LMX1A inhibits C-Myc expression through ANGPTL4 to exert tumor suppressive role in gastric cancer

Peiyu Qian; Jian Li; Xiaohong Zhang; Fan Li; Songhua Bei; Huanqing Li; Qi Sun; Li Feng

doi:10.1371/journal.pone.0221640

LMX1A inhibits C-Myc expression through ANGPTL4 to exert tumor suppressive role in gastric cancer

PLoS One. 2019 Sep 26;14(9):e0221640. doi: 10.1371/journal.pone.0221640. eCollection 2019.

Authors

Peiyu Qian¹, Jian Li², Xiaohong Zhang², Fan Li², Songhua Bei², Huanqing Li², Qi Sun², Li Feng²

Affiliations

¹ Minhang Fudan Medical Research Cooperative Development Research Institute, Minhang Hospital, Fudan University, Shanghai, Minhang District, Shanghai, P.R. China.
² Endoscopy Center, Minhang Hospital, Fudan University, Shanghai, Minhang District, Shanghai, P.R. China.

Abstract

Our research group has showed that the LIM homeobox transcription factor 1 alpha (LMX1A) is inactivated in gastric cancers. Overexpression of LMX1A inhibits tumor growth. However, the mechanisms remains unclear. Considering LMX1A as a transcription factor, a comparison of RNA-seq between gastric cancer cells (GCCs) and GCCs with LMX1A overexpressed was performed to identify genes transcriptionally activated by LMX1A. Among the potential LMX1A target genes, angiopoietin-like 4 (ANGPTL4) has been reported to be an important tumor suppressor and thus was selected for further validation and research. Both LMX1A and ANGPTL4 showed downregulated expression in gastric cancer samples. More importantly, the expression of LMX1A is positively correlated with ANGPTL4, without including other family members in gastric cancer cell lines. What's more, knockdown of ANGPTL4 rescued the tumor suppressive phenotype of LMX1A overexpression, which indicated that LMX1A upregulates ANGPTL4 to exert its role. Mechanistically, we found that LMX1A inhibited the expression of the oncogene C-Myc, which is alleviated by ANGPTL4 knockdown. In general, our results showed that LMX1A exerts its tumor suppressive role by activating ANGPTL4 to inhibit C-Myc.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiopoietin-Like Protein 4 / antagonists & inhibitors
Angiopoietin-Like Protein 4 / genetics*
Angiopoietin-Like Protein 4 / metabolism*
Animals
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Genes, Tumor Suppressor
Genes, myc*
Humans
LIM-Homeodomain Proteins / genetics*
LIM-Homeodomain Proteins / metabolism*
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Transplantation
Proto-Oncogene Proteins c-myc / antagonists & inhibitors
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
Stomach Neoplasms / genetics*
Stomach Neoplasms / metabolism*
Transcription Factors / genetics*
Transcription Factors / metabolism*

Substances

ANGPTL4 protein, human
Angiopoietin-Like Protein 4
LIM-Homeodomain Proteins
LMX1A protein, human
MYC protein, human
Proto-Oncogene Proteins c-myc
Transcription Factors

Grants and funding

The project was funded by Shanghai Municipal Health and Family Planning Commission Science Foundation under the grant 201540035 (to LF), the Shanghai Health and Family Planning commission under the grant 20154Y0141 and Minhang Hospital, Fudan University under the grant 2017MHJCO3 (to PQ). And it is great thankful for that the Talent Development Fund of Minhang District provided 150,000 RMB for our project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.