Journal Article

Potential association of LOXL1 with peritoneal dissemination in gastric cancer possibly via promotion of EMT

Tsuruda, Yusuke, Nambara, Sho, Kuroda, Yosuke, Mori, Masaki, Kuramitsu, Shotaro, Oki, Eiji, Hu, Qingjiang, Tobo, Taro, Mimori, Koshi, Kidogami, Shinya, Sato, Kuniaki, Ito, Shuhei, Ueda, Masami, Masuda, Takaaki

2020

Overview

Peritoneal dissemination (PD) frequently occurs in gastric cancer (GC) and is incurable. In this study, we aimed to identify novel PD-associated genes and clarify their clinical and biological significance in GC. We identified LOXL1 as a PD-associated candidate gene by in silico analysis of GC datasets (highly disseminated peritoneal GC cell line and two freely available GC datasets, GSE15459 and TCGA). Next, we evaluated the clinical significance of LOXL1 expression using RT-qPCR and immunohistochemistry staining (IHC) in a validation cohort (Kyushu cohort). Moreover, we performed gene expression analysis, including gene set enrichment analysis (GSEA) with GSE15459 and TCGA datasets. Finally, we performed a series of in vitro experiments using GC cells. In silico analysis showed that LOXL1 was overexpressed in tumor tissues of GC patients with PD and in highly disseminated peritoneal GC cells, relative to that in the control GC patients and cells, respectively. High expression of LOXL1 was a poor prognostic factor in the TCGA dataset. Next, IHC showed that LOXL1 was highly expressed in GC cells. High LOXL1 mRNA expression was associated with poorly differentiated histological type, lymph node metastasis, and was an independent poor prognostic factor in the Kyushu validation cohort. Moreover, LOXL1 expression was positively correlated with the EMT (epithelial-mesenchymal transition) gene set in GSEA. Finally, LOXL1-overexpressing GC cells changed their morphology to a spindle-like form. LOXL1 overexpression reduced CDH1 expression; increased the expression of VIM, CDH2, SNAI2, and PLS3; and promoted the migration capacity of GC cells. LOXL1 is associated with PD in GC, possibly through the induction of EMT.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aged / Amino Acid Oxidoreductases - genetics / Biology and Life Sciences / Biomarkers, Tumor - genetics / Cancer / Cell Line, Tumor / Cell migration / Cell Movement - genetics / Cohort Studies / Computational Biology / Cytology / Datasets / Datasets as Topic / E-cadherin / Enzymes / Epithelial-Mesenchymal Transition - genetics / Female / Gastric cancer / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Gene set enrichment analysis / Genetic aspects / Humans / Immunohistochemistry / Kaplan-Meier Estimate / Laboratories / Lymph nodes / Lymphatic Metastasis - genetics / Male / Medical prognosis / Medicine and Health Sciences / Mesenchyme / Metastases / Metastasis / Middle Aged / Morphology / Neoplasm Staging / Peritoneal Neoplasms - epidemiology / Peritoneal Neoplasms - genetics / Peritoneal Neoplasms - secondary / Peritoneum / Physiological aspects / Prognosis / RNA, Messenger - metabolism / Snail protein / Stomach - pathology / Stomach cancer / Stomach Neoplasms - genetics / Stomach Neoplasms - mortality / Stomach Neoplasms - pathology / Surgery / Transcription factors