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Open AccessArticle

Prognostic Implication of pAMPK Immunohistochemical Staining by Subcellular Location and Its Association with SMAD Protein Expression in Clear Cell Renal Cell Carcinoma

1
Department of Pathology, Seoul National University Hospital, Seoul 03080, Korea
2
Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul 03722, Korea
3
Department of Pathology, SMG-SNU Boramae Medical Center, Seoul 07061, Korea
4
Kidney Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(10), 1602; https://doi.org/10.3390/cancers11101602
Received: 17 September 2019 / Revised: 17 October 2019 / Accepted: 19 October 2019 / Published: 21 October 2019
(This article belongs to the Special Issue Renal Cell Carcinoma)
Although cytoplasmic AMP-activated protein kinase (AMPK) has been known as a tumor-suppressor protein, nuclear AMPK is suggested to support clear cell renal cell carcinoma (ccRCC). In addition, pAMPK interacts with TGF-β/SMAD, which is one of the frequently altered pathways in ccRCC. In this study, we investigated the prognostic significance of pAMPK with respect to subcellular location and investigated its interaction with TGF-β/SMAD in ccRCC. Immunohistochemical staining for pAMPK, pSMAD2 and SMAD4 was conducted on tissue microarray of 987 ccRCC specimens. Moreover, the levels of pSMAD2 were measured in Caki-1 cells treated with 5-aminoimidazole-4-carboxamide ribonucleotide. The relationship between AMPK/pAMPK and TGFB1 expression was determined using the TCGA database. As a result, pAMPK positivity, either in the cytoplasm or nuclei, was independently associated with improved ccRCC prognosis, after adjusting for TNM stage and WHO grade. Furthermore, pAMPK-positive ccRCC displayed increased pSMAD2 and SMAD4 expression, while activation of pAMPK increased pSMAD2 in Caki-1 cells. However, AMPK/pAMPK expression was inversely correlated with TGFB1 expression in the TCGA database. Therefore, pAMPK immunostaining, both in the cytoplasm and nuclei, is a useful prognostic biomarker for ccRCC. pAMPK targets TGF-β-independent phosphorylation of SMAD2 and activates pSMAD2/SMAD4, representing a novel anti-tumoral mechanism of pAMPK in ccRCC. View Full-Text
Keywords: clear cell renal cell carcinoma; AMP-activated protein kinases; immunohistochemistry; prognosis; SMAD proteins; transforming growth factor beta clear cell renal cell carcinoma; AMP-activated protein kinases; immunohistochemistry; prognosis; SMAD proteins; transforming growth factor beta
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MDPI and ACS Style

Jung, M.; Lee, J.H.; Lee, C.; Park, J.H.; Park, Y.R.; Moon, K.C. Prognostic Implication of pAMPK Immunohistochemical Staining by Subcellular Location and Its Association with SMAD Protein Expression in Clear Cell Renal Cell Carcinoma. Cancers 2019, 11, 1602.

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