AKR1C3 (aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II))

2007-11-01   Hsueh Kung Lin  

Department of Urology, University of Oklahoma Health Sciences Center, 920 Stanton L Young Blvd, WP3150, Oklahoma City, Oklahoma 73104, USA

Identity

HGNC
AKR1C3
LOCATION
10p15.1
LOCUSID
8644
ALIAS
DD3,DDX,HA1753,HAKRB,HAKRe,HSD17B5,PGFS,hluPGFS
FUSION GENES
Show Gene Fusions

DNA/RNA

Transcription

1170 bp mRNA; transcript has been detected in brain, lung, liver, small intestine, mammary gland, uterus, prostate, testis.

Proteins

Description

323 amino acids, molecular weight 37 kDa.

Expression

Activated macrophage, malignant prostate epithelium, normal mammary epithelium, mature blood vessel.

Localisation

Mainly in cytoplasm.

Function

AKR1C3 metabolizes various androgen metabolites including 5a-dihydrotestosterone to 5a-androstane-3a,17b-diol, Delta4-androstene-3,17-dione to testosterone, androstanedione to 5a-dihydrotestosterone, androsterone to 5a-androstane-3a,17b-diol.
AKR1C3 is also involved in estrogen metabolism converting estrone to 17b-estradiol as well as progesterone metabolism converting prostaglandin D2 to 9a,11b-prostaglandin F2a.
AKR1C3 has the capability of regulating the trans-activation of various nuclear receptors including androgen receptor, estrogen receptor, and peroxisome proliferator activated receptor (PPARG) by regulating the ligand availability for the nuclear receptors.

Homology

A member of the of AKR1C family proteins; AKR1C1, AKR1C2, AKR1C3, AKR1C4 in human, and AKR1C9 in rat.

Mutations

Note

Mutation of AKR1C3 has not been identified.

Implicated in

Entity name
Various cancers
Note
Elevated levels of AKR1C3 expression are implicated in leukemia cell differentiation, prostate cancer (in both androgen-dependent and androgen-independent prostate cancer), and endometrial cancer. Expression of AKR1C3 was detected in a patient with myelodysplastic syndrome (MDS, refractory anemia) with progression to acute myelogenous leukemia. Overexpression of AKR1C3 in a human promyelocytic leukemia cell line, HL-60, rendered cells more resistant to all-trans retinoic acid (ATRA) and 1a,25-dihydroxyvitamin D3 induced cell differentiation.
Entity name
Prostate cancer
Disease
Immunohistochemical staining of human prostate tissues detected negative or low levels of AKR1C3 expression in normal prostate epithelial cells. Strong positive AKR1C3 immunoreactivity was demonstrated in primary and androgen-independent prostate cancers. Variable increases in AKR1C3 expression were also demonstrated in non-neoplastic changes in the prostate including chronic inflammation, atrophy, and urothelial cell metaplasia.
Entity name
Endometrial cancer
Disease
Quantitative transcriptosome analysis using real-time polymerase chain reaction, AKR1C3 mRNA expression was shown to be elevated in endometrial cancer versus adjacent normal endometrium.
Entity name
Breast tumor
Disease
Expression of AKR1C3 mRNA was reduced in breast tumor as compared to adjacent normal breast tissue. Immunohistochemstry revealed that the ductal epithelial cells and stromal cells of the breast express AKR1C3. In myoepithelial cells of the breast, immunoreactive AKR1C3 was absent in normal tissues, whereas strong AKR1C3 staining was apparent in cells surrounding the neoplastic epithelium of ductal carcinoma in situ.

Article Bibliography

Pubmed IDLast YearTitleAuthors
167350892006Paracrine-stimulated gene expression profile favors estradiol production in breast tumors.Amin SA et al
125438092003The aldo-keto reductase AKR1C3 is a novel suppressor of cell differentiation that provides a plausible target for the non-cyclooxygenase-dependent antineoplastic actions of nonsteroidal anti-inflammatory drugs.Desmond JC et al
100678771999Localization of type 5 17beta-hydroxysteroid dehydrogenase, 3beta-hydroxysteroid dehydrogenase, and androgen receptor in the human prostate by in situ hybridization and immunocytochemistry.El-Alfy M et al
166012862006Increased expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma.Fung KM et al
154922892004Selective loss of AKR1C1 and AKR1C2 in breast cancer and their potential effect on progesterone signaling.Ji Q et al
152126872004Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma.Lewis MJ et al
94154011997Expression and characterization of recombinant type 2 3 alpha-hydroxysteroid dehydrogenase (HSD) from human prostate: demonstration of bifunctional 3 alpha/17 beta-HSD activity and cellular distribution.Lin HK et al
168383252006Transcriptosome and serum cytokine profiling of an atypical case of myelodysplastic syndrome with progression to acute myelogenous leukemia.Mahadevan D et al
157886422005In situ androgen producing enzymes in human prostate cancer.Nakamura Y et al
111748502001Immunoelectron microscopic localization of 3beta-hydroxysteroid dehydrogenase and type 5 17beta-hydroxysteroid dehydrogenase in the human prostate and mammary gland.Pelletier G et al
164179662006Aldo-keto reductase (AKR) 1C3: role in prostate disease and the development of specific inhibitors.Penning TM et al
163380602006AKR1C1 and AKR1C3 may determine progesterone and estrogen ratios in endometrial cancer.Rizner TL et al
165106042006Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer.Stanbrough M et al

Other Information

Locus ID:

