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 thatGNA14knockdown by small interfering RNA (siRNA) inhibited the proliferation of CRC cells SW403 and HT29.Gna14knockout mice developed normally without obvious abnormalities. However, the number of polyps in the small intestine was significantly reduced inGna14knockout mice compared to control mice after mating withApcMinmice, a representative CRC mouse model. In particular, deletion of theGna14inhibited polyp growth, especially in the distal end of the small intestine. Histological examination showed thatGna14knockout mice suppressed malignant tumor progression due to decreased proliferation and increased apoptosis in polyps compared to controls. In addition,GNA14knockdown 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 ofGna14knockout mice. Collectively, these analyses show that GNA14 may accelerate CRC cell proliferation and malignant tumor progression through ERK and β-catenin pathways.
近期研究表明，G蛋白α家族成员的突变与癌症的发生发展密切相关。然而，GNA14在结直肠癌中的作用机制尚未明确。本研究通过体外及体内遗传学方法，系统探究了GNA14对结直肠癌的影响。研究发现，利用小干扰RNA敲低GNA14表达可显著抑制结直肠癌细胞系SW403和HT29的增殖能力。Gna14基因敲除小鼠发育正常，未见明显异常表型。但与结直肠癌经典模型ApcMin小鼠杂交后，Gna14敲除小鼠小肠息肉数量较对照组显著减少。值得注意的是，Gna14缺失尤其抑制了小肠远端息肉的生长。组织学检测显示，与对照组相比，Gna14敲除小鼠息肉组织中细胞增殖减少、凋亡增加，从而抑制了恶性肿瘤进展。机制研究发现，结直肠癌细胞中GNA14敲低可导致ERK磷酸化水平及β-catenin S675位点磷酸化水平下调。同样，Gna14敲除小鼠息肉组织中ERK磷酸化与β-catenin S675位点磷酸化水平也呈现下降趋势。综上，本研究揭示GNA14可能通过调控ERK和β-catenin信号通路促进结直肠癌细胞增殖及恶性肿瘤进展。
肿瘤(癌症)患者之家