Overexpression of forkhead box C1 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma.
Recurrence and metastasis remain the most common causes of lethal outcomes in hepatocellular carcinoma (HCC) after curative resection. Thus, it is critical to discover the mechanisms underlying HCC metastasis. Forkhead box C1 (FoxC1), a member of the Fox family of transcription factors, induces epithelial-mesenchymal transition (EMT) and promotes epithelial cell migration. However, the role of FoxC1 in the progression of HCC remains unknown. Here, we report that FoxC1 plays a critical role in HCC metastasis. FoxC1 expression was markedly higher in HCC tissues than in adjacent noncancerous tissues. HCC patients with positive FoxC1 expression had shorter overall survival times and higher recurrence rates than those with negative FoxC1 expression. FoxC1 expression was an independent, significant risk factor for recurrence and survival after curative resection. FoxC1 overexpression induced changes characteristic of EMT and an increase in HCC cell invasion and lung metastasis. However, FoxC1 knockdown inhibited these processes. FoxC1 transactivated Snai1 expression by directly binding to the Snai1 promoter, thereby leading to the inhibition of E-cadherin transcription. Knockdown of Snai1 expression significantly attenuated FoxC1-enhanced invasion and lung metastasis. FoxC1 expression was positively correlated with Snai1 expression, but inversely correlated with E-cadherin expression in human HCC tissues. Additionally, a complementary DNA microarray, serial deletion, site-directed mutagenesis, and a chromatin immunoprecipitation assay confirmed that neural precursor cell expressed, developmentally down-regulated 9 (NEDD9), which promotes the metastasis of HCC cells, is a direct transcriptional target of FoxC1 and is involved in FoxC1-mediated HCC invasion and metastasis.


CONCLUSIONS
FoxC1 may promote HCC metastasis through the induction of EMT and the up-regulation of NEDD9 expression. Thus, FoxC1 may be a candidate prognostic biomarker and a target for new therapies.
State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Limin
L
Xia
Wenjie
W
Huang
Dean
D
Tian
Hongwu
H
Zhu
Xingshun
X
Qi
Zheng
Z
Chen
Yongguo
Y
Zhang
Hao
H
Hu
Daiming
D
Fan
Yongzhan
Y
Nie
Kaichun
K
Wu
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D000328:Adult; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000096:biosynthesis; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic; D019694:Hepatitis B, Chronic / Q000503:physiopathology; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D051379:Mice; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000235:genetics / Q000503:physiopathology; D009364:Neoplasm Recurrence, Local / Q000503:physiopathology; D010750:Phosphoproteins / Q000096:biosynthesis; D011379:Prognosis; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis; D015533:Transcriptional Activation; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D015820:Cadherins; C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; C099942:NEDD9 protein, human; D010750:Phosphoproteins; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin