PBX3 promotes gastric cancer invasion and metastasis by inducing epithelial-mesenchymal transition

Abstract

The overexpression of pre-leukemia transcription factor 3 (PBX3) in tumors plays an important role in invasion, metastasis and proliferation in a variety of human cancer types. Tumor metastasis and angiogenesis significantly contribute to the progression of cancer and create challenges for cancer therapy. In the present study, reverse transcription-polymerase chain reaction demonstrated that PBX3 was upregulated in gastric cancer (GC) tissues and Transwell assay revealed that the overexpression of PBX3 promoted GC invasion and metastasis in vitro. In addition, a nude mouse xenograft model was established, which demonstrated that PBX3 promoted peritoneal metastases in vivo. Furthermore, the overexpression of PBX3 in GC promoted the tubular formation of human umbilical vein endothelial cells. Western blot analysis revealed that overexpressed PBX3 induced epithelial-mesenchymal transition (EMT) in GC, as measured by increases in the EMT protein markers N-cadherin and vimentin, while E-cadherin expression was reduced in PBX3-overexpressing GC cells. Contrasting results were observed in PBX3-knockdown GC cells. Additionally, the overexpression of PBX3 increased the levels of phosphorylated AKT (Ser473), which is involved in the progression of a variety of human cancers. Gelatin zymography assay demonstrated that the overexpression of PBX3 also elevated matrix metalloproteinase-9 activity in GC, which was closely associated with tumor metastasis and angiogenesis. Based on these findings, it may be concluded that PBX3 enhances invasion and metastasis in GC by promoting EMT, possibly via the AKT signaling pathway.

PBX3 Is Part of an EMT Regulatory Network and Indicates Poor Outcome in Colorectal Cancer

“…However, because PBX3 depletion had no significant effects on vimentin expression, we suggest that only certain aspects of EMT depend on PBX3. Nevertheless, considering recent findings that PBX3 induces EMT in gastric cancer cells (15,43), this indicates that it may generally be involved in EMT regulation in gastrointestinal cancers. Because PBX3 also has been shown to increase migration and invasion of colon cancer cells (14) both of which are features of EMT, this further supports the notion that PBX3 directly contributes to the infiltrative phenotype of colon cancer cells at the leading tumor edge.…”

“…colon cancer (12)(13)(14). In gastric cancer, PBX3 has been shown to induce an infiltrative tumor cell phenotype with upregulation of vimentin and repression of E-cadherin (15). In addition, microRNAs that were shown to regulate PBX3 included members of the miR-200 family (16).…”

Identification of a novel gene pairs signature in the prognosis of gastric cancer

“…The seven GRGPs consisted of 12 genes, among which two genes (CES1 and TNFRSF11A) were also part of the 11‐Gene signature. Of these 12 genes, only PBX1 has been investigated for potential mechanism in GC . We thought the other 11 genes might also play a role in GC.…”

PBX3 in Cancer

“…In vitro studies have indicated a role for PBX3 in promoting epithelial-to-mesenchymal transition (EMT) [30,49], which in turn enables invasion and metastasis through a reduction in cellular adherence and an increase in migration. This may be partly dependent on activation of the AKT pathway, as there was a significant increase in phosphorylated AKT (Ser473) in the cells overexpressing PBX3 [49].…”

“…In vitro studies have indicated a role for PBX3 in promoting epithelial-to-mesenchymal transition (EMT) [30,49], which in turn enables invasion and metastasis through a reduction in cellular adherence and an increase in migration. This may be partly dependent on activation of the AKT pathway, as there was a significant increase in phosphorylated AKT (Ser473) in the cells overexpressing PBX3 [49]. The overexpression of PBX3 also resulted in an increase in MMP9 activity [49], a key protease involved in metastasis [50], as well as an increase in the ability of gastric cancer cells to promote tubule formation by HUVEC cells, indicating an increase in pro-angiogenic signaling [49].…”