Hematological and Neurological Expressed 1 (HN1): a predictive and pharmacodynamic biomarker of metformin response in endometrial cancers
bioRxiv(2019)
摘要
Preoperative use of metformin in obese women with endometrioid endometrial cancer (EEC) reduces tumor proliferation and inhibits the mammalian target of rapamycin (mTOR) pathway, though is only effective in select cases. This study sought to identify a predictive and/or pharmacodynamic proteomic signature of metformin response to tailor its pharmacologic use. Matched pre- and post-metformin treated tumor tissues from a recently completed phase 0 window trial of metformin in EEC patients (ClinicalTrials.gov: [NCT01911247][1]), were analyzed by mass spectrometry (MS)-based proteomic and immunohistochemical analyses. Hematological and neurological expressed 1 (HN1) was significantly elevated in metformin responders (n=13) versus non-responders (n=7), which was also found to decrease in abundance in metformin responders following treatment; observations that were verified by immunohistochemical staining for HN1. Metformin response and loss of HN1 was assessed in RL95-2 and ACI-181 endometrial cancer cell lines. We further identified that silencing of HN1 abundance does not alter cellular response to metformin or basal cell proliferation, but that HN1 abundance does decrease in response to metformin treatment in RL95-2 and ACI-181 endometrial cancer cell lines. These data suggest that HN1 represents a predictive and pharmacodynamic biomarker of metformin response that, if validated in larger patient populations, may enable pre-operative EEC patient stratification to metformin treatment and the ability to monitor patient response.
Novelty and Impact Hematological and Neurological Expressed 1 (HN1) is elevated in endometrioid endometrial cancer (EEC) patients that respond to metformin vs non-responders and decreases after treatment. HN1 decreases after metformin treatment of EEC cells in vitro, but is not necessary for metformin response or proliferation. We report HN1 as a novel predictive and pharmacodynamic biomarker of metformin response in EEC that may enable pre-operative EEC patient stratification to metformin treatment and the ability to monitor patient response.
* HN1
: Hematological and Neurological Expressed 1
JPT1
: Jupiter microtubule associated homolog 1
EC
: endometrial cancer
EEC
: cndometrioid endometrial cancer
Ki-67
: Antigen Ki-67
MS
: mass spectrometry
MS/MS
: tandem mass spectrometry
LC
: liquid chromatography
mTOR
: mammalian target of rapamycin
AMPK
: adenosine monophosphate kinase
ATP
: adenosine triphosphate
LMD
: laser microdissection
H&E
: hematoxylin and eosin
IHC
: Immunohistochemistry
PSMs
: peptide spectral matches
FDR
: false discovery rate
TMA
: tissue microarray
CO2
: carbon dioxide
siRNA
: small interfering RNA
mM
: millimolar
MTS
: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
siNT
: small interfering non-targeting RNA
siHN1
: small interfering HN1 RNA
qPCR
: quantitative polymerase chain reaction
cDNA
: complimentary DNA
DNA
: deoxyribonucleic acid
RNA
: ribonucleic acid
GAPDH
: glyceraldehyde 3-phosphate dehydrogenase
SDS
: sodium dodecyl sulfate
NaCl
: sodium chloride
PVDF
: polyvinylidene difluoride
AKT
: protein kinase B
IgG
: immunoglobulin
HRP
: horseradish peroxidase
IP-MS
: immunoprecipitation mass spectrometry
EDTA
: ethylenediaminetetraacetic acid
TCGA
: The Cancer Genome Atlas
RNA-seq
: RNA sequencing
LD50
: lethal dose 50
mRNA
: messenger RNA
MYC
: MYC oncogene
Mg
: milligram
logFC
: Log fold-change
CTNNB1
: beta catenin
S473
: serine 473
PCNA
: proliferating cell nuclear antigen
p-S6 kinase
: phosphorylated ribosomal protein S6 kinase beta-1
p-EIF4-BP1
: phosphorylated Eukaryotic translation initiation factor 4E-binding protein 1
[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01911247&atom=%2Fbiorxiv%2Fearly%2F2019%2F04%2F09%2F602870.atom
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关键词
metformin,endometrial cancer,proteomics,Hematological and Neurological Expressed 1,HN1,JPT1
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