Fahmy Karim, Gonzalez Arnaud, Arafa Mohammad, Peixoto Paul, Bellahcène Akeila, Turtoi Andrei, Delvenne Philippe, Thiry Marc, Castronovo Vincent, Peulen Olivier
Metastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, Belgium.
Department of Pathology, Faculty of Medicine, University of Mansoura, Mansoura, Egypt.
Int J Cancer. 2016 Feb 1;138(3):652-63. doi: 10.1002/ijc.29820. Epub 2015 Sep 8.
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.
胰腺导管腺癌是最致命的癌症形式之一，迄今为止尚无令人满意的治疗方法。最近的研究在人类胰腺腺癌中发现了ferlin家族成员肌铁蛋白，其表达与不良预后相关。然而，肌铁蛋白在胰腺腺癌中的功能尚未见报道。在其他细胞类型中，肌铁蛋白参与了几个关键的质膜过程，如融合、修复、内吞作用和酪氨酸激酶受体活性。在本研究中，我们发现沉默BxPC-3人胰腺癌细胞中的肌铁蛋白会导致体外细胞增殖受到抑制，并且在鸡胚绒毛尿囊膜试验中肿瘤体积显著减小。除了体积更小之外，由肌铁蛋白沉默细胞形成的肿瘤还明显缺乏功能性血管。我们进一步证明，这种效应至少部分是由于BxPC-3肌铁蛋白沉默细胞中VEGFA分泌受到抑制。通过免疫荧光和电子显微镜，我们将VEGFA分泌减少与VEGFA胞吐作用受损联系起来。通过测定血管密度评估的一系列人类胰腺恶性病变中的肌铁蛋白表达与其血管生成状态之间的显著相关性，进一步加强了我们结果的临床相关性。
