AKR7A3 suppresses tumorigenicity and chemoresistance in hepatocellular carcinoma through attenuation of ERK, c-Jun and NF-κB signaling pathways.
AKR7A3 suppresses tumorigenicity and chemoresistance in hepatocellular carcinoma through attenuation of ERK, c-Jun and NF-κB signaling pathways.
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DOI：
10.18632/oncotarget.12726
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发表时间：
2017-10-13
期刊：
影响因子：
--
通讯作者：
Guan XY
中科院分区：
文献类型：
--
作者：
Chow RKK;Tsz-Kwan Sin S;Liu M;Li Y;Man Chan TH;Song Y;Chen L;Lai-Wan Kwong D;Guan XY
肝细胞癌（HCC）占原发性肝癌的85-90%，目前是全球癌症相关死亡的第二大原因。本文报道了醛酮还原酶家族7A亚型3（AKR 7A 3）在肝癌中表达下调，与肝癌的低分化、低生存率、血清甲胎蛋白（AFP）升高有关。AKR 7A 3基因启动子区甲基化程度较高。在AKR 7A 3中也检测到杂合性缺失（洛）。对AKR 7A 3过表达和敲低细胞的功能测定，包括病灶形成、软琼脂中的集落形成、迁移、侵袭和裸鼠中的肿瘤形成，证明了AKR 7A 3的强肿瘤抑制功能。此外，化疗药物顺铂的治疗显示AKR 7A 3使肿瘤细胞对凋亡敏感。蛋白质印迹分析显示AKR 7A 3的过表达抑制ERK、c-Jun和NF-κB的活化。综上所述，我们发现AKR 7A 3在HCC中通过减弱c-Jun、ERK和NF-κB信号通路发挥抑癌基因的作用。
Hepatocellular carcinoma (HCC), which accounts for 85–90% of primary liver cancer, is now the second leading cause of cancer-related mortality worldwide. Here we reported that Aldo-Keto Reductase family 7A isoform 3 (AKR7A3) is frequently down-regulated in HCC, associating with poor overall survival rate, elevated serum α-fetoprotein (AFP) and poor differentiation of HCC. The promoter region of AKR7A3 was detected to be hypermethylated. Loss of heterozygosity (LOH) was also detected in AKR7A3. Functional assays on both AKR7A3 overexpressed and knockdown cells, including foci formation, colony formation in soft agar, migration, invasion and tumor formation in nude mice, demonstrated the strong tumor suppressive functions of AKR7A3. In addition, treatment of chemotherapy drug cisplatin showed that AKR7A3 sensitizes tumor cells to apoptosis. Mechanistically, western blot analysis showed that overexpression of AKR7A3 inhibits the activation of ERK, c-Jun and NF-κB. In summary, we found that AKR7A3 functions as a tumor suppressor gene in HCC through attenuating c-Jun, ERK and NF-κB signaling pathways.
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