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.
Highlights
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
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 found that NKX3.1 was down-regulated in HCC tissues compared with matched adjacent noncancerous liver tissues
Summary
As the suppressor role of NKX3.1 in prostate cancer, the association between NKX3.1 and HCC is still unknown. The results of the in vitro woundhealing assay revealed NKX3.1 overexpression decreased migration of the HCC cells compared with the control (Fig. 3A). Expression of FOXO1, p21CIP1, and p27KIP1 increased in NKX3.1-overexpressing cells at 24 h, whereas expression of CDK2, Cyclin E, and phosphorylated RB (Ser-807/811) were decreased compared with control pWPXL cells (Fig. 5D). This implied that overexpression of NKX3.1 results in G1/S phase arrest through up-regulating FOXO1 in HCC cells. We tested the expression changes of cell cycle-related proteins (FOXO1, p21CIP1, p27KIP1, CDK2, Cyclin E, phosphorylated RB, and total RB) in NKX3.1-overexpressing HCC cells after knockdown of FOXO1. Data are mean Ϯ S.D. of three independent experiments
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