Characterized by the low early diagnosis rate, high malignancy and poor prognosis, GC is a serious threat to human health in our country. At present, the malignant progression of GC has not been fully elucidated. Determining new biomarkers for the diagnosis and prognosis of GC has become a prerequisite to conquer GC. Accumulating evidence indicates the significant influences of lncRNAs on tumorigenesis. lncRNAs impact multiple mixed dimensions in the occurrence and progression of tumors, especially at the transcriptional and posttranscriptional levels. For example, Ning Cui experimentally observed that LINC00511 acted as a therapeutic target in GC treatment, targeting inducing the expression of STAT3 by inhibiting the expression of miR-625-5p. LINC00649 functions as an oncogenic lncRNA in accelerating cell proliferation, migration and epithelial-mesenchymal transition. With the continuous development of molecular biotechnology, lncRNAs related to GC have been discovered one after another, but they are still in rudimentary stages. As the most prevalent internal modification of RNA, m6A has been thoroughly and widely studied recently. Published reports indicated that m6A modification targeted at lncRNAs could affect both the occurrence and progression of GC. Four m6A-methylated and expressed lncRNAs were identified, including RASAL2-AS1, LINC00910, SNHG7 and LINC01105, which exerted regulatory roles on GC cell proliferation. However, the prognostic significance and tumor immune mechanism of m6A-related lncRNAs remain elusive.
This study analyzed m6A-related lncRNAs related to the clinical characteristics of gastric cancer patients and found that 12 lncRNAs were risk factors (HR>1) and 13 lncRNAs were protective factors (HR<1). The risk score constructed from 13 m6A-related lncRNAs was also significantly related to overall survival, clusters and grade (G1-2, G3) were significantly related to prognosis, Cluster 1 was related to the high-risk group, and its prognosis was poor. This shows that the risk model based on m6A-related lncRNAs is reliable.
We constructed a risk score model including thirteen lncRNAs, such as LINC00106, TYMSOS, MED8-AS1, SREBF2-AS1, AL390961.2, AC144546.1, and AC005586.1.
Wang and his colleagues found that the expression of LINC00106 in thyroid cancer was significantly lower than that in normal tissues. LINC00106 suppressed the metastasis and invasion of cancer cells by inhibiting epigenetic-mesogenic transition as a tumor suppressor. A risk score model was developed based on five lncRNAs: LINC00205, TRHDE-AS1, OVAAL, LINC00106, and MIR100HG. Wu verified that the incRNA-based risk model performs well in predicting GC prognosis. LINC00106 could be regarded as a significant prognostic biomarker in gastric cancer, which reached a consensus with our study. Studies have found  that TYMSOS is overexpressed in GC cells and exerts growth-promoting effects on GC. Moreover, TYMSOS, as a competitive endogenous RNA, modulated GC progression at the posttranscriptional level. Unlike the abovementioned investigations, lncRNAs AL390961.2, AC144546.1, and AC005586.1 were first reported in GC, leaving a wide scope for further research.
A number of studies in recent years have shown that m6A can play an important role in cancer immunity through different regulatory factors [21–24]. The m6A regulatory factor in colon cancer has three m6A modification modes, and these three m6A modification modes are closely related to the immunophenotype . The tumor immune microenvironment plays an important role in immunotherapy. It has been reported that tumor infiltrating lymphocytes in the tumor microenvironment promote disease progression and increase the chance of invasion and metastasis. M2 macrophage infiltration correlates with a poor prognosis in colon cancer. Furthermore, a higher fraction of M0 macrophages (P=0.001) and a lower fraction of M2 macrophages (P=0.018) were found to be risk factors for a poorer histological grade of hepatocellular carcinoma. Some studies have reported that tumor-associated macrophage infiltration is associated with invasion, angiogenesis, and poor prognosis in GC. This study found that Cluster 2 is rich in activated memory CD4 T cells and follicular helper T cells and has low activation in stromal cells. The results of the relationship between the risk score and immune cell infiltration showed that B cell memory, resting dendritic cells, M0 macrophages, and M2 macrophages were positively correlated with the risk score (all P <0.01), while resting mast cells, monocytes, activated NK cells, and follicular helper T cells were negatively correlated with the risk score (both P<0.01). In summary, we analyzed stromal cells and immune infiltrating cells in the tumor immune microenvironment, and the results showed that m6A-related lncRNAs were involved in the reprogramming of the tumor immune microenvironment.
This study still has some limitations. First, the effectiveness of this model still needs to be verified in a large number of external queues. Second, the m6A-related lncRNAs selected in this study need to be verified by further functional experiments. It is necessary to further reveal the regulatory network between m6A and lncRNAs.
In conclusion, this study conducted a bioinformatics study on the regulatory mechanism of m6A-related lncRNAs in gastric cancer and screened 25 m6A-related lncRNAs. Different gastric cancer patients have different lncRNA subtypes in terms of overall survival, and the overall survival of Cluster 2 is higher. The prognostic risk score of m6A-related lncRNAs is closely related to clinicopathological characteristics (grade), two subtypes and immune cell infiltration.