微型核醣核酸-122和B型肝炎病毒量與肝細胞癌發展的相關性：巢式病例對照研究

Abstract

研究背景與目的： 慢性B型肝炎感染與肝細胞癌有密切的關係，而B型肝炎病毒量被認為是之中最重要的危險因子。目前已有許多微小核糖核酸研究發現miR-122在病毒複製和肝癌致癌機轉扮演重要角色。因此，我們的目的是研究循環miR-122和B型肝炎病毒量重複測量數值與肝細胞癌的關聯性。 材料於方法：本巢式病例對照研究樣本來自於1989至1992年間收取的B型肝炎帶原的男性公務人員世代研究，共納入89名肝癌患者與89名配對對照。進入研究時，我們收取個案的人口學、生活習慣和測量ALT數值，B肝病毒量則是每次回診時都會進行測量。我們使用反轉錄聚合酶連鎖反應和即時定量聚合酶連鎖增幅反應分析血清檢體中miR-122於各次重複測量的表現(於罹病前8.6、5.2和2.6 年)。統計分析使用條件式羅吉斯回歸進行分析。 結果：我們在各時點都觀察到miR-122的表現量與B肝病毒量有反向的關聯性，但在病例組或對照組中都未發現miR-122的表現量有隨時間變化的趨勢。不過從多變量分析的結果發現，在調整了年齡、ALT數值和B型肝炎基因型之後，於發病前5.2年的miR-122低度表現會提高2.54倍(95%CI=1.16－5.57)的肝癌罹患風險。但是我們並未在罹病前8.6年(OR= 1.9, 95% CI=0.92－3.80)或罹病前2.6年 (OR= 1.17, 95% CI=0.56－2.46)發現一樣的顯著結果。 結論：我們發現miR-122低表現量與較高的B型肝炎病毒量，也和肝細胞癌的風險增加有關，然而低表現量的時間點也可能是決定肝癌發生的重要因子。

Background & Aim: Chronic hepatitis B virus (HBV) infection is the predominant cause of hepatocellular carcinoma (HCC), and blood HBV DNA level is one of the most important risk factors for HBV-related HCC. Studies have shown a potential role of miR-122 in viral replication activity and in hepatocellular carcinogenesis. We aimed to investigate the association between circulating miR-122 expression and their concurrent HBV DNA levels, and the repeated measurements of the two factors in relation to subsequent development of HCC. Materials & Methods: The study was conducted in 89 cases with HCC and 89 time-matched controls using a nested case-control design in a cohort study of male, hepatitis B surface antigen-positive civil servants who were recruited between 1989 and 1992. Information on demographics, lifestyle and blood alanine aminotransferase (ALT) were collected at study subjects’ entry into the cohort, while HBV-DNA data were obtained at study entry and follow-up. We used qRT-PCR to quantify the expression levels of miR-122 in serum samples drawn at thee follow-up visits (8.6, 5.2, and 2.6 years prior to the diagnosis of HCC). Conditional logistic regression was used for statistical analyses. Results: ∆Ct value of miR-122 was inversely correlated with HBV viral load at each of the three time-point survey. However, no apparent dynamic change across three measures of miR-122 was observed in either case or control group. When age, ALT level, and HBV genotype were adjusted for their potential confounding effects in multivariate analyses, down-regulation of miR-122 that occurred 5.2 years prior to the diagnosis of HCC was associated with a higher risk of HCC, showing an odds ratio of 2.54 (95%CI=1.16－5.57). Yet, we did not observe significant results from 8.6 years (adjusted-OR= 1.9, 95% CI=0.92－3.80) or 2.6 years (adjusted-OR= 1.17, 95% CI=0.56－2.46) prior to the diagnosis of HCC in the multivariable model. Conclusion: Down-regulation of circulating miR-122 expression was associated with higher HBV viral load and an increased risk of HCC, but the timing of the down-regulation might also be an important factor that determines subsequent HCC development.