Interferon regulatory factor (IRF)-1 and IRF-2 are associated with prognosis and tumor invasion in HCC.
BACKGROUND
Interferon regulatory factor (IRF)-1 and IRF-2 are transcriptional factors that mediate interferons functions; the loss of IRF-1 expression and gain of IRF-2 expression were associated with malignant phenotype in multiple cancers. However, their roles in the progression of hepatocellular carcinoma (HCC) remain poorly described.


METHODS
Immunohistochemistry was used to analyze the nuclear expression of IRF-1/2 in a cohort of 332 HCC patients. The expression of IRF-1/2 in HCC cell lines with stepwise metastasis potential was determined by immunoblotting. Downregulation of IRF-1 or IRF-2 expression was mediated by shRNAs; a series of experiments were conducted to determine the changes of invasion ability and downstream molecular events.


RESULTS
High expression of IRF-1 was associated with good outcome (p<.001 for OS/TTR), while high expression of IRF-2 was relevant to increased recurrence probability (p=.049) in HCC patients. The combination of the 2 IRFs showed better predictive power than either factor alone. Immunoblotting analysis revealed that IRF-2/IRF-1 ratio was positively correlated with the metastatic potential in human HCC cell lines. Downregulation of IRF-2 led to sharply attenuated invasion ability, paralleled with a decreased expression of STAT3, p-STAT3(Ser727), and MMP9. While downregulation of IRF-1 caused a concurrent decrease in IRF-2, little or no change was displayed in IRF-2/IRF-1 ratio, invasion ability, and MMP9 expression.


CONCLUSIONS
IRF-1 and IRF-2 expression were associated with prognosis of HCC patients with opposite predictive power. IRF-2/IRF-1 ratio was associated with tumor invasion, probably through modulation of MMP9 expression mediated by STAT3.
Key Laboratory for Carcinogenesis & Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, The Chinese Ministry of Education, Shanghai, People's Republic of China.
Yong
Y
Yi
Han
H
Wu
Qiang
Q
Gao
Hong-Wei
HW
He
Yi-Wei
YW
Li
Xiao-Yan
XY
Cai
Jia-Xing
JX
Wang
Jian
J
Zhou
Yun-Feng
YF
Cheng
Jian-Jun
JJ
Jin
Jia
J
Fan
Shuang-Jian
SJ
Qiu
D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D050836:Interferon Regulatory Factor-2 / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D011379:Prognosis; D016016:Proportional Hazards Models; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014162:Transfection
D014408:Biomarkers, Tumor; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020780:Matrix Metalloproteinase 9