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Int J Clin Exp Pathol 2012;5(4):278-289

Original Article
Aldo-keto reductase family 1 member C3 (AKR1C3) is expressed in adenocarcinoma and
squamous cell carcinoma but not small cell carcinoma

Valerie L Miller, Hsueh-Kung Lin, Paari Murugan, Michael Fan, Trevor M Penning, Lacy S Brame, Qing Yang, Kar-Ming Fung

College of Medicine, Department of Urology, Department of Pathology, University of Oklahoma Health Sciences Center, Veterans Affairs
Medical Center, Oklahoma City, OK 73104, Department of Chemistry & Chemical Biology, Rutgers University, Piscataway, NJ 08854, Center of
Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104,
University of Oklahoma, Norman, OK 73019, USA.

Received March 23, 2012; accepted April 6, 2012; Epub April 16, 2012; Published May 30, 2012

Abstract: Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as a critical enzyme in reducing 5α-
dihydrotestosterone (5α-DHT) to 5α-androstane-3α,17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. Based on these enzymatic
activities, AKR1C3 was originally named type 2 3α-hydroxysteroid dehydrogenase (HSD)/type 5 17β-HSD. Additionally, AKR1C3 was
demonstrated to be capable of metabolizing other steroids including estrogen and progesterone. Subsequently, AKR1C3 was shown to
possess 11-ketoprostaglandin reductase activity in metabolizing prostaglandins and dihydrodiol dehydrogenase x (DDx) activity in metabolizing
xenobiotics. Tissue distribution of AKR1C3 has been detected in both sex hormone-dependent organs such as the testis, breast,
endometrium, and prostate as well as sex hormone-independent organs including the kidney and urothelium. Although prominent expression
of AKR1C isozymes has been reported in human non-small cell lung carcinoma (NSCLC), the expression of AKR1C3 in small cell carcinoma
of the lung has not been described. Also, the expression of AKR1C3 in normal lung has not been described. In this study, we demonstrated
strong AKR1C3 immunorectivity in bronchial epithelium but not in bronchial glands or alveolar pneuomocytes. Strong AKR1C3
immunoreactivity was also demonstrated in columnar epithlelium but only weak immunoreactivity in squamous epithelium of the
gastrointestinal junction. Although AKR1C3 immunoreactivity was absent in small cell carcinoma of the lung, positive AKR1C3
immunoreactivity was extensively present in both adenocarcinoma and squamous cell carcinoma arising from the lung and the
gastroesophageal junction. AKR1C3 may serve as an adjunct marker for differentiating small cell carcinoma from NSCLC. However, roles of
AKR1C3 in adenocarcinoma, squamous cell carcinoma, and small cell carcinoma pathogenesis require further studies.

Keywords: AKR1C3, small cell carcinoma, non-small cell carcinoma, adenocarcinoma, squamous cell carcinoma, lung, esophagus, stomach,
gastroesophageal junction

Address all correspondence to:
Dr. Kar-Ming Fung
Department of Pathology
University of Oklahoma Health Sciences Center
BMSB 451, 940 Stanton Young Blvd
Oklahoma City, OK 73104, USA.
Tel: 405-271-5653; Fax: 405-271-2524
E-mail: karming-fung@ouhsc.edu