Myoferlin plays a key role in VEGFA secretion and impacts tumor-associated angiogenesis in human pancreas cancer
Myoferlin plays a key role in VEGFA secretion and impacts tumor-associated angiogenesis in human pancreas cancer
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DOI：
10.1002/ijc.29820
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发表时间：
2016-02-01
影响因子：
6.4
通讯作者：
Peulen, Olivier
中科院分区：
文献类型：
--
作者：
Fahmy, Karim;Gonzalez, Arnaud;Peulen, Olivier
胰腺导管腺癌是最致命的癌症之一，目前尚无令人满意的治疗方法。最近的研究发现，myoferlin是Ferlin家族的成员，它在人胰腺癌中的表达与预后不良有关。然而，肌铁蛋白在胰腺癌中的作用尚未见报道。在其他类型的细胞中，Myoferlin参与了几个关键的质膜过程，如融合、修复、内吞和酪氨酸激酶受体活性。在这项研究中，我们发现在BxPC-3人胰腺癌细胞中沉默肌铁蛋白能抑制体外细胞的增殖，并在鸡绒毛膜尿囊膜实验中显著缩小肿瘤体积。除了更小之外，由肌铁蛋白沉默的细胞形成的肿瘤显示明显缺乏功能血管。我们进一步证明，这种作用至少部分归因于抑制BxPC-3肌铁蛋白沉默的细胞分泌VEGFA。利用免疫荧光和电子显微镜，我们将VEGFA分泌减少与VEGFA胞吐功能障碍联系起来。一系列胰腺恶性病变中Myoferlin的表达与血管生成状态之间的显著相关性进一步加强了我们的结果的临床相关性。
Pancreatic ductal adenocarcinoma is one of the most deadly forms of cancers with no satisfactory treatment to date. Recent studies have identified myoferlin, a ferlin family member, in human pancreas adenocarcinoma where its expression was associated to a bad prognosis. However, the function of myoferlin in pancreas adenocarcinoma has not been reported. In other cell types, myoferlin is involved in several key plasma membrane processes such as fusion, repair, endocytosis and tyrosine kinase receptor activity. In this study, we showed that myoferlin silencing in BxPC-3 human pancreatic cancer cells resulted in the inhibition of cell proliferation in vitro and in a significant reduction of the tumor volume in chick chorioallantoic membrane assay. In addition to be smaller, the tumors formed by the myoferlin-silenced cells showed a marked absence of functional blood vessels. We further demonstrated that this effect was due, at least in part, to an inhibition of VEGFA secretion by BxPC-3 myoferlin-silenced cells. Using immunofluorescence and electron microscopy, we linked the decreased VEGFA secretion to an impairment of VEGFA exocytosis. The clinical relevance of our results was further strengthened by a significant correlation between myoferlin expression in a series of human pancreatic malignant lesions and their angiogenic status evaluated by the determination of the blood vessel density.