Hepatocellular carcinoma is one of the most common malignancies worldwide, and although considerable time, effort, and expense have been invested, its incidence and mortality continue to increase annually. Therefore, it is of great clinical significance to explore the early diagnosis of HCC and accurately predict the prognosis, and determine the potential therapeutic targets and prognostic indicators of HCC.
It is known that the TME contains tumor cells and surrounding immune cells, endothelial cells, fibroblasts, extracellular matrix, secreted cytokines, chemokines, etc. Tumors can create a series of favorable conditions for themselves through the TME and even escape the immune cycle. A recent study has found that cellular immune responses are involved in the development of HCC and may be among the factors influencing poor prognosis in HCC. In this study, expression data from the TCGA database was analyzed based on ESTIMATE method, we demonstrated that there were significant differences in EstimateScore, ImmuneScore, StromalScore and TumorPurity between the immunity high group and immunity low group of HCC. Besides, we found that the proportions of TIICs varied between the two groups based on CIBERSORT method.
With the development of next generation sequencing technology, a large number of genomic and transcriptomic sequences are available in public databases. Through mining the public database, researchers found that lncRNAs acted as a key regulator for the development of cancer in various cellular functions, including proliferation, cell differentiation and DNA stability, etc. Although the roles of many lncRNAs in HCC remain elusive, a small part has been extensively investigated. For instance, the HBx-LINE1 activates Wnt signaling, promotes HCC development and progression, and correlates with shorter patient survival. lncRNA HULC is upregulated in HCC and promotes HCC growth, metastasis and drug resistance. LncRNA-WRAP53 is an independent prognostic marker in relapse-free survival and may serve as a serum biomarker for HCC diagnosis and prognosis. These observations point to the considerable potential of lncRNAs as a source of novel targetable molecules for HCC precision therapy and for discovering new diagnostic biomarkers.
Recently, evidence has indicated that lncRNAs can regulate immune cell differentiation and function, such as dendritic cell activity, T cell ratio and metabolism and thus are potential targets for cancer therapeutics and possess predictive value for survival prognosis. Through mining the transcriptome sequencing data via bioinformatics analysis, many studies have already established the lncRNA signature for predicting the prognosis of cancers, including thyroid cancer, breast cancer, renal cell carcinoma, bladder cancer, gastric cancer as well as HCC. In this study, we aimed to construct an immune-related lncRNAs signature in HCC. A total of 331 immune-related genes were obtained from the Molecular Signatures Database (Immune response M19817, immune system process M13664). 236 immune-related lncRNAs were identified by correlation analysis. By using univariate cox regression, we identified six immune-related lncRNAs including MSC-AS1, AC145207.5, SNHG3, AL365203.2, AL031985.3, NRAV as prognostic signature for HCC. By using risk score methods, we developed a six immune-related lncRNA signature which was able to classify HCC patients into the high-risk group and low-risk group with significantly different overall survival. We analyzed the relationship between age, gender, grade, tumor stage and risk score by univariate and multivariate Cox regression analysis. The results showed that only risk score had p < 0.05 in both univariate multivariate Cox regression analysis. The AUC of risk score is 0.775 which was greater than other factors. These data suggested that risk score may be an independent prognostic factor in HCC patients. Then we analyzed the correlation of immune-related lncRNAs and the clinical characteristics, we found that these lncRNAs increased with grade, tumor-stage and T-stage. To investigate the applicability of the signature in different clinical conditions, stratification analyses were performed. It was observed that the signature was able to assess the risk score in subgroups of HCC patients and predict HCC patients survival in each stratum of age, gender, stage and T-stage. Besides, GSEA was employed to further verify the functional annotation, and we found that immune-related responses activation of immune response, immune response and immune system process were enriched in high-risk groups.
Immune cell infiltration in the TME may affect tumor cell survival, metastasis, and therapy resistance[22, 23]. We made a comprehensive analysis of the TME immune cells infiltration landscape by estimation the abundance of 22 TIICs in HCC using CIBERSORT method. We found that eosinophils and T cells follicular helper were positive correlated with lncRNA prognostic signature and monocytes, NK cells activated, plasma cells and T cells CD4 memory resting were negative correlated with lncRNA prognostic signature. These findings suggested that the six immune-related lncRNA signature may play a role in immune infiltration of HCC. However, the underlying mechanism of this association and its clinical significance in HCC require further investigation.
In conclusion, using bioinformatics methods and qRT-PCR experiment, we identified six immune-related lncRNAs that was correlated with HCC progression and prognosis and may be applied as an independent prognostic indicator in predicting survival for HCC. Besides, the six immune-related lncRNAs were related to the level of infiltration of tumor-infiltrating immune cells. Therefore, the identification of immune-related lncRNA may provide new targets for the research of the molecular mechanisms and immunotherapy of HCC.