YKL-40在肝细胞癌肺转移中的作用及机制研究

Primary hepatocellular carcinoma (HCC) is a disease with high mortality, which is characterized with the inclination to recurrence and metastasis. Lung metastasis is the most frequent distant invasion progression. The primary tumor has been supposed to be able to educate the secondary sites by promoting the formation of supportive metastatic environment, termed the pre-metastatic niche. Chitinase-3-like-1 is a secreted protein that is upregulated in various types of lung chronic inflammation diseases, such as bronchial asthma, correlated with the severity of these diseases. Moreover, a number of studies have demonstrated strong correlations between YKL-40 expression and the development of primary and metastatic tumors, as well as chronic inflammatory liver diseases. Therefore, we focused on the role of YKL-40 on lung metastasis of primary hepatocellular carcinoma and its mechanism. In our preliminary study, we have detected significantly higher level of serum YKL-40 in liver cancer patients with lung metastasis. Also, HCC cell line could promote the secretion of YKL-40 in lung epithelial cells in a manner dependent on the invasiveness of tumor cells. Based on the above evidence, this project aims to elucidate the mechanism underlying the secretion of YKL-40 by lung epithelial cells and its role in lung metastasis of HCC. Moreover, this project would also explore the possibility of YKL-40 as a serum biomarker to predict lung metastasis of HCC, which might be of potential value in personalized medicine.

原发性肝细胞癌具有易复发转移的特点，病死率居高不下。肺转移为肝癌远处侵袭转移最常见的类型，最新研究发现肝癌细胞可与肺源性细胞相互作用，促进转移前微环境的形成，利于肿瘤细胞的定植。几丁质酶-3样蛋白-1（YKL-40）是肺部慢性炎症微环境中重要的细胞因子，在哮喘等多种肺部疾病中显著上调，且与多种肿瘤及慢性肝炎患者预后呈负相关。本课题组长期从事肝癌复发转移机制研究，前期预实验发现肝细胞癌肺转移患者血清中YKL-40水平特异性升高；细胞模型发现肝癌细胞可诱导肺上皮细胞分泌YKL-40，分泌水平与肝癌细胞的侵袭性相关。因此，我们提出YKL-40可能介导肝癌细胞肺转移的科学假设。本课题拟评估YKL-40作为肝细胞癌肺转移血清学标志物的潜在价值，并探讨肺源性细胞分泌YKL-40诱导肝癌肺转移的机制。本课题研究为阐释肝癌肺转移的机制提供理论基础，为研发新的干预策略提供新思路。

原发性肝细胞癌具有易复发转移的特点，病死率居高不下。肝癌远处侵袭转移是影响患者预后的重要原因，肺转移为其中最常见的类型。肝癌细胞可与肺源性细胞相互作用，促进转移前微环境的形成，利于肿瘤细胞的定植，然而其具体机制尚不明确。本研究筛选了肝癌患者血清中转移相关细胞因子，发现伴肺转移的肝癌患者与无转移肝癌患者相比血清中YKL-40的水平显著升高；在肝癌肺转移的小鼠模型中，与对照小鼠相比，肺转移小鼠血清YKL-40的水平更高，且肺组织中YKL-40表达显著上调，可能为血清中升高的YKL-40的来源。体内外研究发现YKL-40可以增强肝癌细胞的侵袭转移，促进血管新生，进而利于肝癌肺转移灶的形成。进一步的机制探讨发现高转移肝癌细胞可以显著促进肺上皮细胞表达及分泌YKL-40。高转移性肝癌细胞通过外泌体作为载体，促进肺上皮细胞p-Stat3通路激活进而上调YKL-40的表达。接下来，通过对不同转移能力的肝癌细胞外泌体的RNA芯片检测分析发现高转移肝癌细胞外泌体中PTK6表达水平上调；肝癌细胞敲减PTK6或者利用PTK6抑制剂阻断其功能均可抑制p-Stat3通路激活，有效的减少肺上皮细胞YKL-40的表达及分泌，抑制肝癌肺转移灶的形成。在治疗干预上，本研究发现用于治疗多发性骨髓瘤的药物硼替佐米（Bortezomib）可以下调肺上皮细胞YKL-40的表达及分泌，体内实验中应用硼替佐米可以有效的抑制肝癌肺转移的发生。综上所述，以上研究针对YKL-40在肝细胞癌肺转移中的作用及机制研究展开，表明YKL-40可能为肝癌肺转移的关键驱动因子之一，或可成为肝癌肺转移的血清学诊断标志物，为肝癌肺转移的精准治疗提供了新的分子靶标和治疗策略。