Zhang Feng, Zhang Xutao, Meng Jin, Zhao Yong, Liu Xinli, Liu Yanxia, Wang Yukun, Li Yuhua, Sun Yang, Wang Zhipeng, Mei Qibing, Zhang Tao
Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
Department of Oncology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Oncotarget. 2015 Jun 30;6(18):16239-52. doi: 10.18632/oncotarget.3842.
The proteins of the Inhibitor of Growth (ING) candidate tumor suppressor family are involved in multiple cellular functions such as cell cycle regulation, apoptosis, and chromatin remodeling. ING5 is the new member of the family whose actual role in tumor suppression is not known. Here we show that ING5 overexpression in lung cancer A549 cells inhibited cell proliferation and invasiveness, while ING5 knockdown in lung cancer H1299 cells promoted cell aggressiveness. ING5 overexpression also abrogated tumor growth and invasive abilities of lung cancer cells in mouse xenograft models. Further study showed that ING5 overexpression inhibited EMT indicated by increase of E-cadherin and decrease of N-cadherin, Snail and slug at mRNA and protein levels, which was accompanied with morphological changes. cDNA microarray and subsequent qRT-PCR validation revealed that ING5 significantly downregulated expression of EMT (epithelial to mesenchymal transition)-inducing genes including CEACAM6, BMP2 and CDH11. Clinical study by tissue microarray showed that nuclear ING5 negatively correlated with clinical stages and lymph node metastasis of lung cancer. Furthermore, high level of nuclear ING5 was associated with a better prognosis. Taken together, these findings uncover an important role for ING5 as a potent tumor suppressor in lung cancer growth and metastasis.
生长抑制因子（ING）候选肿瘤抑制家族的蛋白质参与多种细胞功能，如细胞周期调控、细胞凋亡和染色质重塑。ING5是该家族的新成员，其在肿瘤抑制中的实际作用尚不清楚。在此我们表明，肺癌A549细胞中ING5的过表达抑制细胞增殖和侵袭，而肺癌H1299细胞中ING5的敲低则促进细胞侵袭性。ING5的过表达还消除了肺癌细胞在小鼠异种移植模型中的肿瘤生长和侵袭能力。进一步研究表明，ING5的过表达抑制了上皮-间质转化（EMT），这表现为E-钙黏蛋白增加，N-钙黏蛋白、Snail和Slug在mRNA和蛋白质水平下降，同时伴有形态学变化。cDNA微阵列及随后的qRT-PCR验证显示，ING5显著下调包括CEACAM6、BMP2和CDH11在内的EMT诱导基因的表达。组织微阵列的临床研究表明，细胞核内的ING5与肺癌的临床分期和淋巴结转移呈负相关。此外，细胞核内高水平的ING5与较好的预后相关。综上所述，这些发现揭示了ING5作为一种有效的肿瘤抑制因子在肺癌生长和转移中的重要作用。
