All-trans retinoic acid (ATRA) promotes the development and the function of insulin producing cells and induces partial differentiation of pancreatic tumor cells. A number of evidences clearly indicate that the ATRA mediated signaling may have a substantial role in therapeutic approaches based on restoration of functional β-cells. Among the proteins up-regulated by ATRA, Vav1 is involved in maturation and function of haematopoietic cells and is essential for retinoids induced differentiation of tumor promyelocytes. The presence of Vav1 in solid tissues, including pancreas, is considered ectopic and no role in the differentiation of human epithelial cells has so far been described. We demonstrated here that Vav1 sustains the maturation to β-cells of the normal precursors human Biliary Tree Stem/progenitor Cells (hBTSCs) induced by a differentiation medium containing ATRA and that, in the mature normal pancreas, insulin-producing cells express variable levels of Vav1. Using pancreatic ductal adenocarcinoma (PDAC)-derived cells, we also revealed that the ATRA induced up-modulation of Vav1 is essential for the retinoid-induced trans-differentiation of neoplastic cells into insulin producing cells. The results of this study identify Vav1 as crucial molecule in ATRA induced maturation of insulin producing cells and suggest this protein as a marker for new strategies ended to restore functional β-cells.

全反式视黄酸 (ATRA) 促进胰岛素产生细胞的发育和功能，并诱导胰腺肿瘤细胞的部分分化。许多证据清楚地表明，ATRA 介导的信号传导可能在基于功能性 β 细胞恢复的治疗方法中发挥重要作用。在由 ATRA 上调的蛋白质中，Vav1 参与造血细胞的成熟和功能，并且对于类视黄醇诱导的肿瘤早幼粒细胞分化至关重要。Vav1 在包括胰腺在内的实体组织中的存在被认为是异位的，迄今为止尚未描述在人类上皮细胞分化中的作用。我们在此证明，Vav1 维持由含有 ATRA 的分化培养基诱导的正常前体人胆管树干/祖细胞 (hBTSCs) 向 β 细胞的成熟，并且在成熟的正常胰腺中，产生胰岛素的细胞表达不同水平的Vav1。使用胰腺导管腺癌 (PDAC) 衍生细胞，我们还发现 ATRA 诱导的 Vav1 上调对于类视黄醇诱导的肿瘤细胞转分化为胰岛素产生细胞是必不可少的。这项研究的结果将 Vav1 确定为 ATRA 诱导的胰岛素产生细胞成熟中的关键分子，并建议该蛋白质作为新策略的标志物，以恢复功能性 β 细胞。使用胰腺导管腺癌 (PDAC) 衍生细胞，我们还发现 ATRA 诱导的 Vav1 上调对于类视黄醇诱导的肿瘤细胞转分化为胰岛素产生细胞是必不可少的。这项研究的结果将 Vav1 确定为 ATRA 诱导的胰岛素产生细胞成熟中的关键分子，并建议该蛋白质作为新策略的标志物，以恢复功能性 β 细胞。使用胰腺导管腺癌 (PDAC) 衍生细胞，我们还发现 ATRA 诱导的 Vav1 上调对于类视黄醇诱导的肿瘤细胞转分化为胰岛素产生细胞是必不可少的。这项研究的结果将 Vav1 确定为 ATRA 诱导的胰岛素产生细胞成熟中的关键分子，并建议该蛋白质作为新策略的标志物，以恢复功能性 β 细胞。