PMID- 35900839
OWN - NLM
STAT- MEDLINE
DCOM- 20220808
LR  - 20240306
IS  - 1479-6821 (Electronic)
IS  - 1351-0088 (Print)
IS  - 1351-0088 (Linking)
VI  - 29
IP  - 10
DP  - 2022 Oct 1
TI  - miR-3156-5p is downregulated in serum of MEN1 patients and regulates expression 
      of MORF4L2.
PG  - 557-568
LID - 10.1530/ERC-22-0045 [doi]
AB  - Multiple endocrine neoplasia type 1 (MEN1), caused by mutations in the MEN1 gene 
      encoding menin, is an autosomal dominant disorder characterised by the combined 
      occurrence of parathyroid, pituitary and pancreatic neuroendocrine tumours 
      (NETs). Development of these tumours is associated with wide variations in their 
      severity, order and ages (from <5 to >80 years), requiring life-long screening. 
      To improve tumour surveillance and quality of life, better circulating 
      biomarkers, particularly for pancreatic NETs that are associated with higher 
      mortality, are required. We, therefore, examined the expression of circulating 
      miRNA in the serum of MEN1 patients. Initial profiling analysis followed by 
      qRT-PCR validation studies identified miR-3156-5p to be significantly 
      downregulated (-1.3 to 5.8-fold, P < 0.05-0.0005) in nine MEN1 patients, compared 
      to matched unaffected relatives. MEN1 knock-down experiments in BON-1 human 
      pancreatic NET cells resulted in reduced MEN1 (49%, P < 0.05), menin (54%, P < 
      0.05) and miR-3156-5p expression (20%, P < 0.005), compared to control-treated 
      cells, suggesting that miR-3156-5p downregulation is a consequence of loss of 
      MEN1 expression. In silico analysis identified mortality factor 4-like 2 
      (MOR4FL2) as a potential target of miR-3156-5p, and in vitro functional studies 
      in BON-1 cells transfected with either miR-3156-5p mimic or inhibitors showed 
      that the miR-3156-5p mimic significantly reduced MORF4L2 protein expression (46%, 
      P < 0.005), while miR-3156-5p inhibitor significantly increased MORF4L2 
      expression (1.5-fold, P < 0.05), compared to control-treated cells, thereby 
      confirming that miR-3156-5p regulates MORF4L2 expression. Thus, the inverse 
      relationship between miR-3156-5p and MORF4L2 expression represents a potential 
      serum biomarker that could facilitate the detection of NET occurrence in MEN1 
      patients.
FAU - Kooblall, Kreepa G
AU  - Kooblall KG
AD  - OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill 
      Hospital, Oxford, UK.
FAU - Stokes, Victoria J
AU  - Stokes VJ
AD  - OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill 
      Hospital, Oxford, UK.
FAU - Shariq, Omair A
AU  - Shariq OA
AD  - OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill 
      Hospital, Oxford, UK.
FAU - English, Katherine A
AU  - English KA
AD  - OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill 
      Hospital, Oxford, UK.
FAU - Stevenson, Mark
AU  - Stevenson M
AD  - OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill 
      Hospital, Oxford, UK.
FAU - Broxholme, John
AU  - Broxholme J
AUID- ORCID: 0000-0001-5638-0258
AD  - Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, 
      Oxford, UK.
FAU - Wright, Benjamin
AU  - Wright B
AD  - Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, 
      Oxford, UK.
FAU - Lockstone, Helen E
AU  - Lockstone HE
AD  - Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, 
      Oxford, UK.
FAU - Buck, David
AU  - Buck D
AD  - Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, 
      Oxford, UK.
FAU - Grozinsky-Glasberg, Simona
AU  - Grozinsky-Glasberg S
AD  - Neuroendocrine Tumor Unit, ENETS Center of Excellence, Endocrinology & Metabolism 
      Department, Hadassah Medical Center and Faculty of Medicine, The Hebrew 
      University of Jerusalem, Israel.
FAU - Yates, Christopher J
AU  - Yates CJ
AD  - OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill 
      Hospital, Oxford, UK.
FAU - Thakker, Rajesh V
AU  - Thakker RV
AD  - OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill 
      Hospital, Oxford, UK.
AD  - Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, 
      Oxford, UK.
FAU - Lines, Kate E
AU  - Lines KE
AUID- ORCID: 0000-0002-0764-8681
AD  - OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill 
      Hospital, Oxford, UK.
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - G1000467/MRC_/Medical Research Council/United Kingdom
GR  - G9825289/MRC_/Medical Research Council/United Kingdom
GR  - 203141/Z/16/Z/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220804
PL  - England
TA  - Endocr Relat Cancer
JT  - Endocrine-related cancer
JID - 9436481
RN  - 0 (MORF4L2 protein, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Child
MH  - Child, Preschool
MH  - Humans
MH  - *MicroRNAs/genetics
MH  - Middle Aged
MH  - *Multiple Endocrine Neoplasia Type 1/pathology
MH  - Mutation
MH  - Quality of Life
MH  - Transcription Factors/genetics
MH  - Young Adult
PMC - PMC9422251
OTO - NOTNLM
OT  - menin
OT  - microRNA
OT  - mortality factor 4-like protein 2
OT  - multiple endocrine neoplasia type 1
OT  - neuroendocrine tumour
EDAT- 2022/07/29 06:00
MHDA- 2022/08/09 06:00
PMCR- 2022/08/29
CRDT- 2022/07/28 11:54
PHST- 2022/06/29 00:00 [received]
PHST- 2022/07/07 00:00 [accepted]
PHST- 2022/07/29 06:00 [pubmed]
PHST- 2022/08/09 06:00 [medline]
PHST- 2022/07/28 11:54 [entrez]
PHST- 2022/08/29 00:00 [pmc-release]
AID - ERC-22-0045 [pii]
AID - 10.1530/ERC-22-0045 [doi]
PST - epublish
SO  - Endocr Relat Cancer. 2022 Aug 4;29(10):557-568. doi: 10.1530/ERC-22-0045. Print 
      2022 Oct 1.