Up‐regulated microRNA‐143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing fibronectin expression†

Abstract

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-B) and favors liver tumor cell invasive and metastatic behavior. H epatocellular carcinoma (HCC) is a common and aggressive cancer that is strongly associated with chronic infection by the hepatitis B virus (HBV). 1 Poor prognosis and patient survival with HCC are largely due to invasion/metastasis and postsurgical recurrence. 2 The HBV X protein (HBx), a protein encoded by HBV, is thought to play a key role in the molecular pathogenesis of HBV-related HCC (HBV-HCC). 2,3 Invasion and metastasis are fundamental properties of HBV-HCC, which has a very high mortality rate. Alteration of some adhesion molecules in HBV-HCC has been described, including up-regulation of matrix metalloproteinases 1-3 and down-regulation of E-cadherin. Both of these changes indicate that HBx contributes to the metastatic spread of liver tumors. 2,4 Metastasis is a complex cascade, however, and the underlying molecular mechanisms are far from being fully understood.MicroRNAs (miRNAs) are evolutionarily endogenous regulatory noncoding RNAs that play critical roles in gene regulation. 5 Recent studies implicate miRNAs in several cancers, and altered miRNA levels can result in aberrant expression of gene products that may contribute to cancer biology, including tumor metastasis. [5][6][7][8] These findings suggest that expression profiling of miRNAs is an alternative method for cancer subtype classification, prognostication, and treatment. 5,7,8 It is known that HCC develops several years after HBV infection. 2,9 A p21-HBx transgenic mouse model was established by introducing the HBx gene into the p21 locus. About 60% of p21-HBx transgenic mice develop hepato-

miR-143 is downregulated in cervical cancer and promotes apoptosis and inhibits tumor formation by targeting Bcl-2

“…It has been reported that miR-143 is downexpressed in colon (15), lung (16) and prostate cancer (17) and is overexpressed in hepatocarcinoma (18). Furthermore, miR-143 is involved in the regulation of MYO6 expression in prostate cancer (17); extracellular signal-regulated kinase-5 (ERK-5) is a miR-143 target in prostate cancer and miR-143 inhibits the proliferation at least in part by the inhibition of ERK-5 activity (19).…”

MicroRNA Expression Profile in Hyperoxia-Exposed Newborn Mice During the Development of Bronchopulmonary Dysplasia

“…After overnight fixation at 4°C, the tissue was dehydrated and paraffin embedded, cut into 5-m sections, stained with hemotoxylin and eosin, and examined with light microscopy. 15,16 We performed radial alveolar counts, as previously described. 17 From the center of the respiratory bronchiole, a perpendicular line is drawn to the edge of the acinus, and the number of the septa intersected by that line are counted.…”

Is microRNA-143 really a turncoat of tumor suppressor microRNA in hepatitis B virus–related hepatocellular carcinoma? #

“…This is the first study to demonstrate that HBx/nuclear factor B(NF-B)/mir-143/fibronectin type III domain containing 3B (FNDC3B) is an important signal pathway in pathological process of HCC metastasis. 1 Yet, we still have several questions about this study.…”