探討脂聯素對肝癌預後的影響及其潛藏的機轉

Study prognostic implications and underlying mechanisms of adiponectin in hepatocellular carcinoma

蔡馨慧(Hsin-Hui Tsai)

指導教授 ： 王森稔

高雄醫學大學/醫學院/醫學研究所/碩士(2010年)

摘要

根據世界衛生組織之流行病學統計顯示： 80 ％ 的肝癌病例與慢性 B 型及 C 型肝炎有關，其餘 20 ％ 則包含飲酒過度、脂肪肝以及其他的代謝異常。 有趣的是，越來越多的證據指出肝癌的發生與進展和肥胖以及代謝異常有關。部份脂肪組織衍生而出的因子例如脂肪激素也因此被認為可能在肝臟的致癌機轉中扮演某些重要的角色。儘管已有許多的證據指出脂肪激素之ㄧ的脂聯素可能影響癌症的發生及進展，有關脂聯素是否在肝癌發展中有所貢獻的資訊仍舊缺乏。
本篇研究中，我們的結果顯示脂聯素在60 ％ 之肝癌組織切片中的細胞質表現量明顯增加。高達 63.2 ％ 的肝癌組織中脂聯素之核醣核苷酸表現量亦較其對應的非腫瘤肝組織高。當脂聯素染色增加時，肝癌病患術後復發的機率較染色量低之患者高 ( p=0.047 ) ，整體存活率亦相對較差 ( p=0.007 ) ；同時，以多變因之Cox 存活率回歸模式分析後，脂聯素染色量的增加可做為肝癌病患存活率降低的有效決定因子 (Odd ratio 為 3.327；95 % 之信賴區間範圍為從1.207 至 9.173；p=0.020 )。有趣的是，當脂聯素在HepG2和Hep3B 肝癌細胞株中的表現量增加時，不僅可增加活化之 AKT、活化之STAT3 以及 β-catenin 的表現量；細胞增生及移行侵犯能力亦會隨之增加。更甚者，持續提高脂聯素的表現於 Hep3B 與 HepG2 後，癌細胞能夠減少生長附著的需求而在軟瓊脂中形成群落。由於 PI3K/AKT的抑制劑LY294002可抑制脂聯素所誘導的效應，我們推測這些生物性效應可能導因於 AKT 的活化。此外，脂聯素受體二之特異性小干擾性核醣核苷酸以及脂聯素特異性抗體均能有效削弱脂聯素所誘導的 AKT與 STAT3 之活化作用,以及 β-catenin 的表現。這些結果顯示，脂聯素對於肝癌細胞所誘導的生物性效應及訊息傳遞，可能藉由脂聯素受體二以及活化的 AKT 及 STAT3 與 β-catenin 之下游機制所致。綜合上述，增加的脂聯素可能在肝癌的發展上扮演了某些關鍵性的角色，更詳細的機轉仍需進一步的研究探討。

關鍵字

脂聯素 ； 脂聯素受體 ； 肝癌 ； 復發 ； 存活率 ； 增生 ； 移行 ； 侵犯

並列摘要

Epidemiological studies clearly indicate that hepatocellular carcinoma (HCC) is strongly associated with chronic hepatitis B and C, being implicated in 80 % of HCC cases worldwide, with the other 20 % of risk factors including alcohol abuse, fatty liver disease, haemochromatosis and other metabolic disorders. Intriguingly, mounting evidences have showed that HCC is associated with obesity and/or metabolic aberrations. Certain factors namely adipokines derived from adipose tissues may play some roles in liver tumorigenesis. Although there are several lines of evidence indicate that adiponectin (APN), one of adipokines, may influence cancer pathogenesis, absent information concerns if adiponectin contributes to HCC development.
In this study, our results showed that APN staining was dominantly increased in 60 % of HCC lesions, while APN transcript was dominantly increased in 63.2 % of HCC tissue as compared with the matched non-cancer liver tissues. Increased APN staining was positively correlated with recurrence rate (p=0.047) and was negatively associated with a poor overall survival rate (p=0.007) even using multivariable COX’s regression model (OR 3.327; 95 % CI 1.207 to 9.173; p=0.020). Interestingly, we found that APN increased expression of p-Akt and p-STAT3, and β-catenin as well as cell proliferation and migration/invasion rate in HepG2 and Hep3B cells. Furthermore, stable expression of APN in Hep3B and HepG2 cells leaded to form colonies in soft agar. These bio-effects might be mediated by activation of AKT, because LY294002 inhibited these APN-mediated effects. And APN-induced activation of AKT, p-STAT3 and β-catenin was attenuated by the specific siRNA of adiponectin receptor 2 and specific antibodies against APN. These results suggested that APN-induced bio-effects and signalings might act through adiponectin receptor 2 and related downstream p-AKT, p-STAT3 and β-catenin. Taken together, increased APN might play some critical roles in contributing to HCC development. Further investigations are required.

並列關鍵字

adiponectin ； adiponectin receptor ； hepatocellular carcinoma ； recurrence ； survival ； proliferation ； migration ； invasion

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