Aldo-Keto Reductases as Early Biomarkers of Hepatocellular Carcinoma: A Comparison Between Animal Models and Human HCC
The intrinsic heterogeneity of hepatocellular carcinoma (HCC) represents a great challenge for its molecular classification and for detecting predictive biomarkers. Aldo-keto reductase (Akr) family members have shown differential expression in human HCC, while AKR1B10 overexpression is considered a biomarker; AKR7A3 expression is frequently reduced in HCC.
To investigate the time-course expression of Akr members in the experimental hepatocarcinogenesis.
Using DNA-microarray data, we analyzed the time-course gene expression profile from nodules to tumors (4–17 months) of 17 Akr members induced by the resistant hepatocyte carcinogenesis model in the rat.
The expression of six members (Akr1c19, Akr1b10, Akr7a3, Akr1b1, Akr1cl1, and Akr1b8) was increased, comparable to that of Ggt and Gstp1, two well-known liver cancer markers. In particular, Akr7a3 and Akr1b10 expression also showed a time-dependent increment at mRNA and protein levels in a second hepatocarcinogenesis model induced with diethylnitrosamine. We confirmed that aldo-keto reductases 7A3 and 1B10 were co-expressed in nine biopsies of human HCC, independently from the presence of glypican-3 and cytokeratin-19, two well-known HCC biomarkers. Because it has been suggested that expression of Akr members is regulated through NRF2 activity at the antioxidant response element (ARE) sequences, we searched and identified at least two ARE sites in Akr1b1, Akr1b10, and Akr7a3 from rat and human gene sequences. Moreover, we observed higher NRF2 nuclear translocation in tumors as compared with non-tumor tissues.
Our results demonstrate that Akr7a3 mRNA and protein levels are consistently co-expressed along with Akr1b10, in both experimental liver carcinogenesis and some human HCC samples. These results highlight the presence of AKR7A3 and AKR1B10 from early stages of the experimental HCC and introduce them as a potential application for early diagnosis, staging, and prognosis in human cancer.
KeywordsGene expression profile Liver cancer Biomarkers Antioxidant response Tumor heterogeneity
JETM, KNSV, and RSR contributed equally to this work. Authors are grateful to Armando Cruz-Rangel and José Luis Cruz-Colín for their technical assistance. This research was supported by CONACYT-Mexico, Grant: CB-182450 to JIPC.
Compliance with ethical standards
Conflict of interest
Authors declare no conflict of interest.
All applicable institutional guidelines for the care and use of animals were followed, and details are included in the approved protocol:# 0001-02.
Human and animal rights
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee at the Hospital General “Dr. Eduardo Liceaga” and with the 1964 Helsinki Declaration and later amendments.