Background. Inflammation is an important hallmark of cancer. Fibrinogen and albumin are both vital factors in systemic inflammation. This study investigated the prognostic value of the fibrinogen/albumin ratio in HCC patients who underwent curative resection. Methods. HCC patients (n=151) who underwent curative resection were evaluated retrospectively. The optimal cutoff value for the fibrinogen/albumin ratio was selected by receiver operating characteristic (ROC) curve analysis. Correlations between preoperative fibrinogen/albumin ratios and clinicopathologic characteristics were analyzed by χ² test. The area under the receiver operating characteristic curve (AUC) was calculated to compare the prognostic value of the fibrinogen/albumin ratio with other prognostic scores (neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and albumin-bilirubin (ALBI) score). The overall survival (OS) and time to recurrence (TTR) were assessed by the log-rank test and the Cox proportional hazard regression model. Results. An optimal cutoff value of the preoperative fibrinogen/albumin ratio (0.062) was determined for 151 patients who underwent curative resection for HCC via a ROC curve analysis. Fibrinogen/albumin ratio > 0.062 was significantly associated with microvascular invasion, an advanced BCLC stage, and ALBI grade. Multivariate analyses revealed that fibrinogen/albumin ratio was an independent predictor for OS (P=0.003) and TTR (P=0.035). The prognostic ability of fibrinogen/albumin ratio was comparable to other prognostic scores (NLR, PLR, and ALBI score) by AUC analysis. Patients with a fibrinogen/albumin ratio > 0.062 had lower 1-, 3-, and 5-year OS rates (66.0%, 41.8%, and 28.2% versus 81.9%, 69.3%, and 56.1%, resp., P<0.001) and higher 1-, 3-, and 5-year recurrence rates (60.9%, 79.2%, and 90.5% versus 49.5%, 69.1%, and 77.1%, resp., P=0.008) compared with patients with fibrinogen/albumin ratio ≤ 0.062. Conclusion. The preoperative fibrinogen/albumin ratio is an effective prognostic factor for HCC patients who underwent curative resection. An elevated fibrinogen/albumin ratio significantly correlates with poorer survival and a higher risk of recurrence in HCC patients.

Background Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, with a poor long-term prognosis worldwide. The functional deregulations of global transcriptome were associated with the genesis and development of HCC, but lacks systematic research and validation. Methods A total of 519 postoperative HCC patients were included. We built an interactive and visual competing endogenous RNA network. The prognostic signature was established with the least absolute shrinkage and selection operator algorithm. Multivariate Cox regression analysis was used to screen for independent prognostic factors for HCC overall survival. Results In the training set, we identified a four-gene signature (PBK, CBX2, CLSPN, and CPEB3) and effectively predicted the overall survival. The survival times of patients in the high-score group were worse than those in the low-score group (p = 0.0004), and death was also more likely in the high-score group (HR 2.444, p < 0.001). The results were validated in internal validation set (p = 0.0057) and two external validation cohorts (HR 2.467 and 2.6). The signature (AUCs of 1, 2, 3 years were 0.716, 0.726, 0.714, respectively) showed high prognostic accuracy in the complete TCGA cohort. Conclusions In conclusion, we successfully built a more extensive ceRNA network for HCC and then identified a four-gene-based signature, enabling prediction of the overall survival of patients with HCC.

Long noncoding RNAs (lncRNAs) are involved in a variety of biological processes such as tumor proliferation and metastasis. A close relationship between hepatitis B virus X protein (HBx) and SMYD3 in promoting the proliferation and metastasis of hepatocellular carcinoma (HCC) was recently reported. However, the exact oncogenic mechanism of HBx-SMYD3 remains unknown. In this study, by performing lncRNA microarray analysis, we identified a novel lncRNA that was regulated by both HBx and SMYD3, and we named it lncIHS (lncRNA intersection between HBx microarray and SMYD3 microarray). lncIHS was overexpressed in HCC and decreased the survival rate of HCC patients. Knockdown of lncIHS inhibited HCC cell migration, invasion, and proliferation, and vice versa. Further study showed that lncIHS positively regulated the expression of epithelial mesenchymal transition (EMT)-related markers c-Myc and Cyclin D1, as well as the activation of the ERK- and AKT-signaling pathways. lncIHS exerted its oncogenic effect through ERK and AKT signaling. Moreover, results from transcriptome-sequencing analysis and mass spectrometry showed that lncIHS regulated multiple genes that were the upstream molecules of the ERK- and AKT-signaling pathways. Therefore, our findings suggest a regulatory network of ERK and AKT signaling through lncIHS, which is downstream of HBx-SMYD3, and they indicate that lncIHS may be a potential target for treating HCC.

Tumor metastasis is the major reason for poor prognosis of hepatocellular carcinoma (HCC) patients after hepatic resection. SMYD3 has been demonstrated to promote liver tumor metastasis in mice. However, the detailed molecular mechanism is still largely unknown. The effect of SMYD3 on invasiveness and metastasis of HCC was analyzed by immunohistochemistry, migration assay, invasion assay, wound healing assay and in vivo lung metastasis assay. Mass spectrometry analysis was conducted using proteins pulled down by H3K4me3 antibody in SMYD3-overexpressing cells. Luciferase reporter, chromatin immunoprecipitation, Electrophoretic mobility shift assay were used to measure the regulation of SLUG transcription by SMYD3-ANKHD1. In addition, the role of SMYD3-ANKHD1 in determining clinical outcomes for HCC patients was investigated by immunohistochemistry in 243 HCC tissues. SMYD3 was an independent prognostic factor of HCC and promoted migration and invasion of human HCC cells. ANKHD1 was identified by mass spectrometry as a co-regulator with SMYD3. ANKHD1 interacted with H3K4me3 when cells were overexpressing SMYD3. The pro-migratory and pro-invasive effects of SMYD3 were attenuated when ANKHD1 was knocked down by siRNA. Furthermore, we found that SMYD3 bound and activated the SLUG gene promoter in a manner associated with elevating H3K4me3, H3K9Ac and H3K14Ac. Knockdown of ANKHD1 could attenuate the SMYD3-dependent activation of Slug expression. We further detected the expression of SMYD3 and ANKHD1 in 243 HCC patients and found that patients with positive coexpression of SMYD3 and ANKHD1 (SMYD3+ANKHD1+) had the shortest overall and recurrence-free survival. Our findings provide a novel molecular mechanism for the SMYD3-regulated HCC migration and metastasis, and indicates that SMYD3-ANKHD1 may be a potential target for treating HCC.