PMID- 32993793
OWN - NLM
STAT- MEDLINE
DCOM- 20210514
LR  - 20220531
IS  - 1479-5876 (Electronic)
IS  - 1479-5876 (Linking)
VI  - 18
IP  - 1
DP  - 2020 Sep 29
TI  - Characterization of the expression and immunological impact of the 
      transcriptional activator CREB in renal cell carcinoma.
PG  - 371
LID - 10.1186/s12967-020-02544-0 [doi]
LID - 371
AB  - BACKGROUND: The non-classical human leukocyte antigen (HLA)-G is a strong 
      immunomodulatory molecule. Under physiological conditions, HLA-G induces 
      immunological tolerance in immune privileged tissues, while under 
      pathophysiological situations it contributes to immune escape mechanisms. 
      Therefore, HLA-G could act as a potential immune checkpoint for future 
      anti-cancer immunotherapies. Recent data suggest an aberrant expression of the 
      cAMP response element binding protein (CREB) in clear cell renal cell carcinoma 
      (ccRCC), which is correlated with tumor grade and stage. Furthermore, preliminary 
      reports demonstrated a connection of CREB as a control variable of HLA-G 
      transcription due to CREB binding sites in the HLA-G promoter region. This study 
      investigates the interaction between CREB and HLA-G in different renal cell 
      carcinoma (RCC) subtypes and its correlation to clinical parameters. METHODS: The 
      direct interaction of CREB with the HLA-G promoter was investigated by chromatin 
      immunoprecipitation in RCC cell systems. Furthermore, the expression of CREB and 
      HLA-G was determined by immunohistochemistry using a tissue microarray (TMA) 
      consisting of 453 RCC samples of distinct subtypes. Staining results were 
      assessed for correlations to clinical parameters as well as to the composition of 
      the immune cell infiltrate. RESULTS: There exists a distinct expression pattern 
      of HLA-G and CREB in the three main RCC subtypes. HLA-G and CREB expression were 
      the lowest in chromophobe RCC lesions. However, the clinical relevance of CREB 
      and HLA-G expression differed. Unlike HLA-G, high levels of CREB expression were 
      positively associated to the overall survival of RCC patients. A slightly, but 
      significantly elevated number of tumor infiltrating regulatory T cells was 
      observed in tumors of high CREB expression. Whether this small increase is of 
      clinical relevance has to be further investigated. CONCLUSIONS: An interaction of 
      CREB with the HLA-G promoter could be validated in RCC cell lines. Thus, for the 
      first time the expression of CREB and its interaction with the HLA-G in human 
      RCCs has been shown, which might be of clinical relevance.
FAU - Friedrich, Michael
AU  - Friedrich M
AD  - Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, 
      Magdeburger Str. 2, 06110, Halle (Saale), Germany.
FAU - Stoehr, Christine
AU  - Stoehr C
AD  - Institute of Pathology, Friedrich Alexander University Erlangen-Nuremberg, 
      Erlangen, Germany.
FAU - Jasinski-Bergner, Simon
AU  - Jasinski-Bergner S
AD  - Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, 
      Magdeburger Str. 2, 06110, Halle (Saale), Germany.
FAU - Hartmann, Arndt
AU  - Hartmann A
AD  - Institute of Pathology, Friedrich Alexander University Erlangen-Nuremberg, 
      Erlangen, Germany.
FAU - Wach, Sven
AU  - Wach S
AD  - Department of Urology and Pediatric Urology, University Hospital Erlangen, 
      Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
FAU - Wullich, Bernd
AU  - Wullich B
AD  - Department of Urology and Pediatric Urology, University Hospital Erlangen, 
      Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
FAU - Steven, Andre
AU  - Steven A
AD  - Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, 
      Magdeburger Str. 2, 06110, Halle (Saale), Germany.
FAU - Seliger, Barbara
AU  - Seliger B
AUID- ORCID: 0000-0002-5544-4958
AD  - Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, 
      Magdeburger Str. 2, 06110, Halle (Saale), Germany. barbara.seliger@uk-halle.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200929
PL  - England
TA  - J Transl Med
JT  - Journal of translational medicine
JID - 101190741
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (HLA-G Antigens)
SB  - IM
MH  - *Carcinoma, Renal Cell/genetics
MH  - Cyclic AMP Response Element-Binding Protein
MH  - HLA-G Antigens/genetics
MH  - Humans
MH  - *Kidney Neoplasms/genetics
MH  - Promoter Regions, Genetic/genetics
PMC - PMC7526213
OTO - NOTNLM
OT  - CREB
OT  - HLA-G
OT  - Immune cell infiltration
OT  - Renal cell carcinoma
COIS- The authors declare that they have no competing interests.
EDAT- 2020/10/01 06:00
MHDA- 2021/05/15 06:00
PMCR- 2020/09/29
CRDT- 2020/09/30 05:48
PHST- 2020/07/23 00:00 [received]
PHST- 2020/09/22 00:00 [accepted]
PHST- 2020/09/30 05:48 [entrez]
PHST- 2020/10/01 06:00 [pubmed]
PHST- 2021/05/15 06:00 [medline]
PHST- 2020/09/29 00:00 [pmc-release]
AID - 10.1186/s12967-020-02544-0 [pii]
AID - 2544 [pii]
AID - 10.1186/s12967-020-02544-0 [doi]
PST - epublish
SO  - J Transl Med. 2020 Sep 29;18(1):371. doi: 10.1186/s12967-020-02544-0.