Loss of Lkb1 provokes highly invasive endometrial adenocarcinomas
Loss of Lkb1 provokes highly invasive endometrial adenocarcinomas
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DOI：
10.1158/0008-5472.can-07-5014
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发表时间：
2008-02-01
期刊：
影响因子：
11.2
通讯作者：
Castrillon, Diego H.
中科院分区：
文献类型：
--
作者：
Contreras, Cristina M.;Gurumurthy, Sushma;Castrillon, Diego H.
LKB 1肿瘤抑制基因的突变导致Peutz-Jeghers综合征，这是一种常染色体显性疾病，其特征是胃肠道的错构瘤性息肉，并且在其他部位（包括女性生殖道）发生上皮恶性肿瘤的风险显著增加。在这里，我们表明，雌性小鼠杂合子为空Lkb 1等位基因自发发展高度浸润性子宫内膜腺癌。为了证明这些病变确实是由于Lkb 1失活，我们将腺病毒Cre载体引入到携带Lkb 1条件等位基因的小鼠子宫腔中。这种子宫特异性Lkb 1基因缺失引起高度侵袭性，有时转移性子宫内膜腺癌密切类似于Lkb 1杂合子中观察到的。肿瘤分化非常好，组织病理学特征明显，并表现出AMP依赖性激酶信号转导的改变。尽管Lkb 1与细胞极性的建立有关，并且极性的丧失定义了大多数子宫内膜癌，但Lkb 1驱动的子宫内膜癌矛盾地表现出（鉴于其高度侵袭性表型）正常的细胞极性和顶端分化。在人类子宫内膜癌中，Lkb 1表达与肿瘤分级和分期呈负相关，认为Lkb 1失活或下调也有助于女性子宫内膜癌的进展。这项研究表明，Lkb 1在子宫内膜的恶性转化中起着重要作用，Lkb 1的缺失促进了高度侵袭性表型。
Mutations in the LKB1 tumor suppressor gene result in the Peutz-Jeghers syndrome, an autosomal dominant condition characterized by hamartomatous polyps of the gastrointestinal tract and a dramatically increased risk of epithelial malignancies at other sites, including the female reproductive tract. Here we show that female mice heterozygous for a null Lkb1 allele spontaneously develop highly invasive endometrial adenocarcinomas. To prove that these lesions were indeed due to Lkb1 inactivation, we introduced an adenoviral Cre vector into the uterine lumen of mice harboring a conditional allele of Lkb1. This endometrial-specific deletion of the Lkb1 gene provoked highly invasive and sometimes metastatic endometrial adenocarcinomas closely resembling those observed in Lkb1 heterozygotes. Tumors were extremely well differentiated and histopathologically distinctive and exhibited alterations in AMP-dependent kinase signaling. Although Lkb1 has been implicated in the establishment of cell polarity, and loss of polarity defines most endometrial cancers, Lkb1-driven endometrial cancers paradoxically exhibit (given their highly invasive phenotype) normal cell polarity and apical differentiation. In human endometrial cancers, Lkb1 expression was inversely correlated with tumor grade and stage, arguing that Lkb1 inactivation or down-regulation also contributes to endometrial cancer progression in women. This study shows that Lkb1 plays an important role in the malignant transformation of endometrium and that Lkb1 loss promotes a highly invasive phenotype.