title: Galectin-3 germline variant at position 191 enhances nuclear accumulation and activation of β-catenin in gastric cancer.
abstract: 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.
authors.affiliation: Gastric Cancer Branch, Division of Translational & Clinical Research I, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
authors.forename: Seok-Jun
authors.initials: SJ
authors.lastname: Kim
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Shin
authors.forename: Teak-Chin
authors.initials: TC
authors.lastname: Cheong
authors.forename: Il-Ju
authors.initials: IJ
authors.lastname: Choi
authors.forename: Yeon Su
authors.initials: YS
authors.lastname: Lee
authors.forename: Seok Hee
authors.initials: SH
authors.lastname: Park
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Chun
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D005472:Fluorouracil / Q000494:pharmacology; D037502:Galectin 3 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005854:Germ Cells; D006639:Histidine / Q000737:chemistry / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D009154:Mutation / Q000235:genetics*; D011392:Proline / Q000737:chemistry / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D037502:Galectin 3; D012333:RNA, Messenger; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; D006639:Histidine; D011392:Proline; D005472:Fluorouracil