33-kDa 膜联蛋白 A3 同工型促进肝癌发生，调控 ERK、PI3K/Akt-HIF 和内在凋亡途径。
33-kDa ANXA3 isoform contributes to hepatocarcinogenesis modulating ERK, PI3K/Akt-HIF and intrinsic apoptosis pathways.
机构信息
Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
Department of Biochemistry, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
出版信息
J Adv Res. 2020 Nov 8;30:85-102. doi: 10.1016/j.jare.2020.11.003. eCollection 2021 May.
INTRODUCTION
As a member of annexin family proteins, annexin A3 (ANXA3) has 36-kDa and 33-kDa isoforms. ANXA3 plays crucial roles in the tumorigenesis, aggressiveness and drug-resistance of cancers. However, previous studies mainly focused on the role of total ANXA3 in cancers without distinguishing the distinction between the two isoforms, the role of 33-kDa ANXA3 in cancer remains unclear.
OBJECTIVES
Current work aimed to investigate the function and regulation mechanism of 33-kDa ANXA3 in hepatocarcinoma.
METHODS
The expressions of ANXA3, CRKL, Rac1, c-Myc and pAkt were analyzed in hepatocarcinoma specimens by Western blotting. The biological function of 33-kDa ANXA3 in the growth, metastasis, apoptosis, angiogenesis, chemoresistance of hepatocarcinoma cells with the underlying molecular mechanism were investigated using gain-of-function strategy or .
RESULTS
33-kDa ANXA3 was remarkably upregulated in tumor tissues compared with corresponding normal liver tissues of hepatocarcinoma patients. Its stable knockdown decreased the tumor growing velocity and malignancy of hepatocarcinoma HepG2 cells transplanted in nude mice. The experimental results indicated 33-kDa ANXA3 knockdown suppressed the proliferation, colony forming, migration and invasion abilities of HepG2 cells through downregulating CRKL, Rap1b, Rac1, pMEK, pERK2 and c-Myc in ERK pathway; inhibited angiogenesisability of HepG2 cells through inactivating PI3K/Akt-HIF pathway; induced apoptosis and enhanced chemoresistance of HepG2 cells through increasing Bax/decreasing Bcl-2 expressions and inactivating caspase 9/caspase 3 in intrinsic apoptosis pathway. Accordingly, CRKL, Rac1, c-Myc and pAkt were also upregulated in hepatocarcinoma patients ' tumor tissues compared with corresponding normal liver tissues.
CONCLUSIONS
The overexpression of 33-kDa ANXA3 is involved in the clinical progression of hepatocarcinoma and in the malignancy, angiogenesis and apoptosis of hepatocarcinoma cells. It is of potential use in hepatocarcinoma diagnosis and treatment.
简介
作为膜联蛋白家族蛋白的一员，膜联蛋白 A3（ANXA3）有 36kDa 和 33kDa 两种同工型。ANXA3 在肿瘤的发生、侵袭和耐药中发挥着关键作用。然而，之前的研究主要集中在总 ANXA3 在癌症中的作用，而没有区分两种同工型，33kDa ANXA3 在癌症中的作用仍不清楚。
目的
目前的工作旨在研究 33kDa ANXA3 在肝癌中的功能和调控机制。
方法
通过 Western blot 分析肝癌标本中 ANXA3、CRKL、Rac1、c-Myc 和 pAkt 的表达。采用功能获得策略或 研究 33kDa ANXA3 在肝癌细胞生长、转移、凋亡、血管生成、化疗耐药中的作用及其潜在的分子机制。
结果
与肝癌患者相应的正常肝组织相比，肿瘤组织中 33kDa ANXA3 明显上调。其稳定敲低可降低肝癌 HepG2 细胞裸鼠移植瘤的生长速度和恶性程度。实验结果表明，33kDa ANXA3 敲低通过下调 ERK 通路中的 CRKL、Rap1b、Rac1、pMEK、pERK2 和 c-Myc，抑制 HepG2 细胞的增殖、集落形成、迁移和侵袭能力；通过抑制 PI3K/Akt-HIF 通路抑制 HepG2 细胞的血管生成能力；通过增加 Bax/减少 Bcl-2 的表达和失活内在凋亡通路中的 caspase 9/caspase 3，诱导 HepG2 细胞凋亡，增强其化疗耐药性。相应地，CRKL、Rac1、c-Myc 和 pAkt 在肝癌患者肿瘤组织中的表达也高于相应的正常肝组织。
结论
33kDa ANXA3 的过表达参与了肝癌的临床进展以及肝癌细胞的恶性、血管生成和凋亡。它在肝癌的诊断和治疗中有潜在的应用价值。
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