MicroRNA expression, survival, and response to interferon in liver cancer.
BACKGROUND
Hepatocellular carcinoma is a common and aggressive cancer that occurs mainly in men. We examined microRNA expression patterns, survival, and response to interferon alfa in both men and women with the disease.


METHODS
We analyzed three independent cohorts that included a total of 455 patients with hepatocellular carcinoma who had undergone radical tumor resection between 1999 and 2003. MicroRNA-expression profiling was performed in a cohort of 241 patients with hepatocellular carcinoma to identify tumor-related microRNAs and determine their association with survival in men and women. In addition, to validate our findings, we used quantitative reverse-transcriptase-polymerase-chain-reaction assays to measure microRNAs and assess their association with survival and response to therapy with interferon alfa in 214 patients from two independent, prospective, randomized, controlled trials of adjuvant interferon therapy.


RESULTS
In patients with hepatocellular carcinoma, the expression of miR-26a and miR-26b in nontumor liver tissue was higher in women than in men. Tumors had reduced levels of miR-26 expression, as compared with paired noncancerous tissues, which indicated that the level of miR-26 expression was also associated with hepatocellular carcinoma. Moreover, tumors with reduced miR-26 expression had a distinct transcriptomic pattern, and analyses of gene networks revealed that activation of signaling pathways between nuclear factor kappaB and interleukin-6 might play a role in tumor development. Patients whose tumors had low miR-26 expression had shorter overall survival but a better response to interferon therapy than did patients whose tumors had high expression of the microRNA.


CONCLUSIONS
The expression patterns of microRNAs in liver tissue differ between men and women with hepatocellular carcinoma. The miR-26 expression status of such patients is associated with survival and response to adjuvant therapy with interferon alfa.
Ji
Junfang
J
Liver Carcinogenesis Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Shi
Jiong
J
Budhu
Anuradha
A
Yu
Zhipeng
Z
Forgues
Marshonna
M
Roessler
Stephanie
S
Ambs
Stefan
S
Chen
Yidong
Y
Meltzer
Paul S
PS
Croce
Carlo M
CM
Qin
Lun-Xiu
LX
Man
Kwan
K
Lo
Chung-Mau
CM
Lee
Joyce
J
Ng
Irene O L
IO
Fan
Jia
J
Tang
Zhao-You
ZY
Sun
Hui-Chuan
HC
Wang
Xin Wei
XW
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D015331:Cohort Studies; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006509:Hepatitis B / Q000150:complications; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000150:complications; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D010597:Pharmacogenetics; D011379:Prognosis; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D016019:Survival Analysis; D055815:Young Adult
D000998:Antiviral Agents; D016898:Interferon-alpha; D035683:MicroRNAs; C528163:MIRN26 microRNA, human