copy number level was depicted by cBioPortal. We also evaluated the methylation status around the LIMD1 genes by Wanderer.
Results: The expression level of LIMD1 positively correlated with the prognosis of GC patients regardless of tumor stage, size, lymph node, metastasis, Lauren’s classification, differentiation, gender, treatment, and ERBB2 amplification status. Overexpression of LIMD1 impeded the tumor growth, cell motility, invasiveness, and metastasis, and knockdown of LIMD1 promoted these phenotypes in GC cells. Mechanistically, YAP1 was one of the downstream effectors of LIMD1; LIMD1 suppressed the expression of YAP1 as well as its intracellular translocation. Furthermore, we found that LIMD1 expression was reduced in some of the GC profiling datasets. Gene deletion, instead of DNA methylation, contributed to the reduced expression of LIMD1 in GC.
Conclusion: Our results identified LIMD1 as a convincing prognostic marker as well as a potentially therapeutic target for GC.

Keywords: gastric cancer, prognostic marker, oncosuppressor, LIMD1, YAP1

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