乙肝病毒編碼的X抗原(HBx)是一個(gè)反式調(diào)節(jié)蛋白,，實(shí)驗(yàn)表明，它能夠改變特定的轉(zhuǎn)錄因子以及細(xì)胞質(zhì)信號(hào)轉(zhuǎn)導(dǎo)通路的活性,。
HBx通過(guò)上調(diào)一個(gè)獨(dú)特的基因-URG11的表達(dá),，反過(guò)來(lái)上調(diào)β-鏈蛋白(β-catenin)，從而促進(jìn)了肝癌的發(fā)生,。
此外,，HBx和URG11也改變了多種microRNAs的表達(dá)。通過(guò)miRNA 陣列分析發(fā)現(xiàn),，它們都促進(jìn)了miR-148a的表達(dá),。在感染者的HBx陽(yáng)性肝臟標(biāo)本，miR-148a的表達(dá)升高,。
為了研究miR-148a的功能,，美國(guó)天普大學(xué)的研究人員將anti-148a被導(dǎo)入到穩(wěn)定表達(dá)HBx或者穩(wěn)定的過(guò)表達(dá)URG11的HepG2及Hep3B細(xì)胞。
結(jié)果發(fā)現(xiàn),，Anti-miR-148a抑制了細(xì)胞增殖,、細(xì)胞周期的前進(jìn)，細(xì)胞遷移,、在軟瓊脂的停泊非依賴性生長(zhǎng)及SCID老鼠皮下腫瘤的形成,。
引入anti-miR-148a提升了PTEN蛋白及mRNA的表達(dá)，這表明了miR-148a對(duì)PTEN的定向作用,。
然而,，當(dāng)與PTEN mRNA 3′UTR報(bào)告基因突變體聯(lián)合轉(zhuǎn)染時(shí),，Anti-miR-148a卻不能抑制PTEN的表達(dá) 。
實(shí)驗(yàn)還發(fā)現(xiàn),，引入anti-miR-148a通過(guò)HBx和URG11也導(dǎo)致Akt 信號(hào)下調(diào),，致使β-catenin表達(dá)減少。
因此,，miR-148a可能在HBx/URG11介導(dǎo)的肝細(xì)胞癌（HCC）中起到了重要作用,。它可能成為一個(gè)早期診斷標(biāo)記物，或者是這些癌癥類型的一個(gè)新的治療靶點(diǎn),。相關(guān)論文發(fā)表在4月9日的Plos One,。（生物谷Deepblue編譯）
doi: 10.1371/journal.pone.0035331
PMC:
PMID:
Role of miR-148a in Hepatitis B Associated Hepatocellular Carcinoma
Ke Yuan, Zhaorui Lian, Bill Sun, Marcia M. Clayton, Irene O. L. Ng, Mark A. Feitelson.
Hepatitis B virus encoded X antigen (HBx) is a trans-regulatory protein that alters the activity of selected transcription factors and cytoplasmic signal transduction pathways.HBx transcriptionally up-regulates the expression of a unique gene, URG11, which in turn transcriptionally up-regulates β-catenin, thereby contributing importantly to hepatocarcinogenesis. HBx and URG11 also alter the expression of multiple microRNAs, and by miRNA array analysis, both were shown to promote the expression of miR-148a. Elevated miR-148a was also seen in HBx positive liver samples from infected patients. To study the function of miR-148a, anti-148a was introduced into HepG2 and Hep3B cells stably expressing HBx or stably over-expressing URG11. Anti-miR-148a suppressed cell proliferation, cell cycle progression, cell migration, anchorage independent growth in soft agar and subcutaneous tumor formation in SCID mice.Introduction of anti-miR-148a increased PTEN protein and mRNA expression, suggesting that PTEN was targeted by miR-148a.Anti-miR-148a failed to suppress PTEN expression when co-transfected with reporter gene mutants in the 3′UTR of PTEN mRNA.Introduction of anti-miR-148a also resulted in depressed Akt signaling by HBx and URG11, resulting in decreased expression of β-catenin. Thus, miR-148a may play a central role in HBx/URG11 mediated HCC, and may be an early diagnostic marker and/or therapeutic target associated with this tumor type.
