Gou Wen-feng, Shen Dao-fu, Yang Xue-feng, Zhao Shuang, Liu Yun-peng, Sun Hong-zhi, Su Rong-Jian, Luo Jun-sheng, Zheng Hua-chuan
Cancer Research Center, Key Laboratory of Brain and Spinal Cord Injury of Liaoning Province, and Laboratory Animal Center, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China.
Department of Oncological Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.
Oncotarget. 2015 Aug 14;6(23):19552-79. doi: 10.18632/oncotarget.3735.
Here, we found that ING5 overexpression increased autophagy, differentiation, and decreased proliferation, apoptosis, migration, invasion and lamellipodia formation in gastric cancer cells, while ING5 knockdown had the opposite effects. In SGC-7901 transfectants, ING5 overexpression caused G1 arrest, which was positively associated with 14-3-3 overexpression, Cdk4 and c-jun hypoexpression. The induction of Bax hypoexpression, Bcl-2, survivin, 14-3-3, PI3K, p-Akt and p70S6K overexpression by ING5 decreased apoptosis in SGC-7901 cells. The hypoexpression of MMP-9, MAP1B and flotillin 2 contributed to the inhibitory effects of ING5 on migration and invasion of SGC-7901 cells. ING5 overexpression might activate both β-catenin and NF-κB pathways in SGC-7901 cells, and promote the expression of down-stream genes (c-myc, VEGF, Cyclin D1, survivin, and interleukins). Compared with the control, ING5 transfectants displayed drug resistance to triciribine, paclitaxel, cisplatin, SAHA, MG132 and parthenolide, which was positively related to their apoptotic induction and the overexpression of chemoresistance-related genes (MDR1, GRP78, GRP94, IRE, CD147, FBXW7, TOP1, TOP2, MLH1, MRP1, BRCP1 and GST-π). ING5 expression was higher in gastric cancer than matched mucosa. It was inversely associated with tumor size, dedifferentiation, lymph node metastasis and clinicopathological staging of cancer. ING5 overexpression suppressed growth, blood supply and lung metastasis of SGC-7901 cells by inhibiting proliferation, enhancing autophagy and apoptosis in xenograft models. It was suggested that ING5 expression might be employed as a good marker for gastric carcinogenesis and subsequent progression by inhibiting proliferation, growth, migration, invasion and metastasis. ING5 might induce apoptotic and chemotherapeutic resistances of gastric cancer cells by activating β-catenin, NF-κB and Akt pathways.
在此，我们发现ING5过表达可增加胃癌细胞的自噬和分化，并降低其增殖、凋亡、迁移、侵袭及板状伪足形成，而ING5基因敲低则产生相反的效果。在SGC-7901转染细胞中，ING5过表达导致G1期阻滞，这与14-3-3过表达、Cdk4和c-jun低表达呈正相关。ING5诱导的Bax低表达、Bcl-2、survivin、14-3-3、PI3K、p-Akt和p70S6K过表达降低了SGC-7901细胞的凋亡。MMP-9、MAP1B和flotillin 2的低表达促成了ING5对SGC-7901细胞迁移和侵袭的抑制作用。ING5过表达可能激活SGC-7901细胞中的β-连环蛋白和NF-κB信号通路，并促进下游基因（c-myc、VEGF、细胞周期蛋白D1、survivin和白细胞介素）的表达。与对照组相比，ING5转染细胞对曲西立滨、紫杉醇、顺铂、SAHA、MG132和小白菊内酯具有耐药性，这与其诱导凋亡及化疗耐药相关基因（MDR1、GRP78、GRP94、IRE、CD147、FBXW7、TOP1、TOP2、MLH1、MRP1、BRCP1和GST-π）的过表达呈正相关。ING在胃癌中的表达高于配对的黏膜组织。它与肿瘤大小、去分化、淋巴结转移及癌症的临床病理分期呈负相关。在异种移植模型中，ING5过表达通过抑制增殖、增强自噬和凋亡来抑制SGC-7901细胞的生长、血供及肺转移。提示ING5表达可能通过抑制增殖、生长、迁移、侵袭和转移，作为胃癌发生及后续进展的良好标志物。ING5可能通过激活β-连环蛋白、NF-κB和Akt信号通路诱导胃癌细胞的凋亡和化疗耐药。
