Jiang Jingyi, Liu Zheng, Ge Chao, Chen Cong, Zhao Fangyu, Li Hong, Chen Taoyang, Yao Ming, Li Jinjun
From the Shanghai Medical College, Fudan University, Shanghai 200032.
the State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, and.
J Biol Chem. 2017 Nov 24;292(47):19146-19159. doi: 10.1074/jbc.M117.793760. Epub 2017 Sep 27.
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related mortality in China, and the molecular mechanism of uncontrolled HCC progression remains to be explored. NK3 homeobox 1 (), an androgen-regulated prostate-specific transcription factor, suppresses tumors in prostate cancer, but its role in HCC is unknown, especially in hepatocellular carcinoma. In the present study, the differential expression analyses in HCC tissues and matched adjacent noncancerous liver tissues revealed that NKX3.1 is frequently down-regulated in human primary HCC tissues compared with matched adjacent noncancerous liver tissues. We also noted that NKX3.1 significantly inhibits proliferation and mobility of HCC cells both and Furthermore, NKX3.1 overexpression resulted in cell cycle arrest at the G/S phase via direct binding to the promoter of forkhead box O1 () and up-regulation of expression. Of note, FOXO1 silencing in NKX3.1-overexpressing cells reversed the inhibitory effects of NKX3.1 on HCC cell proliferation and invasion. Consistently, both FOXO1 and NKX3.1 were down-regulated in human HCC tissues, and their expression was significantly and positively correlated with each other. These results suggest that functions as a tumor suppressor in HCC cells through directly up-regulating FOXO1 expression.
肝细胞癌（HCC）是中国癌症相关死亡的主要原因，HCC进展失控的分子机制仍有待探索。NK3同源框1（NKX3.1）是一种雄激素调节的前列腺特异性转录因子，可抑制前列腺癌中的肿瘤，但它在HCC中的作用尚不清楚，尤其是在肝细胞癌中。在本研究中，对HCC组织和配对的相邻非癌肝组织进行差异表达分析，结果显示与配对的相邻非癌肝组织相比，NKX3.1在人类原发性HCC组织中经常下调。我们还注意到，NKX3.1在体外和体内均显著抑制HCC细胞的增殖和迁移。此外，NKX3.1过表达通过直接结合叉头框O1（FOXO1）的启动子并上调其表达，导致细胞周期停滞在G1/S期。值得注意的是，在NKX3.1过表达的细胞中沉默FOXO1可逆转NKX3.1对HCC细胞增殖和侵袭的抑制作用。同样，在人类HCC组织中，FOXO1和NKX3.1均下调，且它们的表达彼此显著正相关。这些结果表明，NKX3.1通过直接上调FOXO1表达在HCC细胞中发挥肿瘤抑制作用。
