The LKB1 Tumor Suppressor as a Biomarker in Mouse and Human Tissues

Yuji Nakada, Thomas G. Stewart, Christopher G. Peña, Song Zhang, Ni Zhao, Nabeel Bardeesy, Norman E. Sharpless, Kwok Kin Wong, D. Neil Hayes, Diego H. Castrillon

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Germline mutations in the LKB1 gene (also known as STK11) cause the Peutz-Jeghers Syndrome, and somatic loss of LKB1 has emerged as causal event in a wide range of human malignancies, including melanoma, lung cancer, and cervical cancer. The LKB1 protein is a serine-threonine kinase that phosphorylates AMP-activated protein kinase (AMPK) and other downstream targets. Conditional knockout studies in mouse models have consistently shown that LKB1 loss promotes a highly-metastatic phenotype in diverse tissues, and human studies have demonstrated a strong association between LKB1 inactivation and tumor recurrence. Furthermore, LKB1 deficiency confers sensitivity to distinct classes of anticancer drugs. The ability to reliably identify LKB1-deficient tumors is thus likely to have important prognostic and predictive implications. Previous research studies have employed polyclonal antibodies with limited success, and there is no widely-employed immunohistochemical assay for LKB1. Here we report an assay based on a rabbit monoclonal antibody that can reliably detect endogenous LKB1 protein (and its absence) in mouse and human formalin-fixed, paraffin-embedded tissues. LKB1 protein levels determined through this assay correlated strongly with AMPK phosphorylation both in mouse and human tumors, and with mRNA levels in human tumors. Our studies fully validate this immunohistochemical assay for LKB1 in paraffin-embedded formalin tissue sections. This assay should be broadly useful for research studies employing mouse models and also for the development of human tissue-based assays for LKB1 in diverse clinical settings.

Original languageEnglish (US)
Article numbere73449
JournalPLoS One
Volume8
Issue number9
DOIs
StatePublished - Sep 25 2013

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Biomarkers
Tumors
Assays
biomarkers
Tissue
neoplasms
mice
assays
AMP-activated protein kinase
Neoplasms
Paraffin
Formaldehyde
formalin
alkanes
Peutz-Jeghers Syndrome
animal models
Proteins
AMP-Activated Protein Kinases
Aptitude
Germ-Line Mutation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

The LKB1 Tumor Suppressor as a Biomarker in Mouse and Human Tissues. / Nakada, Yuji; Stewart, Thomas G.; Peña, Christopher G.; Zhang, Song; Zhao, Ni; Bardeesy, Nabeel; Sharpless, Norman E.; Wong, Kwok Kin; Hayes, D. Neil; Castrillon, Diego H.

In: PLoS One, Vol. 8, No. 9, e73449, 25.09.2013.

Research output: Contribution to journalArticle

Nakada, Y, Stewart, TG, Peña, CG, Zhang, S, Zhao, N, Bardeesy, N, Sharpless, NE, Wong, KK, Hayes, DN & Castrillon, DH 2013, 'The LKB1 Tumor Suppressor as a Biomarker in Mouse and Human Tissues', PLoS One, vol. 8, no. 9, e73449. https://doi.org/10.1371/journal.pone.0073449
Nakada Y, Stewart TG, Peña CG, Zhang S, Zhao N, Bardeesy N et al. The LKB1 Tumor Suppressor as a Biomarker in Mouse and Human Tissues. PLoS One. 2013 Sep 25;8(9). e73449. https://doi.org/10.1371/journal.pone.0073449
Nakada, Yuji ; Stewart, Thomas G. ; Peña, Christopher G. ; Zhang, Song ; Zhao, Ni ; Bardeesy, Nabeel ; Sharpless, Norman E. ; Wong, Kwok Kin ; Hayes, D. Neil ; Castrillon, Diego H. / The LKB1 Tumor Suppressor as a Biomarker in Mouse and Human Tissues. In: PLoS One. 2013 ; Vol. 8, No. 9.
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