The mechanisms of preneoplastic nodule formation in the liver by loss of LKB1

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We previously reported that Lkb1+/-mice spontaneously developed multiple hepatic nodular foci (NdFc) followed by HCCs. LKB1, a tumor suppressor gene mutated in the Peutz-Jeghers syndrome, encodes a serine/threonine protein kinase. To investigate the mechanisms of NdFc and HCC formation in Lkb1+/-mice, we compared the gene expression levels between the normal liver and HCC lesions of Lkb1+/- mice. We identified 50 up-regulated and 50 down-regulated genes in HCC (more than 2-fold versus wild type). These lists included inflammatory response genes, cell cycle regulatory genes, transcriptional factors, and lipid metabolism regulatory genes. We further showed that the conditional activation of -catenin accelerated HCC development in the Catnb+/lox(ex3)Lkb1+/-compound mutant mice, affecting displastic hepatocytes in NdFc that suffered loss of heterozygosity (LOH) at the Lkb1 locus. These results indicate that the loss of Lkb1 is responsible for the formation of dyspastic NdFc, and that the W … More nt signaling activation is involved in the following progression toward HCC. A combination of these sequential changes should be a practical model for a subset of human HCCs. Recent biochemical studies have shown that LKB1 activates 14 AMP-activated protein kinase (AMPK)-related kinases including AMPK and MARKs (microtubule-associated protein/microtubule affinity-regulating kinases). To determine whether LKB1 regulated the activation of these kinases in cells, we established Lkb1-/-mouse embryonic fibroblasts (MEFs) and LKB1-knockdown cell lines. AMPK was still activated in these cells under the energy stress. LKB1 phosphorylated and activated MARK2, which in turn phosphorylated microtubule-associated protein Tau at the KXGS motif and suppressed tubulin polymerization in vitro. In cells, forced expression of LKB1 suppressed microtubule regrowth, whereas LKB1 knockdown accelerated it. These results indicate that LKB1 is involved in the regulation of microtubule dynamics through the activation of MARKS. Less