Up-regulated microRNA-143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing fibronectin expression.
It is increasingly clear that hepatocellular carcinoma (HCC) has a distinct microRNA (miRNA) expression profile that is involved in malignancy; however, little is known about how functional miRNA modulates the metastasis of hepatitis B virus (HBV)-related HCC (HBV-HCC). In the present study, we demonstrate that the levels of miRNA-143 (miR-143) are dramatically increased in metastatic HBV-HCC of both p21-HBx transgenic mice and HCC patients. Moreover, we show that overexpression of this miRNA is transcribed by nuclear factor kappa B (NF-kappaB) and favors liver tumor cell invasive and metastatic behavior. Intratumoral administration of miR-143 shows that high levels of miR-143 can significantly promote HCC metastasis in an athymic nude mouse model. An in vivo study that used p21-HBx transgenic mice also showed that local liver metastasis and distant lung metastasis are significantly inhibited by blocking miR-143. Additionally, fibronectin type III domain containing 3B (FNDC3B), which regulates cell motility, was identified as the direct and functional target of miR-143 both in vivo and in vitro.


CONCLUSIONS
Up-regulation of miR-143 expression transcribed by NF-kappaB in HBV-HCC promotes cancer cell invasion/migration and tumor metastasis by repression of FNDC3B expression. The present study provides a better understanding of the specificity of the biological behavior and thus may be helpful in developing an effective treatment against HBV-HCC.
Zhang
Xiaoying
X
Department of Medical Genetics, Second Military Medical University, Shanghai, PR China.
Liu
Shanrong
S
Hu
Tingsong
T
Liu
Shupeng
S
He
Ying
Y
Sun
Shuhan
S
D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000821:virology; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D005260:Female; D005353:Fibronectins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D019694:Hepatitis B, Chronic / Q000150:complications; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000821:virology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015534:Trans-Activators / Q000235:genetics; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins
C543006:FNDC3B protein, human; D005353:Fibronectins; C542359:MIRN143 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein