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Background Hepatocellular carcinoma (HCC) is the most common malignant liver tumor with poor clinical outcomes. Increasing amount of long non-coding RNAs (lncRNAs) have been revealed to be implicated in the carcinogenesis and progression of HCC. However, the expressions, clinical significances, and roles of most lncRNAs in HCC are still unknown. Methods The expression of lncRNA MCM3AP antisense RNA 1 (MCM3AP-AS1) in HCC tissues and cell lines was detected by qRT-PCR and fluorescence in situ hybridization. Immunoblotting, CCK-8, EdU, colony formation and flow cytometry were performed to investigate the role of MCM3AP-AS1 in HCC cell proliferation, cell cycle and apoptosis in vitro. A subcutaneous tumor mouse model was constructed to analyze in vivo growth of HCC cells after MCM3AP-AS1 knockdown. The interactions among MCM3AP-AS1, miR-194-5p and FOXA1 were measured by RNA pull-down, RNA immunoprecipitation and luciferase reporter assay. Results We revealed a novel oncogenic lncRNA MCM3AP-AS1, which is overexpressed in HCC and positively correlated with large tumor size, high tumor grade, advanced tumor stage and poor prognosis of HCC patients. MCM3AP-AS1 knockdown suppressed HCC cell proliferation, colony formation and cell cycle progression, and induced apoptosis in vitro, and depletion of MCM3AP-AS1 inhibited tumor growth of HCC in vivo. Mechanistically, MCM3AP-AS1 directly bound to miR-194-5p and acted as competing endogenous RNA (ceRNA), and subsequently facilitated miR-194-5p’s target gene forkhead box A1 (FOXA1) expression in HCC cells. Interestingly, FOXA1 restoration rescued MCM3AP-AS1 knockdown induced proliferation inhibition, G1 arrest and apoptosis of HCC cells. Conclusions Our results recognized MCM3AP-AS1 as a novel oncogenic lncRNA, which indicated poor clinical outcomes in patients with HCC. MCM3AP-AS1 exerted an oncogenic role in HCC via targeting miR-194-5p and subsequently promoted FOXA1 expression. Our findings suggested that MCM3AP-AS1 could be a potential prognostic biomarker and therapeutic target for HCC. Electronic supplementary material The online version of this article (10.1186/s12943-019-0957-7) contains supplementary material, which is available to authorized users.

Melatonin is a naturally occurring molecule secreted by the pineal gland and known as a gatekeeper of circadian clocks. Mounting evidence indicates that melatonin, employing multiple and interrelated mechanisms, exhibits a variety of oncostatic properties in a myriad of tumors during different stages of their progression. Tumor metastasis, which commonly occurs at the late stage, is responsible for the majority of cancer deaths; metastases lead to the development of secondary tumors distant from a primary site. In reference to melatonin, the vast majority of investigations have focused on tumor development and progression at the primary site. Recently, however, interest has shifted toward the role of melatonin on tumor metastases. In this review, we highlight current advances in understanding the molecular mechanisms by which melatonin counteracts tumor metastases, including experimental and clinical observations; emphasis is placed on the impact of both cancer and nonneoplastic cells within the tumor microenvironment. Due to the broad range of melatonin's actions, the mechanisms underlying its ability to interfere with metastases are numerous. These include modulation of cell-cell and cell-matrix interaction, extracellular matrix remodeling by matrix metalloproteinases, cytoskeleton reorganization, epithelial-mesenchymal transition, and angiogenesis. The evidence discussed herein will serve as a solid foundation for urging basic and clinical studies on the use of melatonin to understand and control metastatic diseases. K E Y W O R D Sangiogenesis, epithelial-mesenchymal transition, matrix metalloproteinase, melatonin, metastasis

