Objective To analyze the mechanism of HOX transcript anti-sense RNA (HOTAIR) promoting invasion and metastasis of gastric cancer from the perspective of its structural domains.

Methods The clinical data of 60 patients with gastric cancer were collected at the Tianjin Medical University Cancer Institute & Hospital from December 2010 to December 2012. Mutants of HOTAIR 3' and 5' domains were constructed as HOT△P and HOT△L, respectively, and the invasion and metastasis of gastric cancer cells were detected using Transwell assay. Western blot was used to detect epithelial-mesenchymal transition (EMT)-related protein expression; RNAseq was used to analyze the differential genes between the NC and the HOT△L group. RNA was extracted from the clinical tissues for analyzing the correlation between gene expression and clinical information.

Results HOT△L promoted the invasive and metastatic ability of gastric cancer cells more visibly than HOT△P. The mechanistic studies demonstrated that HOT△L more significantly promotes the EMT process in gastric cancer cells compared to HOT△P. HOT△L specifically up-regulated the expression of glycine amidinotransferase (GATM). Data analysis and clinical analysis suggested that the high expression of both HOTAIR and GATM group was associated with distal metastasis in gastric cancer patients (P=0.02), which further proved that the high expression of HOTAIR and GATM predicted the poor prognosis of gastric cancer. Molecular investigations suggested that GATM could promote the invasion and metastasis of gastric cancer cells by advancing the progression of EMT. Regulation of EMT by GATM is the key mechanism by which HOT△L promotes the invasive and metastatic ability of gastric cancer, as determined by back-complementary experiments.

Conclusions HOTAIR 5' domain regulates the EMT process through specific up-regulation of GATM, thus, promoting the invasion and metastasis of gastric cancer.