Necroptosis, as a newly discovered mode of regulated cell death, played an important role in maintaining a stable environment and embryonic development in the body. It was also a determinant of the pathological etiology of a variety of human diseases[27]. However, the regulatory mechanism of necroptosis and its correlation with tumor pathological mechanisms still faced many problems and challenges. Under different conditions, necroptosis can not only directly remove tumor cells, but also release damage-associated molecular patterns (DAMPs) to recruit immune cells, build a tumor microenvironment immune signaling system, and indirectly clear tumor cells[28]. It was precise because of necroptosis that it played a dual role in the development of tumorigenesis and anti-tumor therapy. We needed to further explore the key molecules of necroptosis and the exact molecular mechanisms that interact with other genes. Especially in recent years, some lncRNAs studies have shown their important position in STAD, which can be used as a new biomarker for the early diagnosis and a new target for prevention in STAD. Therefore, the role of necroptosis-related lncRNAs in STAD and the anti-tumor immune response can be further elucidated to maximize the anti-tumor effect of necroptosis.
Necroptosis of tumor cells may promote tumorigenesis and metastasis by modulating the TME. In pancreatic ductal carcinoma, RIPK1 and RIPK3 expression were elevated. The deletion of RIPK3 or inhibition of RIPK1 in vivo experiments delayed the progression of pancreatic ductal carcinoma in mice. This phenomenon was associated with an enhanced antitumor immune response, as increased lymphocyte infiltration and decreased immunosuppressive medullary cell infiltration can be observed in RIPK3-deficient pancreatic ductal carcinoma[6]. A recent study used phosphorylated MLKL-specific antibodies to detect necrotizing apoptosis of tumor cells occurring in mouse models of breast cancer MMVT-PyMT[29]. These studies suggest that tumor necroptosis occurred in vivo and showed a pro-tumor effect by stimulating the immune microenvironment that promoted tumor progression. The pro-tumor effects of necroptosis may also be caused by necroptosis of non-tumor cells. Necroptosis of intestinal epithelial cells had been reported to promote cancer by inducing colonic inflammation. In addition, the application of necroptosis drug inhibitors such as necrostatin⁃1 (Nec-1) in a dextran sulfate sodium-induced model of acute colitis significantly inhibits the occurrence of associated tumors due to colitis in mice[30]. In our study, we analyzed the expression of 67 necroptosis-related genes in STAD and found that necroptosis existed in STAD. Therefore, the development of therapeutic strategies that induce necroptosis of tumor cells showed great potential in STAD treatment.
LncRNA HOTAIR, one of the earliest representative LncRNAs, had shown that the higher the expression level of HOTAIR, the greater the risk of STAD and the worse the prognosis. Li et al had shown that BRD4 was a transcriptional regulator of MAGI2-AS3, which can promote the epithelial-mesenchymal transition (EMT) of MAGI2-AS3, thereby promoting the invasion and metastasis of STAD[31]. Numerous studies showed that its role as a molecular marker of tumors related to STAD had been affirmed by researchers. LncRNAs were widely distributed in peripheral plasma/blood, saliva, gastric juice, urine, and other fluids, and were stable and easy to detect. Zhao et al detected serum lncRNA HOTTIP in 126 patients with STAD and 120 healthy people (control group)[32]. After evaluating and comparing the diagnostic capacity of HOTTIP with other serum biomarkers, it was found that the AUC of HOTTIP's ability to diagnose STAD was significantly higher than that of carcinoembryonic antigen (CEA), CA19-9, CA72-4. This suggested that HOTTIP was superior to both in the diagnosis of STAD. Cao et al found that the serum lncRNA SPRY4-IT1 in patients with STAD was highly enriched with normal people[33]. And in patients with large tumor volume, deep invasion depth, positive lymph node metastasis, and advanced gastric cancer, high expression of SPRY4-IT1 were more common. This suggested that SPRY4-IT1 can be used as an early diagnostic marker and clinical staging indicator of STAD. In recent years, a large number of studies had shown that lncRNA was closely related to the prognosis of patients with STAD, and its mechanism had gradually been confirmed. He et al detected the expression of lncRNA UCA1 in 60 cases of STAD tissue and normal tissues, and the median survival of the low expression group of UCA1 was significantly longer than that of the high expression group of UCA1[34]. This indicated that UCA1 overexpression predicts poor prognosis in patients with STAD. Chen et al. detected the expression levels of lncRNA VPS9D1-AS1 in 126 cases of STAD and normal tissues, and the results showed that their expression in tumor tissues was significantly downregulated[35]. The univariate and multifactor survival analysis showed that VPS9D1-AS1 expression was an independent prognostic indicator in patients with STAD. In our study, a total of 472 necroptotic-related lncRNAs were found. Through co-expression analysis, 21 lncRNAs associated with necroptosis have significant OS correlations. We believed that with the extensive and in-depth development of research, the biological effects and molecular mechanisms of necroptosis-related lncRNAs will be further elucidated, and provided new ideas and targets for the diagnosis and treatment of STAD.
In our study, a risk prognostic model consisting of 21 necroptosis-related lncRNAs was constructed to better assess the prognosis of STAD patients. There was already evidence that lncRNAs were key regulators of the immune response, involved in the immune response and gene activation, and promoted immunophenotyping[36, 37]. With the remarkable results of immunotherapy in cancer treatment, immune-related lncRNAs had gradually become a new hot spot. It as a prognostic factor for a variety of tumors, including pancreatic cancer[38], malignant glioma[39], and breast cancer[40]. Considering that the prognosis of tumors was affected by multiple factors, we further combined other clinical features and constructed a nomogram to predict the individual survival rate of STAD patients, which provided a basis for the clinical decision of STAD. Studies in tumor immunology had also found that necroptosis had anti-tumor effects. Necroptosis may play an important role in stimulating immunogenicity and promoting anti-tumor immune surveillance[41]. Some studies had shown that tumor cells undergo necroptosis after releasing interleukin-1α (IL-1α) to activate dendritic cells (DCs). Activated DCs induced an anti-tumor immune response by producing cytotoxic IL-12 or activating CD8 + T cells to eliminate tumor cells[10, 11]. Similarly, the DAMPs released by tumor cells undergoing necroptosis can excite tumor antigen presentation in CD8 + T cells[12]. In addition, the natural killer T (NKT) cells had been reported to be involved in RIPK3-mediated anti-tumor immune responses. Because the deletion of RIPK3 impaired the antitumor activity of NKT cells[42]. In our study, we found that CD44 expression was the highest among all clusters. CD44 was a recognized marker of tumor stem cells and was a key regulator of the EMT, involved in tumorigenesis, progression, and metastasis. Immunotherapy targets and sensitivity of chemotherapy-related drugs were screened according to necroptosis-related lncRNAs. Therefore, fully elucidating the mechanism of necroptosis-related lncRNAs in STAD will deepen the understanding of necroptosis-related lncRNAs enhancing tumor immune response, which will help to explore the mechanism of immunotherapy resistance in STAD.