BackgroundThe E3 ubiquitin ligase Fbxw7 functions as a general tumor suppressor by targeting several well-known oncoproteins for ubiquitination and proteasomal degradation. However, the clinical significance of Fbxw7 and the mechanisms involved in the anti-cancer effect of Fbxw7 in HCC are not clear.MethodThe Fbxw7 and YAP expression in 60 samples of surgical resected HCC and matched normal tumor-adjacent tissues were assessed using IHC or immunoblotting. Flow cytometry, caspase 3/7 activity assay, BrdU cell proliferation assay and MTT assay were used to detect proliferation and apoptosis of HCC cells. The regulatory effect of Fbxw7 on YAP in HCC cells was confirmed by qRT-PCR, immunoblotting and immunofluorescence. Co-immunoprecipitation was used to analyze interaction between YAP and Fbxw7. Nude mice subcutaneous injection, Ki-67 staining and TUNEL assay were used to evaluate tumor growth and apoptosis in vivo.ResultsIn this study, we found that Fbxw7 expression was impaired in HCC tissues and loss of Fbxw7 expression was correlated with poor clinicopathological features including large tumor size, venous infiltration, high pathological grading and advanced TNM stage. Additionally, we demonstrated that patients with positive Fbxw7 expression had a better 5-year survival and Fbxw7 was an independent factor for predicting the prognosis of HCC patients. We confirmed that Fbxw7 inhibited HCC by inducing both apoptosis and growth arrest. Elevated YAP expression was observed in the same cohort of HCC tissues. Pearson's correlation coefficient analysis indicated that Fbxw7 was inversely associated with YAP protein expression in HCC tissues. We also found that Fbxw7 regulated YAP protein abundance by targeting YAP for ubiquitination and proteasomal degradation in HCC. Furthermore, restoring YAP expression partially abrogated Fbxw7 induced HCC cell apoptosis and growth arrest in vitro and in vivo.ConclusionThese results indicate that Fbxw7 may serve as a prognostic marker and that YAP may be a potential target of Fbxw7 in HCC.

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MicroRNA-212 (miR-212) has been reported to play oncogenic or tumor suppressive role in different human malignancies. Here, we demonstrated that the mean level of miR-212 in hepatocellular carcinoma (HCC) tissues was significantly lower than that in matched tumor-adjacent tissues. Similarly, the expression of miR-212 was obviously reduced in HCC cell lines as compared with a nontransformed hepatic cell line. Ectopic expression of miR-212 inhibited cell viability and proliferation, and induced apoptosis in HepG2 cells. In contrast, down-regulation of miR-212 increased cell viability and proliferation, and suppressed apoptosis in Bel-7402 cells. In vivo studies showed that miR-212 inhibited tumor growth of HCC via suppressing proliferation and inducing apoptosis. Furthermore, we confirmed that Forkhead box protein A1 (FOXA1) was a direct target of miR-212, and it abrogated the function of miR-212 in HCC. Finally, we disclosed that the aberrant expression of miR-212 and FOXA1 was evidently correlated with poor prognostic features of HCC. MiR-212, FOXA1 and their combination were valuable prognostic markers for predicting survival of HCC patients. In conclusion, miR-212 may serve as a prognostic indicator for HCC patients and exerts tumor suppressive role, at least in part, by inhibiting FOXA1.

Sterol regulatory element-binding protein 1 (SREBP-1) is a well-known nuclear transcription factor involved in lipid synthesis. Recent studies have focused on its functions in tumor cell proliferation and apoptosis, but its role in cell migration and invasion, especially in hepatocellular carcinoma (HCC), is still unclear. In this study, we found that the expression of SREBP-1 in HCC tissues was significantly higher than those in matched tumor-adjacent tissues (p < 0.05). SREBP-1 was expressed at significantly higher levels in patients with large tumor size, high histological grade and advanced tumor-node-metastasis (TNM) stage (p < 0.05). The positive expression of SREBP-1 correlated with a worse 3-year overall and disease-free survival of HCC patients (p < 0.05). Additionally, SREBP-1 was an independent factor for predicting both 3-year overall and disease-free survival of HCC patients (p < 0.05). In vitro studies revealed that downregulation of SREBP-1 inhibited cell proliferation and induced apoptosis in both HepG2 and MHCC97L cells (p < 0.05). Furthermore, wound healing and transwell assays showed that SREBP-1 knockdown prominently inhibited cell migration and invasion in both HepG2 and MHCC97L cells (p < 0.05). These results suggest that SREBP-1 may serve as a prognostic marker in HCC and may promote tumor progression by promoting cell growth and metastasis.