Hedgehog Signaling, a Critical Pathway Governing the Development and Progression of Hepatocellular Carcinoma.
Hedgehog Signaling, a Critical Pathway Governing the Development and Progression of Hepatocellular Carcinoma.
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Hedgehog信号传导，控制肝细胞癌发生和进展的关键途径
作者：
Ding J;Li HY;Zhang L;Zhou Y;Wu J
Hedgehog（Hh）信号是调控胚胎发育和组织修复的经典形态因子。Hh信号传导的异常激活在肝癌中已经被充分记录，包括肝母细胞瘤、肝细胞癌（HCC）和胆管癌。本文就Hh信号分子在肝癌发生、发展、耐药及转移中的作用作一综述。本文综述了Hh信号在HCC治疗中的分子相互作用和临床意义。在慢性肝损伤中，如非酒精性脂肪性肝炎，Hh信号分子参与癌前病变向恶性特征的转化。GLI靶基因（如ABCC 1和TAP 1）的激活导致肝癌细胞的耐药性，具有CD 133 −/EpCAM−表面分子特征，GLI 1和截短的GLI 1导致肝癌细胞的转移特征，并上调基质金属蛋白酶。组织标本中Sonic Hh配体的一种新的生物测定法可能有助于甲胎蛋白阴性的HCC诊断，并预测早期微血管浸润。对Hh信号通路的深入研究加深了我们对其在HCC发生、药物敏感性和转移中的分子调控的理解，并指导HCC个体化的精确管理。
Hedgehog (Hh) signaling is a classic morphogen in controlling embryonic development and tissue repairing. Aberrant activation of Hh signaling has been well documented in liver cancer, including hepatoblastoma, hepatocellular carcinoma (HCC) and cholangiocarcinoma. The present review aims to update the current understanding on how abnormal Hh signaling molecules modulate initiation, progression, drug resistance and metastasis of HCC. The latest relevant literature was reviewed with our recent findings to provide an overview regarding the molecular interplay and clinical relevance of the Hh signaling in HCC management. Hh signaling molecules are involved in the transformation of pre-carcinogenic lesions to malignant features in chronic liver injury, such as nonalcoholic steatohepatitis. Activation of GLI target genes, such as ABCC1 and TAP1, is responsible for drug resistance in hepatoma cells, with a CD133−/EpCAM− surface molecular profile, and GLI1 and truncated GLI1 account for the metastatic feature of the hepatoma cells, with upregulation of matrix metalloproteinases. A novel bioassay for the Sonic Hh ligand in tissue specimens may assist HCC diagnosis with negative α-fetoprotein and predict early microvascular invasion. In-depth exploration of the Hh signaling deepens our understanding of its molecular modulation in HCC initiation, drug sensitivity and metastasis, and guides precise management of HCC on an individual basis.
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