Ribonucleotide reductase M2B inhibits cell migration and spreading by early growth response protein 1-mediated phosphatase and tensin homolog/Akt1 pathway in hepatocellular carcinoma

Abstract

Ribonucleotide reductase (RR)M2B is an enzyme belonging to the ribonucleotide reductase enzyme family, which is essential for DNA synthesis and repair. RRM2B plays an important role in tumor progression and metastasis; however, little is known about the expression and underlying molecular mechanisms of RRM2B in hepatocellular carcinoma (HCC). In the present study, we report that down-regulation of RRM2B in HCC is negatively associated with intrahepatic metastasis, regardless of p53 status. Moreover, the ectopic overexpression of RRM2B decreased HCC cell migration and invasion in vitro, whereas silencing RRM2B expression resulted in increased migration and invasion in vitro and intrahepatic and lung metastasis in vivo. Additionally, knockdown of RRM2B by short hairpin RNA (shRNA) in HCC cells was associated with epithelialmesenchymal transition (EMT), including the down-regulation of E-cadherin, and the concomitant up-regulation of N-cadherin and slug. A further experiment showed that RRM2B inhibited cell migration and spreading through regulation of the early growth response protein 1 (Egr-1) / phosphatase and tensin homolog (PTEN) / Akt1 pathway. Consistently, we also detected a significant correlation between RRM2B and E-cadherin protein expression in HCC tissues. Furthermore, Egr-1 also directly bound to the RRM2B promoter and repressed RRM2B transcription, thereby establishing a negative regulatory feedback loop. Conclusion: These findings indicate that RRM2B suppresses cell migration and spreading by way of modulation of the Egr-1/PTEN/Akt1 pathway. (HEPATOLOGY 2014;59:1459-1470 H uman hepatocellular carcinoma (HCC) is the most common malignant tumor in the liver and third leading fatal cancer.1 The prognosis for HCC remains poor, mainly due to the propensity for metastatic progression and poor response to pharmacological treatment.2 In HCC, the liver is the major target organ of metastasis, which is known as intrahepatic metastasis. The portal vein is the main route for intrahepatic metastases of HCC cells in animal model systems and in human patients. 3,4 Therefore, the identification of metastatic factors and elucidation of the underlying molecular mechanism that are involved in the progression of metastasis become critical issues.

Overexpression of brachyury contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma

“…Interestingly, Brachyury overexpression could promote TGF-β1 upregulation by activating its promoter, while inhibition of its signaling could decrease Brachyury expression, induce a mesenchymal-to-epithelial transition, and provide increased susceptibility to tumor cells towards chemotherapy [38]. The present study focused on the regulation of AKT pathway, because increasing evidence had demonstrated that activated AKT pathway could play a central role in EMT process and tumor metastasis [26][27][28][29]. Activation of Akt in Brachyury-induced EMT was observed in the study, correlating with vimentin induction and E-cadherin downregulation.…”

“…Numerous studies have suggested that Akt activation plays a pivotal role in tumor progression via induction of EMT [26][27][28][29]. Thus, the Akt activation is usually up-and downregulated by tumor suppressor PTEN.…”

Egr-1 promotes hypoxia-induced autophagy to enhance chemo-resistance of hepatocellular carcinoma cells

“…Conversely, Tian et. al addressed that Egr-1 repressed RRM2B transcription and promote the HCC migration through a negative feedback loop [43]. Of note, HGF, a cytokine involved in the progression of hepatocellular carcinoma, up-regulates Egr-1 expression and increases cell scattering and migration through Egr-1-mediated up-regulation of snail [44].…”

miR-15b regulates cisplatin resistance and metastasis by targeting PEBP4 in human lung adenocarcinoma cells

“…24,27 MiR played its role on the target gene through two ways, one was completely complementary pairing with the target gene that might lead to the degradation of the mRNA of the target gene and the other was incompletely complementary pairing with the target gene that might lead to translation inhibition of the target gene. 18,28,29 Because of the ability of incompletely complementary pairing with the target gene, one miR could regulate 200 target genes and played a role in nearly 35% of human diseases. 19,20 In the current study, we demonstrate that upregulation of miR-15b is critical for cisplatin resistance and tumor metastasis of lung adenocarcinoma cells both in vitro and in vivo, and miR-15b induces mesenchymal features and promotes tumor metastasis of chemoresistant lung adenocarcinoma via silencing PEBP4.…”