Tumor-Promoting Role of GNA14 in Colon Cancer Development

SIMPLE SUMMARY: In this study, we showed that knockdown of GNA14 gene, which encodes one of the α subunits of G-protein, inhibits the proliferation of colorectal cancer (CRC) cells harboring truncated APC mutations, and that Gna14 deletion in Apc(Min/+) mice attenuates intestinal carcinogenesis through reduced cell proliferation and survival. Knockdown of GNA14 in CRC cells reduced ERK phosphorylation and β-catenin phosphorylation at S675. Similarly, ERK phosphorylation and β-catenin (S675) phosphorylation in polyps from Apc(Min/+) mice were reduced in Gna14 knockout mice compared to the controls. In sum, this study revealed that GNA14 may promote CRC progression through the ERK and β-catenin pathways. ABSTRACT: Recent studies have shown that mutations in members of the G-protein α family contribute to the onset and progression of cancer. However, the role of GNA14 in CRC remains unknown. In this study, we examined the effect of GNA14 on CRC through genetic approaches in vitro and in vivo. We found that GNA14 knockdown by small interfering RNA (siRNA) inhibited the proliferation of CRC cells SW403 and HT29. Gna14 knockout mice developed normally without obvious abnormalities. However, the number of polyps in the small intestine was significantly reduced in Gna14 knockout mice compared to control mice after mating with Apc(Min) mice, a representative CRC mouse model. In particular, deletion of the Gna14 inhibited polyp growth, especially in the distal end of the small intestine. Histological examination showed that Gna14 knockout mice suppressed malignant tumor progression due to decreased proliferation and increased apoptosis in polyps compared to controls. In addition, GNA14 knockdown in CRC cells resulted in downregulation of ERK phosphorylation and β-catenin and β-catenin phosphorylation at S675. Similarly, ERK phosphorylation and phospho-β-catenin phosphorylation at S675 were decreased in polyps of Gna14 knockout mice. Collectively, these analyses show that GNA14 may accelerate CRC cell proliferation and malignant tumor progression through ERK and β-catenin pathways.