Instituto Nacional de Medicina Genómica, Periférico Sur No. 4809, Col. Arenal Tepepan, Delegación Tlalpan, C.P. 14610, Mexico, CDMX, Mexico.
Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, Mexico, Mexico.
Dig Dis Sci. 2018 Apr;63(4):934-944. doi: 10.1007/s10620-018-4943-5. Epub 2018 Jan 30.
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.
肝细胞癌（HCC）的内在异质性对其分子分类和预测生物标志物的检测构成了巨大挑战。醛酮还原酶（Akr）家族成员在人类 HCC 中表现出差异表达，而 AKR1B10 的过表达被认为是一种生物标志物；AKR7A3 的表达在 HCC 中经常降低。
研究 Akr 成员在实验性肝癌发生中的时程表达。
使用 DNA 微阵列数据，我们分析了 17 个 Akr 成员在大鼠耐药肝细胞癌发生模型诱导的结节到肿瘤（4-17 个月）的时程基因表达谱。
六个成员（Akr1c19、Akr1b10、Akr7a3、Akr1b1、Akr1cl1 和 Akr1b8）的表达增加，与两个著名的肝癌标志物 Ggt 和 Gstp1 相当。特别是，Akr7a3 和 Akr1b10 的表达在第二个用二乙基亚硝胺诱导的肝癌发生模型中也表现出 mRNA 和蛋白水平的时间依赖性增加。我们证实，aldo-keto 还原酶 7A3 和 1B10 在九个人类 HCC 活检中共同表达，与 glypican-3 和 cytokeratin-19 无关，这两个是著名的 HCC 生物标志物。因为已经表明 Akr 成员的表达通过抗氧化反应元件（ARE）序列的 NRF2 活性来调节，所以我们在大鼠和人类基因序列中搜索并鉴定了至少两个 Akr1b1、Akr1b10 和 Akr7a3 的 ARE 位点。此外，我们观察到肿瘤中的 NRF2 核易位高于非肿瘤组织。
我们的结果表明，Akr7a3 mRNA 和蛋白水平在实验性肝癌发生和一些人类 HCC 样本中与 Akr1b10 一致地共同表达。这些结果突出了 AKR7A3 和 AKR1B10 从实验性 HCC 的早期阶段存在，并将其引入作为人类癌症早期诊断、分期和预后的潜在应用。
