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.
Highlights
LIM homeobox transcription factor 1 alpha (LMX1A) is a member of the group of LIM-homeobox-containing genes that encode LIMhomeodomain (LIM-HD) proteins[1]
By identifying LMX1A-regulated genes using RNA sequencing in gastric cancer cell lines, we show that LMX1A exerts its tumor suppressive role partly through up-regulating angiopoietin-like 4 (ANGPTL4)
Gastric cancer cell line AGS cells were infected with retrovirus carrying LMX1A-expressing plasmids, with empty vector (EV) as control
Summary
LMX1A is a member of the group of LIM-homeobox-containing genes that encode LIMhomeodomain (LIM-HD) proteins[1]. LMX1A is initially known to participate in developmental events[2, 3]. It is proven that LMX1A is a critical regulator of cell-fate decisions using genetic fate mapping in wild-type and LMX1A deficient mice[3]. LMX1A plays a pivotal role in the mDA differentiation of human embryonic stem (hES) cells. Loss of LMX1A completely abolishes roof plate induction in the spinal cord[2]. Evidence for the role of LMX1A in cancers has been found.
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