Journal
CANCERS
Volume 11, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/cancers11101602
Keywords
clear cell renal cell carcinoma; AMP-activated protein kinases; immunohistochemistry; prognosis; SMAD proteins; transforming growth factor beta
Categories
Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [2018R1D1A1B07045763]
- National Research Foundation of Korea [2018R1D1A1B07045763] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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-beta/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-beta/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-beta-independent phosphorylation of SMAD2 and activates pSMAD2/SMAD4, representing a novel anti-tumoral mechanism of pAMPK in ccRCC.
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