Annexin A1 contributes to pancreatic cancer cell phenotype, behaviour and metastatic potential independently of Formyl Peptide Receptor pathway.
Annexin A1 contributes to pancreatic cancer cell phenotype, behaviour and metastatic potential independently of Formyl Peptide Receptor pathway.
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DOI：
10.1038/srep29660
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发表时间：
2016-07-14
影响因子：
4.6
通讯作者：
Petrella A
中科院分区：
文献类型：
--
作者：
Belvedere R;Bizzarro V;Forte G;Dal Piaz F;Parente L;Petrella A
膜联蛋白A1（Annexin A1，ANXA 1）是一种钙结合蛋白，在胰腺癌组织中高表达。我们最近报道，细胞外ANXA 1介导PC细胞运动作用于甲酰肽受体（FPRs）。在这里，我们描述了细胞内ANXA 1介导PC进展的其他机制。我们使用CRISPR/Cas9基因组编辑技术获得了ANXA 1敲除（KO）MIA PaCa-2细胞。LC-MS/MS分析表明，参与细胞骨架组织的几种蛋白质的表达发生了变化。结果，ANXA 1 KO MIA PaCa-2部分丧失了其迁移和侵袭能力，其机制似乎独立于FPR。已在体内进一步研究了侵袭性较低的表型的获得。将野生型（WT）、PGS（乱序）和ANXA 1 KO MIA PaCa-2细胞原位移植到SCID小鼠中。未发现PC原发质量的差异，相反，ANXA 1 KO MIA PaCa-2移植小鼠的肝转移似乎特别减少。总之，我们表明，细胞内ANXA 1是能够保持细胞骨架的完整性，并在体外维持恶性表型。该蛋白在体内转移过程中具有相关作用，因此它似乎有吸引力并且适合作为PC进展中的预后和治疗标志物。
Annexin A1 (ANXA1) is a Ca2+-binding protein over-expressed in pancreatic cancer (PC). We recently reported that extracellular ANXA1 mediates PC cell motility acting on Formyl Peptide Receptors (FPRs). Here, we describe other mechanisms by which intracellular ANXA1 could mediate PC progression. We obtained ANXA1 Knock-Out (KO) MIA PaCa-2 cells using the CRISPR/Cas9 genome editing technology. LC-MS/MS analysis showed altered expression of several proteins involved in cytoskeletal organization. As a result, ANXA1 KO MIA PaCa-2 partially lost their migratory and invasive capabilities with a mechanism that appeared independent of FPRs. The acquisition of a less aggressive phenotype has been further investigated in vivo. Wild type (WT), PGS (scrambled) and ANXA1 KO MIA PaCa-2 cells were engrafted orthotopically in SCID mice. No differences were found about PC primary mass, conversely liver metastatization appeared particularly reduced in ANXA1 KO MIA PaCa-2 engrafted mice. In summary, we show that intracellular ANXA1 is able to preserve the cytoskeleton integrity and to maintain a malignant phenotype in vitro. The protein has a relevant role in the metastatization process in vivo, as such it appears attractive and suitable as prognostic and therapeutic marker in PC progression.