中文摘要

在現今醫療高度發展的社會下,經由免疫療法和酪氨酸激酶抑製劑藥物的治療已經顯著提高了癌症的存活率。然而這些藥物對心血管系統的毒性尚不清楚,因此在癌症治療後監測心臟功能至關重要。肝癌在台灣與全球是最常見的癌症之一，最近研究發現肝癌患者在經由酪氨酸激酶抑製劑治療後心臟功能會受到不同程度的損傷。五聯蛋白 3是長五聯蛋白家族的成員，具有保守的C 端五聯蛋白結構域，類似於典型的短型五聯蛋白，如C 反應蛋白。五聯蛋白 3是由 CCAAT/增強子結合蛋白直接調控的基因。先前研究發現肝癌的患者血液中的五聯蛋白 3濃度明顯高於健康人。先前的動物模型中也可發現抑制五聯蛋白 3可以修復心肌肥厚與左心室功能障礙。因此我們的目的是將五聯蛋白 3抗體作為一種新藥用來改善酪氨酸激酶抑製劑治療肝癌後所造成心臟功能受損。我們本次題目使用幹細胞分化成的心肌細胞來找出索拉非尼引起的心臟損傷的分子機制,並藉由酪氨酸激酶抑製劑抑制劑來修復索拉非尼造成的心臟損傷。
我們首先使用酵素連結免疫吸附分析法分析了肝癌病患血液中的五聯蛋白 3濃度, 並用心臟超音波或心電圖確定了酪氨酸激酶抑製劑治療後肝癌患者的心臟功能。接著我們使用30天到40天的幹細胞分化的心肌細胞來進行實驗。在本次研究中我們發現酪氨酸激酶抑製劑 治療的 肝癌患者血液中的五聯蛋白 3表現量顯著高於未接受 酪氨酸激酶抑製劑治療的肝癌患者,並且發現在酪氨酸激酶抑製劑治療後有38%的男性與33%的女性有發生QT間期延長的情況發生。我們進一步找出 CD44 是心肌細胞中五聯蛋白 3的受體。索拉非尼治療會使心肌細胞的細胞骨架重構、收縮減少、鈉電流抑制以及線粒體呼吸功能障礙。索拉非尼造成心臟毒性的機制受ERK-JNK信號通路調控，索拉非尼降低ERK1/2，增加細胞凋亡下游蛋白表達。藉由抑制五聯蛋白 3可以改善細胞凋亡相關的蛋白表達、細胞骨架斷裂、心肌細胞收縮功能異常和線粒體呼吸功能障礙。整體來說五聯蛋白 3抑制劑治療可修復索拉非尼引起的心臟功能受損。

關鍵字: 心肌細胞、肝癌、酪氨酸激酶抑製劑、、索拉非尼、五聯蛋白 3、QT間期、粒線體呼吸功能、鈉電流、細胞凋亡、細胞骨架、收縮功能

Nowadays, treatment of cancer, including immunotherapy and tyrosine kinase inhibitor (TKI) drugs, has significantly improved the survival rate of cancer. However, their toxicity to the cardiovascular system is unclear. Therefore, it is essential to monitor the heart function after cancer treatment. Hepatocellular carcinoma (HCC) is currently one of the most common cancers in Taiwan and the world. Recent studies have found that after TKI treatment, the heart function of patients with HCC suffered from varying degrees of damage. Pentraxin 3 (PTX3) is one member of the long pentraxin family with a conserved C-terminal pentraxin domain, similar to typical short pentraxins, such as C-reactive protein (CRP), and the structure of PTX3 is similar to CRP. PTX3 is a gene directly regulated by CCAAT/enhancer binding protein delta (CEBPD). Previous studies have shown that the plasma concentration of PTX3 in patients with HCC was significantly higher than healthy people. In animal models, it was also found that inhibiting PTX3 could repair myocardial hypertrophy and left ventricular dysfunction. Therefore, we purposed that PTX3 inhibitor could be used as a new drug to improve the heart dysfunction of HCC patients after TKI treatment. We thus used stem cell-derived cardiomyocytes to find out the molecular mechanism of heart damages caused by sorafenib treatment, which were restored of PTX3 inhibitor.
We first used ELISA to analyze the concentration of PTX3 in the plasma of HCC patients, and used cardiac echo or electrocardiogram to determine the cardiac function of HCC patients after TKI treatment. Then we used stem cells to derive them into cardiomyocytes and used 30-40 days of derived cardiomyocytes for experiments. In this study, we found that the expression of PTX3 plasma levels patients with TKI treatment was significantly higher than the HCC patients without TKI treatment. We also found that QTc prolongation appeared in 38% of male and 33% of female patients after TKI treatment. We further defined that CD44 could be a PTX3 receptor in cardiomyocytes. The treatment of sorafenib caused the cytoskeleton remodeling, decreasing in contraction, inhibition of sodium current, as well as the mitochondria respiration dysfunction in cardiomyocytes. The mechanism of sorafenib-induced cardiotoxicity was regulated by ERK-JNK signaling pathway. Sorafenib decreased ERK1/2 and increased apoptosis downstream signaling pathway. Treatment with PTX3 inhibitor could repair the cardiac dysfunction caused by sorafenib.

Key Words: cardiomyocyte, hepatocellular carcinoma, tyrosine kinase inhibitor, sorafenib, pentraxin 3, QTc prolongation, mitochondria respiration, sodium current, apoptosis, cytoskeleton, contractile function

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