2012/09/19

LKB1 drives Ras activation in bad prognosis hepatocellular carcinoma: A new axis in liver tumorigenesis.

Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancers and it is becoming a major health problem. HCC incidence is growing with more than 750.000 annual cases worldwide. Liver cirrhosis at a high risk of HCC development has abnormal S-Adenosylmethionine (SAMe) levels, the main methyl donor in liver. Catabolism of SAMe is mainly mediated by Glycine N-methyltransferase (GNMT), and mounting evidence assigns an essential role of GNMT in HCC development. Actually, lack in GNMT expression leads to epigenetic regulation of critical carcinogenesis pathways.

In the article by Martinez-Lopez N & Garcia-Rodriguez JL and colleagues published in Gastroenterology and led by Dr. M.L Martinez-Chantar in the Metabolomics Unit at CIC bioGUNE-CIBERehd, we demonstrate that Ras-mediated hyperactivation of LKB1 contributes to the proliferation of GNMT-deficient HCC in an ERK/p90RSK-dependent manner resulting in an LKB1-AMPK misconnection and a positive regulation of the cAMP-PKA-CaMKK cascade.

In the absence of GNMT, LKB1 is the driving force of Ras activation by modulation of RASGRP3 expression. Notably, the human HCC tumors with poorer prognosis showed the lowest levels of GNMT, AMPK (Thr172) and the highest activation of Ras/LKB1/RASGRP3 axis.

Identify targets amenable for early selective therapies and improving the allocation of resources will contribute to reduce liver cancer mortality.

Hepatoma Cells From Mice Deficient in Glycine N-Methyltransferase Have Increased RAS Signaling and Activation of Liver Kinase B1.
Martínez-López N, García-Rodríguez JL, Varela-Rey M, Gutiérrez V, Fernández-Ramos D, Beraza N, Aransay AM, Schlangen K, Lozano JJ, Aspichueta P, Luka Z, Wagner C, Evert M, Calvisi DF, Lu SC, Mato JM, Martínez-Chantar ML.
Gastroenterology. 2012 Sep;143(3):787-798.e13. Epub 2012 Jun 8.