Connexin 43 enhances liver metastatic ability of GIST cells in vivo

Small intestinal gastrointestinal stromal tumors (SI-GISTs) have a higher risk of distant metastasis and recurrence than gastric GISTs (G-GISTs). However, the underlying mechanisms contributing to the poor prognosis of SI-GISTs remain elusive. Previous research has demonstrated that SI-GISTs exhibit elevated expression of Connexin 43 (Cx43), a component of gap junctions, whereas G-GISTs exhibit minimal expression. The differential expression of Cx43 between G-GISTs and SI-GISTs may account for their distinct clinical behavior. This study aimed to investigate the impact of Cx43 on the liver metastatic potential of GIST cells, both in vivo and in vitro.

To elucidate the relationship between Cx43 expression and poor prognosis in SI-GISTs, we conducted a comparative analysis of original GIST-T1 cells, which express minimal levels of Cx43 and represent G-GISTs, and GIST-T1 cells engineered to express high levels of Cx43 through transfection with Cx43 cDNA (GIST-T1-Cx43 cells), representing SI-GISTs. This was achieved using a newly developed in vivo liver metastasis xenograft mouse model, and the results were corroborated by conventional in vitro experiments.

In GIST cells, Cx43 enhanced the liver metastatic potential in vivo (p = 0.010). In vitro, Cx43 suppressed cell proliferation (p < 0.001) while promoting migration (p < 0.001), invasion (p = 0.036), tumor-endothelial cell adhesion (p < 0.001), and transendothelial migration (p < 0.001).

Elevated Cx43 expression may contribute to the poor prognosis of patients with SI-GISTs by enhancing their metastatic potential. Cx43 represents a potential novel therapeutic target for the inhibition of SI-GIST metastasis.