The pattern of hMENA isoforms is regulated by TGF-β1 in pancreatic cancer and may predict patient outcome.
The pattern of hMENA isoforms is regulated by TGF-β1 in pancreatic cancer and may predict patient outcome.
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DOI：
10.1080/2162402x.2016.1221556
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发表时间：
2016
期刊：
影响因子：
7.2
通讯作者：
Nisticò P
中科院分区：
文献类型：
--
作者：
Melchionna R;Iapicca P;Di Modugno F;Trono P;Sperduti I;Fassan M;Cataldo I;Rusev BC;Lawlor RT;Diodoro MG;Milella M;Grazi GL;Bissell MJ;Scarpa A;Nisticò P
胰腺导管腺癌（PDAC）是一种侵袭性疾病，需要预后标志物来解决治疗选择。我们之前已经证明，肌动蛋白调节因子 hMENA 的选择性剪接会产生 hMENA11a 和 hMENAΔv6 亚型，在细胞侵袭中发挥相反的作用。我们使用抗泛 hMENA 和特异性抗 hMENA11a 抗体，通过免疫组织化学检查了 285 个 PDAC、15 个 PanIN、10 个胰腺炎和正常胰腺中 hMENA 亚型的表达模式。 Pan hMENA 免疫染色在正常胰腺和低级别 PanIN 中不存在，在 PanIN-3 中较弱，并且在几乎所有 PDAC 中具有较高水平，其中 64% 的病例显示强染色。相反，抗侵袭性 hMENA11a 亚型仅在 26% 的 PDAC 中显示出强染色。泛 hMENA 阳性肿瘤亚群 (34%) 中 hMENA11a 的缺失与不良预后显着相关。通过在 TGF-β1 处理的 PDAC 细胞系中进行功能丧失和获得实验来分析 hMENA 亚型的功能效应。 PDAC 细胞系中的 hMENA11a 敲除影响细胞间粘附，但不影响侵袭。 TGF-β1 与 β-catenin 信号传导协同上调 hMENA 和 hMENAΔv6 表达，但不上调 hMENA11a 在 hMENA11a 缺失的情况下，hMENA/hMENAΔv6 上调对于 SMAD2 介导的 TGF-β1 信号传导和 TGF-β1 诱导的 EMT 至关重要。由于 hMENA 亚型表达模式与患者结果相关，因此数据表明 hMENA 剪接和相关途径是胰腺肿瘤微环境中的新关键参与者，并且可能代表 PDAC 中新预后和治疗工具开发的有希望的目标。
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease in need of prognostic markers to address therapeutic choices. We have previously shown that alternative splicing of the actin regulator, hMENA, generates hMENA11a, and hMENAΔv6 isoforms with opposite roles in cell invasion. We examined the expression pattern of hMENA isoforms by immunohistochemistry, using anti-pan hMENA and specific anti-hMENA11a antibodies, in 285 PDACs, 15 PanINs, 10 pancreatitis, and normal pancreas. Pan hMENA immunostaining, absent in normal pancreas and low-grade PanINs, was weak in PanIN-3 and had higher levels in virtually all PDACs with 64% of cases showing strong staining. Conversely, the anti-invasive hMENA11a isoform only showed strong staining in 26% of PDAC. The absence of hMENA11a in a subset (34%) of pan-hMENA-positive tumors significantly correlated with poor outcome. The functional effects of hMENA isoforms were analyzed by loss and gain of function experiments in TGF-β1-treated PDAC cell lines. hMENA11a knock-down in PDAC cell lines affected cell–cell adhesion but not invasion. TGF-β1 cooperated with β-catenin signaling to upregulate hMENA and hMENAΔv6 expression but not hMENA11a In the absence of hMENA11a, the hMENA/hMENAΔv6 up-regulation is crucial for SMAD2-mediated TGF-β1 signaling and TGF-β1-induced EMT. Since the hMENA isoform expression pattern correlates with patient outcome, the data suggest that hMENA splicing and related pathways are novel key players in pancreatic tumor microenvironment and may represent promising targets for the development of new prognostic and therapeutic tools in PDAC.