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: Seok-Jun Kim, Ji-Young Shin, Teak-Chin Cheong, Il-Ju Choi, Yeon Su Lee, Seok Hee Park, Kyung-Hee Chun
• Journal: Clinical & experimental metastasis (Clin Exp Metastasis) Vol. 28 Issue 8 Pg. 743-50 (Dec 2011) ISSN: 1573-7276 [Electronic] Netherlands
• PMID: 21750908 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Galectin 3
• RNA, Messenger
• TCF4 protein, human
• Transcription Factor 4
• Transcription Factors
• beta Catenin
• Histidine
• Proline
• Fluorouracil

Topics

• Antimetabolites, Antineoplastic (pharmacology)
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (genetics, metabolism)
• Blotting, Western
• Cell Nucleus (metabolism)
• Cell Proliferation
• Fluorouracil (pharmacology)
• Galectin 3 (genetics)
• Gene Expression Regulation, Neoplastic
• Germ Cells
• Histidine (chemistry, genetics)
• Humans
• Immunoenzyme Techniques
• Immunoprecipitation
• Mutation (genetics)
• Proline (chemistry, genetics)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Stomach Neoplasms (genetics, metabolism, pathology)
• Transcription Factor 4
• Transcription Factors (genetics, metabolism)
• Tumor Cells, Cultured
• beta Catenin (genetics, metabolism)