ANXA3/JNK Signaling Promotes Self-Renewal and Tumor Growth, and Its Blockade Provides a Therapeutic Target for Hepatocellular Carcinoma.
ANXA3/JNK Signaling Promotes Self-Renewal and Tumor Growth, and Its Blockade Provides a Therapeutic Target for Hepatocellular Carcinoma.
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ANXA3/JNK 信号传导促进自我更新和肿瘤生长，其阻断为肝细胞癌提供了治疗靶点。
DOI：
10.1016/j.stemcr.2015.05.013
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发表时间：
2015-07-14
影响因子：
5.9
通讯作者：
Ma S
中科院分区：
文献类型：
--
作者：
Tong M;Fung TM;Luk ST;Ng KY;Lee TK;Lin CH;Yam JW;Chan KW;Ng F;Zheng BJ;Yuan YF;Xie D;Lo CM;Man K;Guan XY;Ma S
肝细胞癌（HCC）中频繁的肿瘤复发通常归因于常规治疗后残留的癌症干细胞（CSC）的存在。我们先前已经鉴定和表征了CD133，以标记HCC中特定的CSC亚群。在本研究中，我们发现内源性和分泌性膜联蛋白A3（ANXA 3）通过JNK通路失调在促进CD133+肝CSC中的癌症和干细胞样特征中发挥关键作用。在体外以及在人HCC异种移植模型中用抗ANXA 3单克隆抗体阻断ANXA 3导致肿瘤生长和自我更新显著减少。临床上，ANXA 3在HCC患者血清中的表达与侵袭性临床特征密切相关。我们的研究结果表明，ANXA 3可以作为一种新的诊断生物标志物，抑制ANXA 3可能是治疗CD 133+肝CSC驱动的HCC的可行治疗选择。ANXA 3增强CD133+肝CSC中的癌症和干细胞样性质ANXA 3通过小窝介导的内吞作用内化并激活JNK途径开发了一种新型中和抗ANXA 3抗体ANXA 3是用于HCC诊断的新型生物标志物Ma和同事报道了增强的内源性和分泌性ANXA 3在维持CD133+肝CSC中的癌症干细胞样性质中的作用。ANXA 3通过小窝依赖性内吞作用内化并激活JNK通路。用ANXA 3单克隆抗体治疗HCC导致肿瘤生长、自我更新和肝脏CSC比例降低。
Frequent tumor relapse in hepatocellular carcinoma (HCC) has been commonly attributed to the presence of residual cancer stem cells (CSCs) after conventional treatments. We have previously identified and characterized CD133 to mark a specific CSC subset in HCC. In the present study, we found endogenous and secretory annexin A3 (ANXA3) to play pivotal roles in promoting cancer and stem cell-like features in CD133+ liver CSCs through a dysregulated JNK pathway. Blockade of ANXA3 with an anti-ANXA3 monoclonal antibody in vitro as well as in human HCC xenograft models resulted in a significant reduction in tumor growth and self-renewal. Clinically, ANXA3 expression in HCC patient sera closely associated with aggressive clinical features. Our results suggest that ANXA3 can serve as a novel diagnostic biomarker and that the inhibition of ANXA3 may be a viable therapeutic option for the treatment of CD133+ liver-CSC-driven HCC. ANXA3 potentiates cancer and stem cell-like properties in CD133+ liver CSCs ANXA3 is internalized via caveolae-mediated endocytosis and activates the JNK pathway A novel neutralizing anti-ANXA3 antibody is developed ANXA3 is a novel biomarker for HCC diagnosis Ma and colleagues report the role of enhanced endogenous and secretory ANXA3 in the maintenance of cancer stem cell-like properties in CD133+ liver CSCs. ANXA3 is internalized via a caveolae-dependent endocytosis and activates the JNK pathway. Treatment of HCC with ANXA3 monoclonal antibody resulted in decreased tumor growth, self-renewal, and liver CSC proportions.