Although nowadays some progress has been made in the improvement of diagnosis and treatment for HCC in recent years, the prognosis of HCC patients is still poor. Even several markers such as AFP and AFU have been employed extensively, the specificity and sensitivity of these biomarkers are not sufficient[19]. It is false positives that make us hard to distinguish early-stage HCC from other liver disorders, for instance, acute hepatitis and cirrhosis[20]. Therefore, searching for more convenient, more reliable markers which can guide early diagnosis and indicate the prognosis of HCC is an important research direction.
FGL1 has been implicated as both a hepatic protectant and a hepatocyte mitogen conducive to mitogenic and metabolic activity[21]. In cases of liver injury or acute inflammation, FGL1 expression levels are also enhanced[10, 15, 22], and FGL1 can promote the proliferation of normal hepatocytes in vivo. Similarly, FGL1 also can affect the proliferation of HCC cells. Down-regulation of FGL1 in HCC cells may contribute to the growth and proliferation of HCC[23] It has been demonstrated that FGL1 promotes hepatic cell proliferation by an autocrine mechanism while inhibiting HCC cell proliferation via an intracrine pathway[24]. However, the exact role of FGL1 in HCC remains controversial. Therefore, we performed a series of experiments to verify.
Previous research had reported the down-regulation of FGL1 in HCC, and the expression level of FGL1 was strongly related to the differentiation statuses of tumors[25]. Consistently, we confirmed that FGL1 expression of HCC tissues had the lower expression level compared to normal liver tissues by GEPIA in our study. In addition, western blot analysis also confirmed that FGL1 showed lower expression in HCC cell lines (LM3, SKHEP1, 7721, SNU182, C3A, HepaG2, HUH7, and Hep3B cells) than in normal liver cells (LO2), and FGL1 of HCC tissues was lower than normal tissues and peri-tumor tissues. In order to further clarify its prognostic significance in liver cancer, we then performed survival analysis to plot a Kaplan-Meier curve of overall survival using the OncoLnc Database, showing that FGL1 expression level was connected with OS in HCC patients and down-regulated FGL1 was connected with poor OS (P<0.05). As we can see, FGL1 expression was significantly related to individual cancer stages in UALCAN online website. Our results of TMAs demonstrated that FGL1 expression levels in HCC were related to Edmondson grade and metastasis. Multivariate Cox regression analysis certified that FLG1 expression level could be regarded as a prognostic factor for HCC patients. As predicted, the Kaplan-Meier analysis demonstrated that down-regulation of FGL1 was related to poor prognosis of LIHC. Therefore, we hypothesized that the expression levels of FGL1 were linked to the progression and prognosis of HCC and that the prognosis of HCC might be improved by adjusting the expression of FGL1 in the future.
With consistent researches of cancers, FGL1 was paid more and more attention. There were other cancers whose prognoses were also associated with FGL1. Recent evidence showed that the upregulation of FGL1 was linked to poor prognosis of gastric cancer[16]. In LKB1 mutant lung adenocarcinoma, loss of FGL1 could promote angiogenesis and epithelial-mesenchymal transition[26]. Suppression of FGL1 contributed to inhibiting the expression of caspase 3 and PARP1, enhanceing gefitinib to perform the inhibitory and apoptosis-inducing actions in NSCLC cell line PC9/GR[27]. Yeonghoon Son et al. reported that sorafenib-induced antitumous effects were relieved by knocking down FGL1[28]. FGL1 played an inhibitory role in the growth of HCC and acted a part as a tumor suppressor in the proliferation of HCC[23]. Above researches proved that FGL1 could regulate the growth and proliferation of tumor cells. Interestingly, high expression levels of FGL1 were related to high densities of LAG3+cells, confirming that FGL1 was a high-affinity ligand for LAG-3[29]. The activation of T cell could be enhanced and anti-tumor immunity could be promoted by blocking the interaction of FGL1-LAG-3 pathway[18]. Hence, targeting the FGL1-LAG-3 pathway and anti-PD1 dual blockade might play a significant part in the treatment of HCC patients whose anti-PD1 therapy was not efficient. It had reported that FGL1 expression was decreased when oxysophocarpine down-regulated IL-6-mediated JAK2/STAT3 signaling, which resulted in enhancing the immunotherapy effect of CD8+ T cells against HCC in vivo and in vitro[30]. Above evidences proved that FGL1 and LAG-3 were strongly connected with the clinicopathological features and prognosis of various tumors[31]. Our study was validated with clinical data on the basis of biogenic evidence and demonstrated its prognostic significance in HCC. Nevertheless, the underlying mechanisms of signaling pathways in HCC remained unclear. Further study and improvement were needed for further mechanisms, and we would continue to explore the detailed mechanisms between FGL1 and HCC in the future. In conclusion, our study indicated that FGL1 might be a potential prognosis indicator for HCC. And our study provided a basis for further study of FGL1 in HCC.