Galectin-3 germline variant at position 191 enhances nuclear accumulation and activation of β-catenin in gastric cancer

Mutation of galectin-3 at position 191 (rs4644) substituting proline to histidine (gal-3H ⁶⁴) resulted in the acquisition of resistance to drug-induced apoptosis by breast cancer cells. This study employed gastric cancer cells and patient tissues in attempts to elucidate how and why this mutation in galectin-3 (gal-3H ⁶⁴) enhances cancer progression, compared to wild type galectin-3 (gal-3P ⁶⁴). First, we prepared lenti-virus constructs containing gal-3P ⁶⁴, gal-3H ⁶⁴ and LacZ, and used them to infect galectin-3 null SNU-638 cells. We found that gal-3H ⁶⁴ over-expression increases gastric cancer cell growth more than gal-3P ⁶⁴ or LacZ over-expression. Also, gal-3H ⁶⁴ over-expression conferred more resistance to cisplatin or 5-FU induced cytotoxicity than gal-3P ⁶⁴. Gal-3H ⁶⁴ also enhanced nuclear accumulation of β-catenin as well as increased expression of TCF-4 target genes, such as fascin-1 and c-Myc through the augmented promoter binding activity of TCF-4, than gal-3P ⁶⁴. We also demonstrated stronger staining of β-catenin and galectin-3 in malignant tissues from gastric cancer patients with mutated galectin-3 at position 191 (gal-3 191) (A/A) (H ⁶⁴) and greater localization in the nucleus than in gal-3 191 A/C (P ⁶⁴) cancer patients. Taken together, we elucidated in this study that germline variant of gal-3H ⁶⁴ increases nuclear accumulation of β-catenin and promotes TCF transcriptional activity and enhances more the galectin-3's role in gastric cancer progression.