MCM6 promotes metastasis of hepatocellular carcinoma via MEK/ERK pathway and serves as a novel serum biomarker for early recurrence

Abstract

BackgroundThe high incidence of recurrence and metastasis of hepatocellular carcinoma (HCC) necessitate the discovery of new predictive biomarkers of invasion and prognosis. Minichromosome maintenance complex component 6 (MCM6), which has been reported to up-regulate in multiple malignancies, was considered to be a novel diagnoses biomarker in HCC. However, its functional contributions and prognostic value remain unclear.MethodsThe expression of MCM6 was analyzed in 70 HCC tissues and 5 HCC cell lines by immunohistochemistry and real-time RT-PCR. The roles of MCM6 in HCC cell proliferation, migration and invasion were explored by CCK8, Wound healing and Transwell assays, respectively. Western blotting and Immunofluorescence staining were conducted to detect the protein expressions of ERK signaling pathway and EMT-related markers. To verify the above findings in vivo, we established subcutaneous xenograft tumor and orthotopic xenograft tumor models in nude mice. Finally, Enzyme-linked immunosorbent assay was used to evaluate the serum MCM6 level.ResultsMCM6 was significantly up-regulated in HCC tissues. Increased MCM6 expression was associated with aggressive clinicopathological features and worse prognosis in HCC patients. These results were consistent with our analyses of The Cancer Genome Atlas database (TCGA). Furthermore, knockdown of MCM6 significantly decreased proliferative and migratory/invasive capability of HCC cells in vitro, as well as decreased tumor volume, weight and the number of pulmonary metastases in vivo. Mechanistic analyses indicated that MCM6 promoted EMT and activated MEK/ERK signaling. More importantly, serum MCM6 levels in HCC patients were significantly higher than those in cirrhosis and healthy controls (P < 0.0001), and allowed distinguishing early recurrence with high accuracy (AUC = 0.773).ConclusionsOur findings indicate that MCM6 predicts poor prognosis and promotes metastasis in HCC. Postoperative serum MCM6 level could be valuable to detect preclinical early recurrence, indicative of a need for more careful surveillance and aggressive therapeutic intervention.Electronic supplementary materialThe online version of this article (10.1186/s13046-017-0669-z) contains supplementary material, which is available to authorized users.

METTL3 Promotes the Progression of Gastric Cancer via Targeting the MYC Pathway

“…It was reported that high MCM5 expression was associated with poor clinicopathological parameters and poor survival in GC. According to a previous report, MCM6 can serve as a prognostic predictor and promote metastasis in hepatocellular carcinoma (HCC) (45)(46)(47). In our research, m6A abundances of MCM5 and MCM6 transcripts were sharply decreased upon the depletion of METTL3 in cells.…”

GTSE1, CDC20, PCNA, and MCM6 Synergistically Affect Regulations in Cell Cycle and Indicate Poor Prognosis in Liver Cancer

“…The minichromosome maintenance protein (MCM) family is implicated in the control of eukaryotic genome replication and proves to be useful markers for tumor proliferation [24]. Several studies demonstrated overexpression of MCM6 also predicts poor survival in patients with several types of cancer, including HCC [31][32][33][34]. Future studies should attempt to clarify the underlying mechanism of GTSE1 together with minichromosome-related protein-mediated DNA replication and cancer prognosis.…”

Gene Expression Alterations and Molecular Analysis of CHEK1 in Solid Tumors

“…Interestingly, CHEK1 was co-expressed with minichromosome maintenance complex component (MCM family) and flap eendonuclease 1 (FEN1) expressed in colorectal cancer. The MCM family (MCMs) has been reported to be associated with numerous cancer types [35][36][37], such as the promotion of metastasis of liver cancer through the Mitogen-activated protein kinase kinase(MEK)/ extracellular signal-regulated kinases (ERK) pathway (MCM6) [38], as a prognostic factor in patients with lung squamous cell carcinoma [39]. Many studies indicate the central roles of MCMs in genome stability, including the regulation of transcription, chromatin remodeling, and checkpoint responses [40][41][42].…”