Cheung Arthur Kwok Leung, Ip Joseph Chok Yan, Chu Adrian Chi Hang, Cheng Yue, Leong Merrin Man Long, Ko Josephine Mun Yee, Shuen Wai Ho, Lung Hong Lok, Lung Maria Li
Department of Clinical Oncology, University of Hong Kong, Hong Kong (SAR), People's Republic of China.
Centre for Cancer Research, University of Hong Kong, Hong Kong (SAR), People's Republic of China.
Oncotarget. 2015 May 30;6(15):13434-47. doi: 10.18632/oncotarget.3876.
Protein Tyrosine Phosphatase, Receptor Type G (PTPRG) was identified as a candidate tumor suppressor gene in nasopharyngeal carcinoma (NPC). PTPRG induces significant in vivo tumor suppression in NPC. We identified EGFR as a PTPRG potential interacting partner and examined this interaction. Dephosphorylation of EGFR at EGFR-Y1068 and -Y1086 sites inactivated the PI3K/Akt signaling cascade and subsequent down-regulation of downstream pro-angiogenic and -invasive proteins (VEGF, IL6, and IL8) and suppressed tumor cell proliferation, angiogenesis, and invasion. The effect of Akt inhibition in NPC cells was further validated by Akt knockdown experiments in the PTPRG-down-regulated NPC cell lines. Our results suggested that inhibition of Akt in NPC cells induces tumor suppression at both the in vitro and in vivo levels, and also importantly, in vivo metastasis. In conclusion, we confirmed the vital role of PTPRG in inhibiting Akt signaling with the resultant suppression of in vivo tumorigenesis and metastasis.
蛋白酪氨酸磷酸酶受体G型（PTPRG）被鉴定为鼻咽癌（NPC）中的一个候选肿瘤抑制基因。PTPRG在体内对NPC具有显著的肿瘤抑制作用。我们鉴定出表皮生长因子受体（EGFR）是PTPRG的一个潜在相互作用伙伴，并对这种相互作用进行了研究。EGFR在EGFR-Y1068和-Y1086位点的去磷酸化使PI3K/Akt信号级联失活，随后下游促血管生成和侵袭蛋白（血管内皮生长因子、白细胞介素6和白细胞介素8）表达下调，并抑制肿瘤细胞增殖、血管生成和侵袭。在PTPRG下调的NPC细胞系中通过Akt基因敲低实验进一步验证了Akt抑制在NPC细胞中的作用。我们的结果表明，抑制NPC细胞中的Akt在体外和体内水平均能诱导肿瘤抑制，重要的是，还能抑制体内转移。总之，我们证实了PTPRG在抑制Akt信号传导以及由此导致的体内肿瘤发生和转移抑制中的关键作用。
