PMID- 29357919 OWN - NLM STAT- MEDLINE DCOM- 20190509 LR - 20190509 IS - 1756-9966 (Electronic) IS - 0392-9078 (Print) IS - 0392-9078 (Linking) VI - 37 IP - 1 DP - 2018 Jan 22 TI - MCM6 promotes metastasis of hepatocellular carcinoma via MEK/ERK pathway and serves as a novel serum biomarker for early recurrence. PG - 10 LID - 10.1186/s13046-017-0669-z [doi] LID - 10 AB - BACKGROUND: The 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. METHODS: The 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. RESULTS: MCM6 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). CONCLUSIONS: Our 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. FAU - Liu, Mingyu AU - Liu M AD - Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510315, China. AD - Cancer center, Southern Medical University, Guangzhou, Guangdong, 510315, China. FAU - Hu, Qiaoting AU - Hu Q AD - Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510315, China. AD - Cancer center, Southern Medical University, Guangzhou, Guangdong, 510315, China. FAU - Tu, Mengxian AU - Tu M AD - Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510315, China. AD - Cancer center, Southern Medical University, Guangzhou, Guangdong, 510315, China. FAU - Wang, Xinyi AU - Wang X AD - Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China. FAU - Yang, Zike AU - Yang Z AD - Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510315, China. AD - Cancer center, Southern Medical University, Guangzhou, Guangdong, 510315, China. FAU - Yang, Guoxiong AU - Yang G AD - Medical Imaging Center, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, 518100, China. FAU - Luo, Rongcheng AU - Luo R AD - Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510315, China. luorc02@vip.163.com. AD - Cancer center, Southern Medical University, Guangzhou, Guangdong, 510315, China. luorc02@vip.163.com. LA - eng GR - 201604020009/Science and Technology Foundation of Guangzhou, China/ GR - 2016ZC0056/Science and Technology Foundation of Guangdong Province, China/ PT - Journal Article DEP - 20180122 PL - England TA - J Exp Clin Cancer Res JT - Journal of experimental & clinical cancer research : CR JID - 8308647 RN - 0 (Biomarkers, Tumor) RN - EC 3.6.4.12 (MCM6 protein, human) RN - EC 3.6.4.12 (Minichromosome Maintenance Complex Component 6) SB - IM MH - Adult MH - Aged MH - *Biomarkers, Tumor MH - Carcinoma, Hepatocellular/genetics/*metabolism/mortality/*pathology MH - Cell Line, Tumor MH - Epithelial-Mesenchymal Transition/genetics MH - Gene Expression MH - Gene Knockdown Techniques MH - Hepatectomy MH - Humans MH - Immunohistochemistry MH - Liver Neoplasms/genetics/*metabolism/mortality/*pathology MH - *MAP Kinase Signaling System MH - Middle Aged MH - Minichromosome Maintenance Complex Component 6/*blood/genetics MH - Neoplasm Grading MH - Neoplasm Staging MH - Prognosis MH - Proportional Hazards Models MH - ROC Curve MH - Recurrence MH - Treatment Outcome PMC - PMC5778693 OTO - NOTNLM OT - EMT OT - MEK/ERK pathway OT - Metastasis OT - Minichromosome maintenance complex component 6 OT - Survival COIS- ETHICS APPROVAL: Clinical data have been approved by the Integrated Hospital of Traditional Chinese Medicine of Southern Medical University Office and approved by the patients. All animal handling and procedures were approved by the Animal Care and Use Committee of Southern Medical University. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/01/24 06:00 MHDA- 2019/05/10 06:00 PMCR- 2018/01/22 CRDT- 2018/01/24 06:00 PHST- 2017/11/19 00:00 [received] PHST- 2017/12/25 00:00 [accepted] PHST- 2018/01/24 06:00 [entrez] PHST- 2018/01/24 06:00 [pubmed] PHST- 2019/05/10 06:00 [medline] PHST- 2018/01/22 00:00 [pmc-release] AID - 10.1186/s13046-017-0669-z [pii] AID - 669 [pii] AID - 10.1186/s13046-017-0669-z [doi] PST - epublish SO - J Exp Clin Cancer Res. 2018 Jan 22;37(1):10. doi: 10.1186/s13046-017-0669-z.