J Cancer 2021; 12(11):3277-3290. doi:10.7150/jca.55077

Research Paper

High expression of TREM2 promotes EMT via the PI3K/AKT pathway in gastric cancer: bioinformatics analysis and experimental verification

Chunmei Li1,2,3#, Xiaoming Hou3#, Shuqiao Yuan4#, Yigan Zhang5, Wenzhen Yuan6, Xiaoguang Liu1,2,7, Juan Li1,2,8, Yuping Wang1,2, Quanlin Guan6, Yongning Zhou1,2✉

1. Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.
2. Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China.
3. Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, China.
4. Department of medical laboratory, The First Hospital of Lanzhou University, Lanzhou, China.
5. The First School of Clinical Medicine, Lanzhou University, Lanzhou, China.
6. Department of Oncology Surgery, The First Hospital of Lanzhou University, Lanzhou, China.
7. Department of Rheumatology, The First Hospital of Lanzhou University, Lanzhou, China.
8. Department of Gastroenterology, Gansu Provincial Hospital, Lanzhou, China.
#These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Li C, Hou X, Yuan S, Zhang Y, Yuan W, Liu X, Li J, Wang Y, Guan Q, Zhou Y. High expression of TREM2 promotes EMT via the PI3K/AKT pathway in gastric cancer: bioinformatics analysis and experimental verification. J Cancer 2021; 12(11):3277-3290. doi:10.7150/jca.55077. Available from https://www.jcancer.org/v12p3277.htm

File import instruction

Abstract

Background: To date, the pathogenesis of gastric cancer (GC) remains unclear. We combined public database resources and bioinformatics analysis methods, explored some novel genes and verified the experiments to further understand the pathogenesis of GC and to provide a promising target for anti-tumor therapy.

Methods: We downloaded the chip data related to GC from the Gene Expression Omnibus (GEO) database, extracted differentially expressed genes (DEGs), and then determined the key genes in the development of GC via PPI networks and model analysis. Functional annotation via GO and KEGG enrichment of DEGs was used to understand the latent roles of DEGs. The expression of the triggering receptor expressed on myeloid cells 2 (TREM2) gene in GC cell lines was verified via RT-PCR and western blotting. Moreover, the CCK-8, wound healing assay, and transwell migration and invasion assays were used to understand the changes in the proliferation, migration, and invasion abilities of GC cells after silencing TREM2. Western blotting verified the interaction between TREM2 and PI3K predict of the string website, as well as the effect of TREM2 on EMT. Finally, a lung metastasis model was used to explore the relationship between TREM2 and metastasis.

Results: Our study identified 16 key genes, namely BGN, COL1A1, COL4A1, COL5A2, NOX4, SPARC, HEYL, SPP1, TIMP1, CTHRC1, TREM2, SFRP4, FBXO32, GPX3, KIF4A, and MMP9 genes associated with GC. The EMT-related pathway was the most significantly altered pathway. TREM2 expression was higher in GC cell lines and was remarkably associated with tumor invasion depth, TNM stage, histological grade, histological type, anatomic subdivision, and Helicobacter pylori state. Knockdown of TREM2 expression inhibited the proliferation, migration, and invasion of GC cells as well as the progression of EMT by PI3K/AKT signaling in vitro. In addition, lung metastasis were decreased in vivo.

Conclusions: We identified some important genes associated with the progression of GC via public database analysis, explored and verified the effects of proto-oncogene TREM2 on EMT via the PI3K/AKT pathway. TREM2 may be a novel target in the GC therapy.

Keywords: TREM2, gastric cancer (GC), EMT, PI3K/AKT pathway, bioinformatics