Specific pattern of LKB1 and phospho-acetyl-CoA carboxylase protein immunostaining in human normal tissues and lung carcinomas.
The LKB1 tumor suppressor gene codes for a serine/threonine protein kinase, and among its substrates is the adenosine monophosphate-dependent protein kinase, a sensor of intracellular energy levels. LKB1 is genetically inactivated in several types of tumors, especially lung adenocarcinomas. Here we used immunohistochemistry to evaluate the levels of LKB1 and the phosphorylated form of the acetyl-CoA carboxylase (ACC) protein in a variety of human adult normal tissues and in 159 lung carcinomas. The enzyme ACC becomes inactive upon phosphorylation by adenosine monophosphate-dependent protein kinase. Our analysis in normal tissues revealed strong LKB1 immunostaining in most epithelia, in the seminiferous tubules of the testis, in myocytes from skeletal muscle, and in glia cells. In contrast to the cytosolic location of LKB1 found in most tissues, glia cells carried mainly nuclear LKB1. Some epithelial cells showed apical accumulation of LKB1, supporting its role in cell polarity. Regarding phospho-ACC (p-ACC), strong immunostaining was observed in myocytes from the skeletal muscle and heart, and in Leydig cells of the testis. In lung tumors, LKB1 immunostaining was absent, moderate, and high in 20%, 61%, and 19% of the tumors, respectively, whereas p-ACC immunostaining was found to be absent/low, moderate, and high in 35%, 34%, and 31% of the tumors, respectively. High levels of LKB1 and p-ACC immunostaining predominated in lung adenocarcinomas compared with squamous cell carcinomas. Finally, high p-ACC was an independent marker for prediction of better survival in lung adenocarcinoma patients. Median overall survival was longer in patients with p-ACC-positive than those with p-ACC-negative tumors (96 versus 44 months, P = .04). In conclusion, our observations provide complete information about the pattern and levels of LKB1 and p-ACC immunostaining in normal tissues and in lung tumors, and highlight the special relevance of abnormalities of the LKB1 pathway in lung adenocarcinoma.
Conde
Esther
E
Lung Cancer Group, Pathology Programme, Spanish National Cancer Centre (CNIO), 28029 Madrid, Spain.
Suarez-Gauthier
Ana
A
García-García
Elena
E
Lopez-Rios
Fernando
F
Lopez-Encuentra
Angel
A
García-Lujan
Ricardo
R
Morente
Manuel
M
Sanchez-Verde
Lydia
L
Sanchez-Cespedes
Montserrat
M
D000091162:AMP-Activated Protein Kinase Kinases; D000103:Acetyl-CoA Carboxylase / Q000032:analysis* / Q000378:metabolism; D000230:Adenocarcinoma / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis*; D002277:Carcinoma / Q000737:chemistry* / Q000201:enzymology / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000737:chemistry* / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation; D011237:Predictive Value of Tests; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000032:analysis*; D014018:Tissue Distribution
D014408:Biomarkers, Tumor; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D000103:Acetyl-CoA Carboxylase