Up-regulation of Krüppel-like factor 8 promotes tumor invasion and indicates poor prognosis for hepatocellular carcinoma.
OBJECTIVE
The transcription factor Krüppel-like factor 8 (KLF8) has a role in tumor development, growth, and metastasis, but its role in hepatocellular carcinoma (HCC) is not clear.


METHODS
KLF8 expression in human HCC cell lines and tumor tissues was measured by quantitative real-time polymerase chain reaction, immunoblot, and immunochemical analyses. The effects of KLF8 depletion or overexpression in HCC cells were observed in cultured cells and in mice. Changes in gene expression patterns in HCC cells in which levels of KLF8 were reduced using small interfering RNA were investigated by microarray analysis. The clinical significance of KLF8 expression levels were validated using tissue microarray analysis of surgical samples from 314 HCC patients.


RESULTS
KLF8 was overexpressed in highly metastatic HCC cell lines and in samples from patients with recurrent HCC. In cultured cells, KLF8 up-regulation promoted cell proliferation and invasion; inhibited apoptosis; down-regulated N-cadherin, vimentin, and fibronectin; and up-regulated E-cadherin. In mice, overexpression of KLF8 increased HCC progression and metastasis. Microarray analysis showed that reduction of KLF8 in HCC cells down-regulated expression of multiple genes involved in tumor progression and metastasis. KLF8 expression was a significant predictor of overall survival (P = .040) and time to HCC recurrence (P = .006) and was associated with early tumor recurrence (P = .001).


CONCLUSIONS
KLF8 promotes HCC cell proliferation and invasion, inhibits apoptosis, and induces the epithelial-to-mesenchymal transition. KLF8 up-regulation might be used to indicate poor prognosis or early recurrence of cancer in patients who have had surgery for HCC.
Li
Jia-Chu
JC
Experimental Research Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China.
Yang
Xin-Rong
XR
Sun
Hai-Xiang
HX
Xu
Yang
Y
Zhou
Jian
J
Qiu
Shuang-Jian
SJ
Ke
Ai-Wu
AW
Cui
Yue-Hong
YH
Wang
Zhi-Jun
ZJ
Wang
Wei-Min
WM
Liu
Kang-Da
KD
Fan
Jia
J
D017209:Apoptosis / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000401:mortality / Q000556:secondary; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D053208:Kaplan-Meier Estimate; D051741:Kruppel-Like Transcription Factors; D008113:Liver Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
C507402:KLF8 protein, human; D051741:Kruppel-Like Transcription Factors; D034741:RNA, Small Interfering; D012097:Repressor Proteins