Boudhraa Zied, Rondepierre Fabien, Ouchchane Lemlih, Kintossou Roselyne, Trzeciakiewicz Anna, Franck Frederic, Kanitakis Jean, Labeille Bruno, Joubert-Zakeyh Juliette, Bouchon Bernadette, Perrot Jean Luc, Mansard Sandrine, Papon Janine, Dechelotte Pierre, Chezal Jean-Michel, Miot-Noirault Elisabeth, Bonnet Mathilde, D'Incan Michel, Degoul Françoise
Clermont-Ferrand Université, Université d'Auvergne, INSERM U990, Imagerie Moléculaire et Thérapie Vectorisée, BP 184, 63000, Clermont-Ferrand, France.
Clin Exp Metastasis. 2014 Oct;31(7):749-60. doi: 10.1007/s10585-014-9665-2. Epub 2014 Jul 6.
Metastatic melanoma is one of the most aggressive forms of skin cancer and has a poor prognosis. We have previously identified Annexin A1 (ANXA1) as a potential murine melanoma-spreading factor that may modulate cell invasion by binding to formyl peptide receptors (FPRs). Here, we report that (1) in a B16Bl6 spontaneous metastasis model, a siRNA-induced decrease in tumoral ANXA1 expression significantly reduced tumoral MMP2 activity and number of lung metastases; (2) in a retrospective study of 61 patients, metastasis-free survival was inversely related to ANXA1 expression levels in primary tumors (HR 3.15 [1.03-9.69], p = 0.045); (3) in human melanoma cell lines, ANXA1 level was positively correlated with in vitro invasion capacity whereas normal melanocytes contained low ANXA1 levels, and (4) the ANXA1 N-terminal peptide ANXA12-26 stimulated MMP2 activity after interaction with FPRs and significantly stimulated the in vitro invasion of melanomas by acting on FPRs. These findings identify ANXA1 as a proinvasive protein in melanoma that holds promise as a potential prognostic marker and therapeutic target.
转移性黑色素瘤是皮肤癌中侵袭性最强的类型之一，预后较差。我们之前已将膜联蛋白A1（ANXA1）鉴定为一种潜在的小鼠黑色素瘤扩散因子，它可能通过与甲酰肽受体（FPRs）结合来调节细胞侵袭。在此，我们报告：（1）在B16Bl6自发转移模型中，siRNA诱导的肿瘤ANXA1表达降低显著降低了肿瘤MMP2活性和肺转移灶数量；（2）在一项对61例患者的回顾性研究中，无转移生存期与原发性肿瘤中ANXA1表达水平呈负相关（风险比3.15 [1.03 - 9.69]，p = 0.045）；（3）在人黑色素瘤细胞系中，ANXA1水平与体外侵袭能力呈正相关，而正常黑素细胞中ANXA1水平较低，以及（4）ANXA1 N端肽ANXA12 - 26与FPRs相互作用后刺激MMP2活性，并通过作用于FPRs显著刺激黑色素瘤的体外侵袭。这些发现确定ANXA1为黑色素瘤中的一种促侵袭蛋白，有望作为潜在的预后标志物和治疗靶点。
