Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity
Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity
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DOI：
10.1073/pnas.1120421109
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发表时间：
2012-02-14
影响因子：
11.1
通讯作者：
Klefstrom, Juha
中科院分区：
文献类型：
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作者：
Partanen, Johanna I.;Tervonen, Topi A.;Klefstrom, Juha
虽然上皮完整性的丧失是晚期癌症的标志，但对破坏这种完整性的遗传改变是否因果地促进肿瘤发生仍知之甚少。我们发现，在乳腺癌的肿瘤抑制基因Lkb 1（Par-4）的条件性缺失损害上皮完整性表现为细胞极性标记的错误定位，偏侧的紧密连接，恶化的桥粒和基底膜（BM），和乳腺导管树的超支化。我们确定桥粒BM重塑丝氨酸蛋白酶Hepsin作为一个关键因素介导的Lkb 1损失诱导的乳腺上皮和BM碎片的结构改变。虽然Lkb 1单独缺失不会促进乳腺肿瘤发生，但Lkb 1缺陷与致癌性c-Myc的结合导致肿瘤形成的急剧加速。结果耦合Lkb 1损失介导的上皮完整性缺陷的丝氨酸蛋白酶Hepsin的错误定位和致癌协同c-Myc意味着Lkb 1损失促进致癌增殖释放上皮细胞从结构BM边界。
Although loss of epithelial integrity is a hallmark of advanced cancer, it remains poorly understood whether genetic alterations corrupting this integrity causally facilitate tumorigenesis. We show that conditional deletion of tumor suppressor gene Lkb1 (Par-4) in the mammary gland compromises epithelial integrity manifested by mislocalization of cell polarity markers, lateralization of tight junctions, deterioration of desmosomes and basement membrane (BM), and hyper-branching of the mammary ductal tree. We identify the desmosomal BM remodelling serine protease Hepsin as a key factor mediating Lkb1 loss-induced structural alterations in mammary epithelium and BM fragmentation. Although loss of Lkb1 alone does not promote mammary tumorigenesis, combination of Lkb1 deficiency with oncogenic c-Myc leads to dramatic acceleration in tumor formation. The results coupling Lkb1 loss-mediated epithelial integrity defects to mislocalization of serine protease Hepsin and to oncogenic synergy with c-Myc imply that Lkb1 loss facilitates oncogenic proliferation by releasing epithelial cells from structural BM boundaries.