The study from Dr. Sun's group explained an interesting phenomenon on why microRNA-143, a commonly down-regulated microRNA in many types of cancer, expressed at a high level in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). They used a hepatitis B virus x protein (HBx) transgenic mouse model and tissue samples from clinical patients to show that microRNA-143 is a key mediator in HBV-related HCC metastasis. This is the first study to demonstrate that HBx/nuclear factor κB(NF-κB)/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.
First, is it really true that mir-143 is an oncomir in HCC? Previous studies demonstrated that mir-143 belongs to a member of putative tumor suppressor microRNAs, because it is frequently underexpressed in many types of cancers.2–4 Its expression is always consistent with mir-145, another putative tumor suppressor microRNA that is close to mir-143.2–4 The expression of these two microRNAs are frequently changed simultaneously. If mir-143 was up-regulated by NF-κB, as has been shown in this study, what is the trend of mir-145 expression in HCC cells? A recent study demonstrated that p53 can transcriptionally up-regulate mir145, and mir145 can down-regulate an oncogene, c-myc, by directly binding to its 3′-untranslated region. It functions as a tumor suppressor in carcinogenesis.5 Therefore, what are the authors' opinions on the role of mir-143, a partner of mir145, in HBV-related HCC: does it act as tumor suppressor microRNA or oncomir?
Second, is mir-143 directedly transcribed by the transcription factor NF-κB? To date, the transcription regulation of mir-143 is still not very clear. In this study, the authors used in vitro and in vivo assay (Fig. 3 in the article) to demonstrate that mir-143 expression was transcriptionally up-regulated by NF-κB. But all these designed experiments can not avoid the possibility that mir-143 is regulated by NF-κB in an indirect manner, because NF-κB plays a critical role in multisignal pathways.6 We think that a reporter assay to detect the activity of mir-143 promoter with the mutant NF-κB binding site may further confirm the authors' conclusion.
Third, what is the relationship of HBx, mir-143, and FNDC3B expression patterns in clinical HCC with HBV infection? Although the authors demonstrated the possible signal pathway of HBx/NF-κB/mir-143/FNDC3B in HCC, there are no data to show its clinical significance. We think that if such a close relationship exists in clinical patients, it would be a promising biomarker for clinical prognosis.