NCBI: 8644
MIM: 603966
HGNC: 386
Ensembl: ENSG00000196139

Variants:

dbSNP: 8644
ClinVar: 8644
TCGA: ENSG00000196139
COSMIC: AKR1C3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000196139ENST00000380554P42330
ENSG00000196139ENST00000439082A0A0A0MSS8
ENSG00000196139ENST00000602997S4R3D5
ENSG00000196139ENST00000605149S4R3Z2

Expression (GTEx)

0
10
20
30
40
50
60
70
80
90
100
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

Pathways

PathwaySourceExternal ID
Steroid hormone biosynthesisKEGGko00140
Arachidonic acid metabolismKEGGko00590
Steroid hormone biosynthesisKEGGhsa00140
Arachidonic acid metabolismKEGGhsa00590
Metabolic pathwaysKEGGhsa01100
Ovarian steroidogenesisKEGGhsa04913
Ovarian steroidogenesisKEGGko04913
Signal TransductionREACTOMER-HSA-162582
Visual phototransductionREACTOMER-HSA-2187338
Retinoid metabolism and transportREACTOMER-HSA-975634
Signaling by Retinoic AcidREACTOMER-HSA-5362517
RA biosynthesis pathwayREACTOMER-HSA-5365859
MetabolismREACTOMER-HSA-1430728
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Bile acid and bile salt metabolismREACTOMER-HSA-194068
Synthesis of bile acids and bile saltsREACTOMER-HSA-192105
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterolREACTOMER-HSA-193368
Synthesis of bile acids and bile salts via 24-hydroxycholesterolREACTOMER-HSA-193775
Synthesis of bile acids and bile salts via 27-hydroxycholesterolREACTOMER-HSA-193807
Arachidonic acid metabolismREACTOMER-HSA-2142753
Synthesis of Prostaglandins (PG) and Thromboxanes (TX)REACTOMER-HSA-2162123
Metabolism of vitamins and cofactorsREACTOMER-HSA-196854
Metabolism of fat-soluble vitaminsREACTOMER-HSA-6806667

Protein levels (Protein atlas)

Not detected
Low
Medium
High
cerebral cortex
cerebellum
hippocampus
caudate
thyroid gland
parathyroid gland
adrenal gland
nasopharynx
bronchus
lung
oral mucosa
salivary gland
esophagus
stomach 1
stomach 2
duodenum
small intestine
colon
rectum
liver
gallbladder
pancreas
kidney
urinary bladder
testis
epididymis
seminal vesicle
prostate
vagina
ovary
fallopian tube
endometrium 1
endometrium 2
cervix, uterine
placenta
breast
heart muscle
smooth muscle
skeletal muscle
soft tissue 1
soft tissue 2
adipose tissue
skin 1
skin 2
appendix
spleen
lymph node
tonsil
bone marrow

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA443560Breast NeoplasmsDiseaseClinicalAnnotationassociated23116553
PA449212daunorubicinChemicalVariantAnnotationassociatedPK20837989
PA449383docetaxelChemicalClinicalAnnotationassociated23116553
PA449412doxorubicinChemicalClinicalAnnotation, Pathway, VariantAnnotationassociatedPK20837989, 21048526, 23116553
PA449563exemestaneChemicalClinicalAnnotationassociatedPK27111237

References

Pubmed IDYearTitleCitations
381229232024Inhibition of aldo-keto reductase 1C3 overcomes gemcitabine/cisplatin resistance in bladder cancer.2
383492662024AKR1C3 silencing inhibits autophagy-dependent glycolysis in thyroid cancer cells by inactivating ERK signaling.0
381229232024Inhibition of aldo-keto reductase 1C3 overcomes gemcitabine/cisplatin resistance in bladder cancer.2
383492662024AKR1C3 silencing inhibits autophagy-dependent glycolysis in thyroid cancer cells by inactivating ERK signaling.0
364137582023Availability of aldo-keto reductase 1C3 and ATP-binding cassette B1 as therapeutic targets for alleviating paclitaxel resistance in breast cancer MCF7 cells.1
368418452023Influence of aldo-keto reductase 1C3 polymorphisms in early-onset female psoriasis patients.0
369019442023Establishing a Proteomics-Based Signature of AKR1C3-Related Genes for Predicting the Prognosis of Prostate Cancer.4
369200422023AKR1C3 suppresses ferroptosis in hepatocellular carcinoma through regulation of YAP/SLC7A11 signaling pathway.7
373441792023In Vitro Evaluation of the Reductase Activities of Human AKR1C3 Allelic Variants.1
380033792023Keratinocytes Exposed to Blue or Red Light: Proteomic Characterization Showed Cytoplasmic Thioredoxin Reductase 1 and Aldo-Keto Reductase Family 1 Member C3 Triggered Expression.1
381886842023Aldo-keto reductase family member C3 (AKR1C3) promotes hepatocellular carcinoma cell growth by producing prostaglandin F2α.1
364137582023Availability of aldo-keto reductase 1C3 and ATP-binding cassette B1 as therapeutic targets for alleviating paclitaxel resistance in breast cancer MCF7 cells.1
368418452023Influence of aldo-keto reductase 1C3 polymorphisms in early-onset female psoriasis patients.0
369019442023Establishing a Proteomics-Based Signature of AKR1C3-Related Genes for Predicting the Prognosis of Prostate Cancer.4
369200422023AKR1C3 suppresses ferroptosis in hepatocellular carcinoma through regulation of YAP/SLC7A11 signaling pathway.7

Citation

Hsueh Kung Lin

AKR1C3 (aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II))

Atlas Genet Cytogenet Oncol Haematol. 2007-11-01

Online version: http://atlasgeneticsoncology.org/gene/612/tumors-explorer/js/lib/gene-explorer/