探討微核醣核酸miR-196a 和牡丹酚衍生物在肝癌中的作用

Abstract

1.肝癌是世界上死亡率最高的癌症之一，根據中華民國衛生福利部統計指出，目前肝癌死亡率是在癌症病患中排名第二位，僅次於肺癌。根據臨床資料的統計，我們把四十歲以下得到肝癌的病患稱之為年輕型肝癌(yHCC)，此類型病患有著較高的死亡率和手術後復發的機率。已有研究指出，此類型病患有著較高的肝病毒(Hepatitis B, C) 和甲胎蛋白(AFP)的表現，但實際上的機制仍不是很清楚，因此急需我們討論與研究。 微核醣核酸(MicroRNA)是一系列20~22核甘酸所組成的單元，在生物體內可以透過鹼基配對方式和目標核糖核酸相接，達到干擾其功能的作用。我們和陽明大學吳肇欽老師合作並且發現miR-196a在年輕型肝癌病患中表現明顯比老年型增加，在我們的研究中，發現在抑制miR-196a後可以降低PLC 細胞的癌幹性和遷徙能力，同時DKK-1和HOXC-8的表現也在抑制miR-196a後增加。DKK-1在WNT訊息路徑上扮演很重要的角色，而WNT路徑又和細胞遷徙和幹性息息相關。雖然miR-196a是否是一個致癌的基因仍不是很清楚，但在我們研究中指出miR-196a可以調控PLC細胞的遷徙能力和癌幹性。 2.牡丹酚最初是從牡丹花提煉出來的中草藥並且已被證實有抗氧化的作用，我們和清華大學許銘華老師合作，利用噻唑(Thiazole)修飾形成牡丹酚衍生物。我們研究結果顯示3c,3h和3k2等化合物有抑制肝癌的作用，未來希望能找到最佳劑量並可以期望應用在臨床治療上。

Hepatocellular carcinoma (HCC) is one of the most malignant cancer in the world. According to Ministry of Health and Welfare in Taiwan, HCC is the second malignant cancer following lung cancer. Recent studies have shown that the overall survival rate in younger patients (≤40) (yHCC) is less than elder patients (oHCC). HCC in younger group is more aggressive due to higher hepatitis B incidence and alpha-fetoprotein (AFP) levels driving poor outcome for young patients. However, the mechanisms how yHCC exacerbates HCC progression are still unclear.

MicroRNAs are a series of small RNAs that contain 20 ~ 22 nucleotides. In vivo, microRNAs can bind to its target mRNAs through base pairing to the 3 UTRs (untranslated regions). We have collaborated with Professor Wu in Yang Ming University and find miR-196a expression is significantly higher in yHCC than in oHCC. For study miR-196a in yHCC, we transfected miR-196a into HCC cell line PLC, which is from young HCC patients. We found that miR-196a can affect the ability of epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) formation. Moreover, Dkk-1 is significantly increased in miR-196a knockdown PLC cells using in cytokine analysis. DKK-1 plays an important role in WNT signaling pathway which is the crucial pathway for stemness. This indicates miR-196a can regulate cell development and migration in vivo. Although the oncogenic phenotype of miR-196a remains to be elucidated, this study identify miR-196a can regulate cell migration in PLC cell line.

Paeonol is an aromatic compound isolated from plant Paeonia moutan Sims and is well known for its anti-oxidation effect. Here, we designed and synthesized novel paeonol-thiazol derivatives compounds and investigated whether paeonol-thiazol derivatives compounds can be as the therapeutic drug in yHCC. We found that 3c、3h and 3k2 can inhibit yHCC cell proliferation and increased apoptosis. In conclusions, based on our data, inhibition of miR-196a causes suppression of stemness and EMT in yHCC and paeonol-thiazol derivatives compounds 3c、3h and 3k2 can inhibit yHCC development.