HOXA11 promotes lymphatic metastasis of gastric cancer via transcriptional activation of TGFß1
Most gastric cancer (GC) patients with early stage often have no lymph node (LN) metastases, while LN metastases appear in the advanced stage. However, there are some patients who present with early stage LN metastases and no LN metastases in the advanced stage. To explore the deeper molecular mechanisms involved, we collected clinical samples from early and advanced stage GC with and without LN metastases, as well as metastatic lymph nodes. Herein, we identified a keytarget, HOXA11, that was upregulated in GC tissues and closely associated with lymphatic metastases. HOXA11 transcriptionally regulates TGFß1 expression and activates the TGFß1/Smad2 pathway, which in turn promotes the development of EMT. In addition, enhanced Smad2 expression promotes the secretion of VEGF-C, which in turn induces lymphangiogenesis. These findings provide a plausible mechanism forHOXA11-modulated tumor in lymphatic metastasis and suggest thatHOXA11 may represent a potential therapeutic target for clinical intervention in LN-metastatic gastric cancer. Overall design: To identify critical genes that promote lymph node metastasis in gastric cancer, next-generation sequencing (NGS) was performed in 16 pairs gastric cancer tissues (GCs) and normal adjacent tissues (NATs), as well as 8 cases of metastatic lymph nodes (LNMs). These clinical samples included 4 pairs of T1 and T2 early LN-negative GCs and NATs, 4 pairs of T1 and T2 early LN-positive GCs and NATs, and the corresponding LNMs, 4 pairs of T3 and T4 advanced LN-negative GCs and NATs, 4 pairs of T3 and T4 advanced LN-positive GCs and NATs, and the corresponding LNMs. Genes (a) are those that are highly expressed in differential analysis of gastric cancer with LN metastasis and its adjacent normal gastric tissue. It represent the portion of genes that are associated with gastric carcinogenesis and also with lymph node metastasis. Genes (b) are those that are highly expressed in differential analysis of gastric cancer without LN metastasis and its adjacent normal gastric tissue. It represent this fraction of genes that are associated with gastric carcinogenesis, but less associated with lymph node metastasis. Therefore, the genes we obtained by (a-b) are those that are not only associated with the development of gastric cancer, but also have a higher correlation with gastric cancer lymph node metastasis. Subsequently, Genes (c) are those obtained from differential analysis of metastatic lymph nodes versus normal gastric tissue. It represent those that are highly expressed in metastatic lymph nodes. Finally, the genes obtained from the Genes (a-b) and Genes (c) intersection analysis were those with the highest correlation with lymph node metastasis in gastric cancer.