Endoplasmic Reticulum Stress in Pancreatic Neuroendocrine Tumors is Linked to Clinicopathological Parameters and Possible Epigenetic Regulations.
BACKGROUND
Endoplasmic reticulum (ER) stress is a highly-conserved cellular defense mechanism in response to perturbations of ER function. The role of ER stress in pancreatic neuroendocrine tumors (pNET) still remains unclear.


METHODS
We analyzed the protein expression pattern of the four key players of ER stress, (chaperone binding imunoglobluin protein (BiP), C/EBP homologous protein (CHOP), activating transcription factor 4 (ATF4) and caspase 4) as well as histone deacetylases (HDACs) by a tissue microarray (TMA) of 49 human pNET resected between 1997 and 2013 following, extensive clinicopathological characterization.


RESULTS
Immunohistochemical profiling revealed a significant up-regulation of BiP, ATF4, CHOP and caspase 4 in pNET cases compared to normal controls. Correlated to clinicopathological parameters especially BiP expression could be linked to higher grading and proliferation as well as to lower survival probability. Finally, expression of ER stress markers correlated with HDAC expression in situ and pharmalogical inhibition by panobinostat significantly reduced cell viability in vitro.


CONCLUSIONS
Up-regulation of ER stress in pNET indicates the presence and engagement of ER stress signaling in this tumor entity demonstrating another possible anticancer therapy option in pNET.
Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria.
Eckhard
E
Klieser
Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria.
Romana
R
Illig
Department of Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria.
Stefan
S
Státtner
Department of Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria.
Florian
F
Primavesi
Department of Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria.
Tarkan
T
Jáger
Department of Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria.
Stefan
S
Swierczynski
Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria.
Tobias
T
Kiesslich
Medizinisches Versorgungszentrum für Histologie, Zytologie und Molekulare Diagnostik, Trier, Germany.
Ralf
R
Kemmerling
Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany.
Carmen
C
Bollmann
Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany.
Pietro
P
Di Fazio
Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria d.neureiter@salk.at.
Daniel
D
Neureiter
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D053471:Caspases, Initiator / Q000378:metabolism; D002470:Cell Survival; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D044127:Epigenesis, Genetic; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D015996:Survival Rate; D046888:Tissue Array Analysis; D051742:Transcription Factor CHOP / Q000378:metabolism; D014407:Tumor Cells, Cultured; D055815:Young Adult
C497109:ATF4 protein, human; D014408:Biomarkers, Tumor; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; C093516:CASP4 protein, human; D053471:Caspases, Initiator
Pancreatic neuroendocrine tumor; endoplasmic reticulum stress; grading