HCC is a common malignant tumor with high incidence and mortality . And HCC is easy to recur even the tumor was resected as complete as possible, especially among the patients with vascular invasion . The AJCC TNM staging system as a clinical prognostic evaluation method, was not effective to predict the prognosis of HCC patients . Increasing evidence showed that miRNAs were satisfying biomarks in many human malignant tumor .To improve the accuracy of HCC prognostic evaluation, various miRNAs signatures were found based on TCGA-LIHC cohort [10, 24].However, these studies mainly focused on the differentially expressed of miRNAs between normal tissues and tumor tissues. Vascular invasion is an important risk factor. It’s still necessary to investigate the predictive powers and molecular mechanisms of vascular invasion-related miRNAs. The advantage of the present study was identifying prognostic miRNAs via LASSO regression model, which could effectively reduce variables and assure the predictive powers . Additionally, nomogram was established to assess the value of clinical application.
In current study, a total of 125 DEMs were screened out in GEO database, and 3-miRNA signature was selected to predict the overall survival of HCC in TCGA-LIHC cohort. Risk score was constructed based on the three-miRNA signature. Time-dependent ROC analysis demonstrated that risk score had a good prognostic prediction ability both in training set and validation set. And survival analysis showed that risk score was associated with survival significantly. Multivariate Cox regression analysis indicated that risk score is an independent risk factor in HCC. Besides, nomogram could accurately predict the prognosis of HCC patients and was better than clinical stage as the ROC curves and calibration curves showed. The above results suggested that the 3-miRNA signature could play an important role in clinical application.
Risk score contained three miRNAs, which were hsa-mir-210, hsa-mir-149 and hsa-mir-99a. Previous study showed that hsa-mir-210 could be a diagnostic biomark with relatively moderate accuracy in various cancers including breast invasive carcinoma, Lung squamous cell carcinoma and rectum adenocarcinoma . And augmented expression of hsa-mir-210-3p suppressed the expression of negative regulators of NF-κB signaling, which promoted the epithelial to mesenchymal transition, invasion and migration in prostate cancer . Current study also demonstrated that silencing of hsa-mir-210 inhibited the progression of liver cancer . Additionally, studies have reported that miR-210 could promote cancer angiogenesis and venous metastasis in hepatocellular carcinoma [29, 30]. There were studies showed that hsa-mir-149 inhibited the progression of various tumor. Hsa-mir-149 blocked paracrine interactions of macrophages via decreasing the expression of colony-stimulating factor-1 and epidermal growth factor, which could suppress breast cancer metastasis . In liver cancer, mir-149 suppressed tumor progression by restraining the expression of tumor necrosis factor receptor type 1-associated death domain protein in NF-κB signaling pathway . Interestingly, in present study, higher expression of hsa-miR-149 meant worse prognosis in HCC. It is possible that the expression of hsa-mir-149 is increasing to prevent the development of tumor while HCC is progressing. Hsa-mir-99a-5p could act as a diagnostic and prognostic biomarker in gastric cancer . Evidence also verified that miR-99a induced cell cycle arrest, which resulted in suppression of HCC growth . What’s more, miR-99a suppressed the development of many malignancy such as breast cancer, bladder cancer, ovarian cancer [35–37]. However, the mechanisms of above three miRNAs in HCC are not clear and need to investigate further.
To further understand the regulatory mechanism of the 3-miRNA signature in HCC, functional enrichment analysis of target genes was utilized. The target genes of the miRNAs were enriched in Ras signaling pathway, PI3K-Akt signaling pathway, MAPK signaling pathway and so on, which might be potential mechanisms of HCC vascular invasion. There were studies displayed that activated Ras signaling could promote HCC proliferation , and MAPK signaling pathway was associated with epithelial-to-mesenchymal transition, invasion, and metastasis in HCC [39, 40]. Additionally, activation of the PI3K/AKT pathway could also promote HCC progression . These results of enrichment analysis could provide the direction for next research.
Similar to other data mining research, limitations of the study are certain. Firstly, though risk score was checked in validation set of TCGA cohort, it still needs to verify in an external and larger cohort. Secondly, the clinical information of TCGA cohort is not complete, so some HCC samples were excluded, which might affect research results. Taken together, clinical perspective studies and experimental studies should be designed to confirm our results in the future.