NK3 homeobox 1 (NKX3.1) up-regulates forkhead box O1 expression in hepatocellular carcinoma and thereby suppresses tumor proliferation and invasion

  1. Jinjun Li§2
  1. From the Shanghai Medical College, Fudan University, Shanghai 200032,
  2. the §State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, and
  3. the Qi Dong Liver Cancer Institute, Qi Dong 226200, China
  1. 2 To whom correspondence should be addressed: 25/Ln 2200 Xietu Rd., Shanghai 200032, China. Tel.: 86-21-64432140; E-mail: jjli{at}shsci.org.
  1. 1 Both authors contributed equally to this work.

  2. Edited by Eric R. Fearon

Abstract

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 (NKX3.1), 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 in vitro and in vivo. Furthermore, NKX3.1 overexpression resulted in cell cycle arrest at the G1/S phase via direct binding to the promoter of forkhead box O1 (FOXO1) 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 NKX3.1 functions as a tumor suppressor in HCC cells through directly up-regulating FOXO1 expression.

Footnotes

  • This work was supported in part by National Natural Science Foundation of China Grant 81472726, National Key Sci-Tech Special Project of China Grant 2013ZX10002-011, and SKLORG Research Foundation Grant 91-15-03. The authors declare that they have no conflicts of interest with the contents of this article.

  • This article contains .

  • Received April 28, 2017.
  • Revision received September 22, 2017.
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This Article

  1. The Journal of Biological Chemistry 292, 19146-19159.
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    1. M117.793760v1
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