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. 2014 Apr;45(4):834-43.
doi: 10.1016/j.humpath.2013.12.002. Epub 2013 Dec 18.

Aldoketoreductase family 1B10 (AKR1B10) as a biomarker to distinguish hepatocellular carcinoma from benign liver lesions

Kristina A Matkowskyj  1 , Han Bai  2 , Jie Liao  3 , Wanying Zhang  3 , Haonan Li  3 , Sambasiva Rao  3 , Reed Omary  4 , Guang-Yu Yang  5
Affiliations

Aldoketoreductase family 1B10 (AKR1B10) as a biomarker to distinguish hepatocellular carcinoma from benign liver lesions

Kristina A Matkowskyj et al. Hum Pathol. 2014 Apr.

Abstract

Hepatocellular carcinoma (HCC) is one of the most common highly aggressive malignant tumors worldwide. Aldoketoreductase 1B10 (AKR1B10) was first isolated from HCC and further identified to be over-expressed in many cancers from various organs. AKR1B10 contributes to detoxification of xenobiotics by lipid peroxidation and metabolizes physiological substrates such as farnesal, retinal, and carbonyls. Metabolizing these lipid substrates plays a crucial role in promoting carcinogenesis. In the present study, immunohistochemical analysis was performed to determine the prevalence/pattern of AKR1B10 expression in HCC and its usefulness to differentiate benign liver lesions from HCC. Oncogenic function of AKR1B10 was examined in hepatocellular carcinoma cells in vitro using Western blotting and shRNA knockdown approaches, with emphasis on cell apoptosis and response to chemotherapy. Immunohistochemistry analysis revealed AKR1B10 was overexpressed in 97% (86/89) of hepatocellular carcinomas, with minimal to no expression in adjacent hepatic tissue, while hepatic adenomas and focal nodular hyperplasia did not exhibit expression of AKR1B10. shRNA-mediated silencing of AKR1B10 expression in hepatocellular carcinoma cells resulted in (1) increased cell apoptosis, (2) decreased colony formation and size, and (3) enhanced cytoreductive response following exposure to doxorubicin chemotherapy. Our findings provide first time evidence that AKR1B10 is a unique biomarker involved in hepatocellular carcinogenesis via modulation of proliferation, cell apoptosis and chemoresistance and is a potential promising biomarker to differentiate HCCs from benign hepatic lesions.

Keywords: AKR1B10; Focal nodular hyperplasia; Hepatic adenoma; Hepatocellular carcinoma.

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Conflict of interest statement

Disclosure/Conflict of Interest: The authors have no conflict of interest to declare.

Figures

Figure 1
Figure 1
Semi-quantitative analysis of AKR1B10 staining intensity in hepatocellular carcinoma. Staining intensity for each slide was graded from 0 to 3+ and a mean intensity was calculated. Immunoreactivity was semi-quantitatively evaluated as strong and diffuse cytoplasmic and nuclear positivity (3+) with >50% of cells staining for AKR1B10 (A), positive (2+) with 10%–50% of cells staining (B), minimally positive (1+) with 5%–10% of cells staining (C) and negative (0) with <5% of cells staining for AKR1B10 (D).
Figure 2
Figure 2
AKR1B10 expression in hepatocellular carcinomas. Hepatocellular carcinoma (HCC) arising in a cirrhotic liver (A; H&E stain, 100X). Strong and diffuse AKR1B10 protein expression in HCC with faint cytoplasmic staining observed in the proliferating cells at the periphery of regenerative nodules (B, 100X and C, 600X). HCC in a non-cirrhotic liver (D; H&E stain, 200X) highlights strong and diffuse cytoplasmic and nuclear staining of AKR1B10 (E, 200X) and negligible AKR1B10 expression in the adjacent hepatic parenchyma (F, 600X).
Figure 3
Figure 3
AKR1B10 expression in benign mass-forming liver lesions. Faint cytoplasmic staining of AKR1B10 can be observed in the proliferating cells adjacent to the central scar in focal nodular hyperplasia (A, 100X; B, 400X; C, 600X). Negligible AKR1B10 expression was identified in hepatic adenomas (D, 200X; E, 600X).
Figure 4
Figure 4
Silencing of AKR1B10 dynamic expression using a shRNA approach. Western blot demonstrates markedly decreased expression of AKR1B10 in 2 separate Hu7 knockdown clones (#1 and #2, respectively) (A) with concomitant decrease in colony size and formation that parallels AKR1B10 expression (B and C; *p<0.05).
Figure 5
Figure 5
Effect of shRNA-mediated silencing of AKR1B10 expression on apoptosis and chemosensitivity based on flow cytometry. Inhibition of AKR1B10 expression results in increased cell apoptosis based on Annexin 5 expression. Compared to vector, Hu7 cells silenced using shRNA to AKR1B10 had increased levels of apoptosis (A; red squares), which was a function of AKR1B10 expression levels. Hu7 cells treated with vector control exhibited 3.03±0.5% apoptosis, in contrast to 5.39±0.3% and 3.74±1.3% percent in the shRNA clones #1 and #2, respectively (B). Dynamically silenced clones were treated with 50μM HHE as control or with the chemotherapeutic agent doxorubicin (3μM) for 24 hrs and analyzed for apoptosis by flow cytometry. Silencing of AKR1B10 expression resulted in increased apoptosis following treatment with HHE as control as seen by Annexin V positivity in the scatter plots (red boxes) (C; red boxes). Exposure of shRNA treated cells to doxorubicin resulted in a marked increase in apoptosis compared to vector as well as HHE treated cells. Hu7 cells treated with vector control had similar levels of apoptosis following treatment with HHE and doxorubicin (6.17±1.0% vs. 7.58±1.2%). In contrast, Hu7 cells treated with shRNA to AKR1B10 had marked apoptosis following treatment with doxorubicin for shRNA#1 and #2 (34.2±3.0% and 23.6±2.8%, respectively) (D).
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References

    1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. - PubMed
    1. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27:1485–1491. - PMC - PubMed
    1. Wong R, Corley DA. Racial and ethnic variations in hepatocellular carcinoma incidence within the United States. Am J Med. 2008;121(6):525–531. - PubMed
    1. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45(4):529–538. - PubMed
    1. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51(6):1972–1978. - PubMed

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