Author's reply to: AKR1B10 and its emerging role in tumor carcinogenesis and as a cancer biomarker

Authors

  • Deliang Cao,

    Corresponding author
    1. Department of Medical Microbiology, Immunology, and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL
    • Department of Medical Microbiology, Immunology, and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, 913 N. Rutledge Street, Springfield, IL 62794, USA
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    • Tel.: +217-545-9703, Fax: +217-545-3227

  • Duan-Fang Liao

    1. Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan, China
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Dear Editor,

We very much appreciate the high enthusiasm of Dr. Kapoor shown toward our study.1 Since the first identification that aldo–keto reductase 1B10 (AKR1B10) is upregulated in human hepatocellular carcinoma,2 numerous studies from our and other colleagues' laboratories have recognized and defined its roles in cancer development and as a prognostic marker.3 In our report, AKR1B10 was found to be upregulated in breast cancer, and more importantly, AKR1B10 expression was correlated with tumor size, lymph node metastasis and the patient survival in a cohort of 220 breast cancer cases with complete clinicopathological settings and a mean follow-up time of 25 years. Our study also found for the first time that AKR1B10 was increased in the serum of patients with breast cancer, being a potential serum marker. These findings support an extensive study to understand the pathophysiological role of AKR1B10 in cancer development and progression and its potential as a serum marker of tumors.

AKR1B10 demonstrates a differential expression in normal and tumor tissues. In normal tissues, AKR1B10 is primarily abundant in gastrointestine (GI), but oppositely, AKR1B10 is downregulated in colorectal cancer.2, 4 AKR1B10 is expressed in the liver at a low level and is undetectable in the lung and breast,2 but highly upregulated in liver,2 lung3 and breast1 cancers. In the airway epithelium, AKR1B10 is upregulated by cigarette smoke. A reasonable explanation of this expression pattern of AKR1B10 may be largely ascribed to its biological function understood thus far, that is, an efficient detoxicant of α,β-unsaturated carbonyl compounds5 and a regulator of long-chain fatty acid synthesis.6 Unique to the GI epithelium is the carbonyl stress that is derived from diets and luminal microbes (colon). Intestinal epithelial cells are also rapidly and perpetually renewed with active needs of fatty acids for phospholipid synthesis for cell growth and proliferation. Therefore, AKR1B10 is expressed in the epithelial cells to protect from carbonyl lesions and to promote lipid synthesis for renewal. Downregulation of AKR1B10 may play an initiating role in the carcinogenesis of the colorectum while transformed cells would obtain adaption to grow and develop tumors due to activation of oncogenic signaling cascades. Similarly, rapidly dividing cancer cells feature high lipid needs and metabolic carbonyl stress, where AKR1B10 is upregulated to facilitate cancer cell growth and survival. In fact, small-interfering RNA (siRNA)-mediated AKR1B10 silencing in cancer cells results in carbonyl lesions and apoptotic cell death secondary to lipid depletions and mitochondrial dysfunction.7 AKR1B10 is also expressed in adrenal gland, which may indicate its role in steroid hormone metabolism; however, further studies are required to address this assumption.

AKR1B10 may be implicated in cancer development and therapeutics via other mechanisms. AKR1B10 can activate polycyclic aromatic hydrocarbons, a procarcinogen in environment and cigarette smoke.8 AKR1B10 also have strong enzymatic activity toward all-trans-retinal, 9-cis-retinal and 13-cis-retinal, reducing them to the corresponding retinols, which may deprive the receptors of retinoic acid ligand, a signaling molecule regulating cell proliferation and differentiation,9 which may render an oncogenic role of AKR1B10. In addition, recent studies have shown that AKR1B10 can reduce the C13 ketonic group in daunorubicin and idarubicin, leading to chemoresistance of cancer cells to these cytostatic agents.

In conclusion, emerging in the past 5 years, AKR1B10 is marked as a functionally important protein in either normal cells or cancer cells. AKR1B10 is primarily expressed in GI epithelium for lipid synthesis and prevention of carbonyl lesions; AKR1B10 is expressed at a low level in the liver (an important metabolic organ) and AKR1B10 is induced by cigarette smoke in the airway epithelium where it is involved in the metabolism of smoke components. On the other hand, AKR1B10 is overexpressed in lung, breast, pancreas and liver cancers where rapidly growing cancer cells are featured of lipid needs and metabolic pressure. Therefore, AKR1B10 may play a protective role in normal cells, but an oncogenic role in cancer cells promoting tumor growth, progression and even metastasis. The finding that AKR1B10 is a secretory protein10 and a potential serum marker of breast cancer enhances its interest in cancer research and clinics. Further studies on AKR1B10 protein, including clinical trials for validation as a tumor marker, are merited.

Acknowledgements

This work was supported in part by the Department of Defense Breast Cancer Research Program (BC083555) for D.C.

Yours sincerely, Deliang Cao Duan-Fang Liao

Deliang Cao*, Duan-Fang Liao†, * Department of Medical Microbiology, Immunology, and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, † Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan, China.

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