Department of Biotechnology, Dalian Medical University, 9 West Section, Lvshun Southern Road, Dalian, 116044, China.
Department of Biochemistry and Molecular Biology, Dalian Medical University, 9 West Section, Lvshun Southern Road, Dalian, 116044, China.
Cell Death Dis. 2018 May 25;9(6):637. doi: 10.1038/s41419-018-0685-8.
As a calcium-dependent phospholipid binding annexin protein, annexin A5 (Anxa5) links to the progression, metastasis, survival, and prognosis of a variety of cancers. Current work showed ANXA5 overexpression was positively correlated with the upregulations of CRKI/II and RAC1 in hepatocarcinoma (HCC) patients' tissues, which potentially enhanced the clinical progression and lymphatic metastasis of HCC. The role and action mechanism of ANXA5 in hepatocarcinoma was then investigated using a hepatocarcinoma Hca-P cell line, an ideal and well-established murine cell model with 100% inducible tumorigenicity of implanted mice with low (~25%) lymph node metastatic (LNM) rate. In vitro evidences indicated ANXA5 stable knockdown resulted in decreased proliferation, migration, invasion and adhesion to lymph node (LN), and increased intercellular cohesion behaviors of hepatocarcinoma Hca-P cells. Consistently, stable ANXA5 knockdown led to reduced in vivo tumorigenicity and malignancy, LNM rate and level potentials of Hca-P- transplanted mice via inhibiting CD34 and VEGF3. The levels of CRKI/II and RAC1 were reduced in tumor tissues from mice transplanted with Hca-P cells with stable ANXA5 knockdown. Molecular action investigation further showed ANXA5 downregulation apparently suppressed the expressions of molecules CRKI/II, DOCK180, RAC1 in integrin pathway, p-MEK, p-ERK, c-Myc, and MMP-9 in MEK- ERK pathway together with VIMINTIN in Hca-P cells in appropriate to knockdown extent. Collectively, Anxa5 was able to mediate HCC carcinogenesis via integrin and MEK-ERK pathways. It is of potential use in the research and treatment of HCC.
作为一种钙依赖性磷脂结合膜联蛋白蛋白，膜联蛋白 A5（Anxa5）与多种癌症的进展、转移、存活和预后有关。目前的研究表明，肝癌（HCC）患者组织中 ANXA5 的过表达与 CRKI/II 和 RAC1 的上调呈正相关，这可能增强了 HCC 的临床进展和淋巴转移。然后，使用肝癌 Hca-P 细胞系研究了 ANXA5 在肝癌中的作用和作用机制，该细胞系是一种理想且成熟的小鼠细胞模型，植入小鼠的肿瘤发生率为 100%（诱导性），淋巴结转移（LNM）率低（~25%）。体外证据表明，ANXA5 的稳定敲低导致肝癌 Hca-P 细胞的增殖、迁移、侵袭和对淋巴结（LN）的黏附减少，细胞间黏附力增强。一致地，稳定的 ANXA5 敲低通过抑制 CD34 和 VEGF3 导致移植 Hca-P 细胞的小鼠体内肿瘤发生和恶性程度降低、LNM 率和水平降低。肿瘤组织中 CRKI/II 和 RAC1 的水平在稳定敲低 ANXA5 的 Hca-P 细胞移植小鼠中降低。进一步的分子作用研究表明，在适当的敲低程度下，ANXA5 下调明显抑制了整合素途径中分子 CRKI/II、DOCK180、RAC1 的表达，以及 MEK-ERK 途径中的 p-MEK、p-ERK、c-Myc 和 MMP-9 以及 Hca-P 细胞中的 VIMINTIN。总之，Anxa5 能够通过整合素和 MEK-ERK 途径介导肝癌的发生。它在肝癌的研究和治疗中具有潜在的应用价值。
