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首页> 外文期刊>Molecular and Cellular Biology >Pancreatic Lkb1 Deletion Leads to Acinar Polarity Defects and Cystic Neoplasms
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Pancreatic Lkb1 Deletion Leads to Acinar Polarity Defects and Cystic Neoplasms

机译：胰腺Lkb1删除导致腺泡极性缺陷和囊性肿瘤。

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LKB1 is a key regulator of energy homeostasis through the activation of AMP-activated protein kinase (AMPK) and is functionally linked to vascular development, cell polarity, and tumor suppression. In humans, germ line LKB1 loss-of-function mutations cause Peutz-Jeghers syndrome (PJS), which is characterized by a predisposition to gastrointestinal neoplasms marked by a high risk of pancreatic cancer. To explore the developmental and physiological functions of Lkb1 in vivo, we examined the impact of conditional Lkb1 deletion in the pancreatic epithelium of the mouse. The Lkb1-deficient pancreas, although grossly normal at birth, demonstrates a defective acinar cell polarity, an abnormal cytoskeletal organization, a loss of tight junctions, and an inactivation of the AMPK/MARK/SAD family kinases. Rapid and progressive postnatal acinar cell degeneration and acinar-to-ductal metaplasia occur, culminating in marked pancreatic insufficiency and the development of pancreatic serous cystadenomas, a tumor type associated with PJS. Lkb1 deficiency also impacts the pancreas endocrine compartment, characterized by smaller and scattered islets and transient alterations in glucose control. These genetic studies provide in vivo evidence of a key role for LKB1 in the establishment of epithelial cell polarity that is vital for pancreatic acinar cell function and viability and for the suppression of neoplasia.
机译：LKB1是通过激活AMP激活的蛋白激酶（AMPK）来调节能量稳态的关键调节剂，在功能上与血管发育，细胞极性和肿瘤抑制有关。在人类中，生殖细胞系LKB1功能丧失突变会导致Peutz-Jeghers综合征（PJS），其特征是易患胃肠道肿瘤，其特征是胰腺癌的高风险。为了探索体内Lkb1的发育和生理功能，我们检查了小鼠胰腺上皮中条件性Lkb1缺失的影响。缺乏Lkb1的胰腺虽然在出生时就大体正常，但显示出有缺陷的腺泡细胞极性，异常的细胞骨架组织，紧密连接的丧失以及AMPK / MARK / SAD家族激酶的失活。出生后迅速发生腺泡细胞变性和腺泡到导管的化生，最终导致明显的胰腺机能不全和胰腺浆液性囊腺瘤的发展，这是一种与PJS相关的肿瘤类型。 Lkb1缺乏症也影响胰腺内分泌区室，其特征是胰岛较小且分散，并且葡萄糖控制的短暂改变。这些遗传学研究提供了LKB1在建立上皮细胞极性中的关键作用的体内证据，而上皮细胞极性对于胰腺腺泡细胞的功能和生存力以及对瘤形成的抑制至关重要。

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