Aldolase B inhibits metastasis through Ten–Eleven Translocation 1 and serves as a prognostic biomarker in hepatocellular carcinoma

Abstract

BackgroundDownregulation of Aldolase B (ALDOB) has been reported in hepatocellular carcinoma. However, its clinical significance and its role in pathogenesis of HCC remain largely unknown.MethodsWe analyzed the expression of ALDOB and its clinical features in a large cohort of 313 HCC patients using tissue microarray and immunohistochemistry. Moreover, the function of stably overexpressed ALDOB in HCC cells was explored in vitro and in vivo. Gene expression microarray analysis was performed on ALDOB-overexpressing SMMC7721 cells to elucidate its mechanism of action.ResultsALDOB downregulation in HCC was significantly correlated with aggressive characteristics including absence of encapsulation, increased tumor size (>5 cm) and early recurrence. ALDOB downregulation was indicative of a shorter recurrence-free survival (RFS) and overall survival (OS) for all HCC patients and early-stage HCC patients (BCLC 0-A and TNM I stage patients). Multiple analyses revealed that ALDOB downregulation was an independent risk factor of RFS and OS. Stable expression of ALDOB in HCC cell lines reduced cell migration in vitro and inhibited lung metastasis, intrahepatic metastasis, and reduced circulating tumor cells in vivo. Mechanistically, we found that cells stably expressing ALDOB show elevated Ten–Eleven Translocation 1 (TET1) expression. Moreover, ALDOB expressing cells have higher levels of methylglyoxal than do control cells, which can upregulate TET1 expression.ConclusionThe downregulation of ALDOB could indicate a poor prognosis for HCC patients, and therefore, ALDOB might be considered a prognostic biomarker for HCC, especially at the early stage. In addition, ALDOB inhibits the invasive features of cell lines partly through TET1 expression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0437-7) contains supplementary material, which is available to authorized users.

High Expression of Aldolase B Confers a Poor Prognosis for Rectal Cancer Patients Receiving Neoadjuvant Chemoradiotherapy

“…Furthermore, Aldolase B under-expression in HCC was significantly associated with adverse clinico-pathological characteristics and worse recurrence-free survival and overall survival in both univariate and multivariate analyses (all P < .05) 15. By using HCC cell lines for in vitro and in vivo study in the same article, over-expression of Aldolase B was also negatively correlated with cell migration in vitro and occurrence of lung metastasis and intrahepatic metastasis, as well as the numbers of circulating tumor cells in vivo 15. On the contrary, up-regulation and over-expression of ALDOB gene and Aldolase B protein were detected in human tissue of pseuomyxoma peritonei (PMP) 18.…”

“…Nevertheless, down-regulation of ALDOB gene or Aldolase B protein were frequently observed in HCC tissues 13, 14, 16, 33-35. Furthermore, Aldolase B under-expression in HCC was significantly associated with adverse clinico-pathological characteristics and worse recurrence-free survival and overall survival in both univariate and multivariate analyses (all P < .05) 15. By using HCC cell lines for in vitro and in vivo study in the same article, over-expression of Aldolase B was also negatively correlated with cell migration in vitro and occurrence of lung metastasis and intrahepatic metastasis, as well as the numbers of circulating tumor cells in vivo 15.…”

Aldolase B Overexpression is Associated with Poor Prognosis and Promotes Tumor Progression by Epithelial-Mesenchymal Transition in Colorectal Adenocarcinoma

“…Although the role of aldolase in metabolism is well established, there is growing evidence for many alternative functions of this enzyme. In particular, aldolase interacts with various proteins unrelated to glycolytic enzymes, including F-actin [23], ARNO [24], tubulin [25] and is crucial for proliferation [26] and invasion [27] of cancer cells through a non-glycolytic pathway. In the present study, ALDOB was highly expressed in CRC and its expression was correlated with tumor stage.…”

Overactivated neddylation pathway in human hepatocellular carcinoma

“…The tissue microarrays and IHC were performed as previously described . After heating, the sections were incubated with primary antibody for 30 min and then with the secondary antibody for an hour at room temperature.…”