Bist Pradeep, Phua Qian Hui, Shu Shinla, Yi Yuan, Anbalagan Durkeshwari, Lee Lay Hoon, Sethi Gautam, Low Boon Chuan, Lim Lina H K
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore; NUS Immunology Program, Life Sciences Institute, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore.
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore.
Biochem Biophys Res Commun. 2015 May 22;461(1):47-53. doi: 10.1016/j.bbrc.2015.03.166. Epub 2015 Apr 9.
Wound healing is critical for normal development and pathological processes including cancer cell metastasis. MAPK, Rho-GTPases and NFκB are important regulators of wound healing, but mechanisms for their integration are incompletely understood. Annexin-A1 (ANXA1) is upregulated in invasive breast cancer cells resulting in constitutive activation of NFκB. We show here that silencing ANXA1 increases the formation of stress fibers and focal adhesions, which may inhibit wound healing. ANXA1 regulated wound healing is dependent on the activation of ERK1/2. ANXA1 increases the activation of RhoA, which is dependent on ERK activation. Furthermore, active RhoA is important in NF-κB activation, where constitutively active RhoA potentiates NFκB activation, while dominant negative RhoA inhibits NFκB activation in response to CXCL12 stimulation and active MEKK plasmids. These findings establish a central role for ANXA1 in the cell migration through the activation of NFκB, ERK1/2 and RhoA.
伤口愈合对于包括癌细胞转移在内的正常发育和病理过程至关重要。丝裂原活化蛋白激酶（MAPK）、Rho鸟苷三磷酸酶（Rho-GTPases）和核因子κB（NFκB）是伤口愈合的重要调节因子，但其整合机制尚未完全明确。膜联蛋白A1（ANXA1）在侵袭性乳腺癌细胞中上调，导致NFκB的组成性激活。我们在此表明，沉默ANXA1会增加应力纤维和粘着斑的形成，这可能会抑制伤口愈合。ANXA1调节的伤口愈合依赖于细胞外信号调节激酶1/2（ERK1/2）的激活。ANXA1增加RhoA的激活，这依赖于ERK的激活。此外，活性RhoA在NF-κB激活中很重要，其中组成性活性RhoA增强NFκB激活，而显性负性RhoA抑制对趋化因子配体12（CXCL12）刺激和活性丝裂原活化蛋白激酶激酶（MEKK）质粒的NFκB激活。这些发现确立了ANXA1在通过激活NFκB、ERK1/2和RhoA进行细胞迁移中的核心作用。
