Minichromosome maintenance 3 promotes hepatocellular carcinoma radioresistance by activating the NF-κB pathway

Abstract

Background Hepatocellular carcinoma (HCC) is the most common tumors in the worldwide, it develops resistance to radiotherapy during treatment, understanding the regulatory mechanisms of radioresistance generation is the urgent need for HCC therapy. Methods qRT-PCR, western blot and immunohistochemistry were used to examine MCM3 expression. MTT assay, colony formation assay, terminal deoxynucleotidyl transferase nick end labeling assay and In vivo xenograft assay were used to determine the effect of MCM3 on radioresistance . Gene set enrichment analysis, luciferase reporter assay, western blot and qRT-PCR were used to examine the effect of MCM3 on NF-κB pathway. Results We found DNA replication initiation protein Minichromosome Maintenance 3 (MCM3) was upregulated in HCC tissues and cells, patients with high MCM3 expression had poor outcome, it was an independent prognostic factor for HCC. Cells with high MCM3 expression or MCM3 overexpression increased the radioresistance determined by MTT assay, colony formation assay, TUNEL assay and orthotopic transplantation mouse model, while cells with low MCM3 expression or MCM3 knockdown reduced the radioresistance. Mechanism analysis showed MCM3 activated NF-κB pathway, characterized by increasing the nuclear translocation of p65, the expression of the downstream genes NF-κB pathway and the phosphorylation of IKK-β and IκBα. Inhibition of NF-κB in MCM3 overexpressing cells using small molecular inhibitor reduced the radioresistance, suggesting MCM3 increased radioresistance through activating NF-κB pathway. Moreover, we found MCM3 expression positively correlated with NF-κB pathway in clinic. Conclusions Our findings revealed that MCM3 promoted radioresistance through activating NF-κB pathway, strengthening the role of MCM subunits in the tumor progression and providing a new target for HCC therapy. Electronic supplementary material The online version of this article (10.1186/s13046-019-1241-9) contains supplementary material, which is available to authorized users.

Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3

“…5d). Among the most significant genes we identified SKP2, IRF2 and MCM3, all related to tumor progression and metastases [33][34][35]. In agreement with these shared cues, 5 signaling pathways (MAPK, JAK-STAT, p53, VEGF and PI3K) that were not significantly different between immunosuppressive monocytes and tumoreducated monocytes, were observed; however, we found other signaling pathways uniquely upregulated in suppressive monocytes NF-κB, TGFβ, TNFα, Hypoxia, TRAIL and EGFR (Additional file 1: Figure S5D).…”

Jie‐Du‐Hua‐Yu Granules Promote Liver Regeneration in Rat Models of Acute Liver Failure: miRNA‐mRNA Expression Analysis

“…In rat models of ALF, DNA replication is essential for hepatic regeneration [ 18 ]. MCM3, a key component of the heterohexameric minichromosome maintenance (MCM) complex, plays an important role in mammalian DNA helicase activity and the initiation of DNA replication [ 24 ]. Similarly, CDK4 plays a key role in cell proliferation, particularly during the progression of cells from the G1 to S phase of the cell cycle [ 25 ].…”

Transcriptional Expression of Minichromosome Maintenance 10 as an Independent Negative Predictor of Survival in Hepatocellular Carcinoma

“…In conformity to their crucial roles in replication, MCM genes are determined as potential prognostic indicators for cancers [10,11] . Previous studies have found that genetic up-regulation or ampli cation of several MCM proteins including MCM2, MCM3, MCM6 and MCM7 can promote cell proliferation and HCC tumorigenicity [12][13][14][15] . However, research on the role of MCM10 in HCC is scarce.…”