Autoimmune diseases are known to result from an abnormal response of the immune system against the body's own tissues. Some autoimmune diseases have been linked to promoting dysplasia of gastric epithelium and increasing the risk of GC. For example, autoimmune gastritis is characterized by abnormal immune response leading to a reduction in gastric parietal cells and hyperplasia of chromaffin cells.And autoimmune gastritis has been associated with GC [7]. The diagnosis of DM can sometimes be challenging due to the absence of specific clinical signs, such as muscle weakness and rash. The relationship between DM and malignant tumors has been a subject of study for a long time. Early studies proposed that DM may have a paraneoplastic nature, given the short time interval between the onset of the two conditions and the parallel trend of their disease courses [8]. Although subsequent research has found that DM patients with malignancies have a worse prognosis, the underlying mechanism requires further exploration [9].
The inflammatory pathological features of DM suggest that it may produce more specific autoantigens in the body. Specifically, the researchers found that the expression level of myositis-specific autoantigen (MSA) was significantly higher in the regenerating myoblasts of myositis tissue than in normal muscle cells. More importantly, myositis-specific antigen levels are increased in cancers closely associated with myositis, such as lung cancer [10]. This suggests that the occurrence of malignant tumors leads to an increased level of myositis-specific antigens, activating immune cells in the body and generating anti-tumor immune responses. Due to the existence of specific immune response mechanisms targeting myositis specific antigens in the body, patients will develop myositis after muscle injury.
Several diagnostic markers with clinical significance have been identified for DM, including various antinuclear antibodies associated with an increased incidence of malignant tumors. For instance, anti-transcription intermediate factor 1 (TIF1) antibodies, targeting tumor suppressor, have shown a high negative predictive value for cancer-associated DM [12, 13]. Patients with positive anti-TIF1-γ antibodies have a 9.4-fold higher risk of malignancy compared to negative patients [14]. Positive anti- nuclear matrix protein (NXP)-2 antibodies have also been associated with an increased incidence of malignancies in DM patients, with the proportion of males being particularly high [15, 16]. Additionally, the incidence of malignancy in patients with anti-SAE antibody-positive DM is approximately 14–57%, although there is no specific advantage for any particular malignancy [17–19].
Existing data show that the pathological manifestations of DM in the skin are hyperkeratosis, dermal edema and epidermal atrophy. The pathological manifestations of DM in the skin are composed of CD4 + lymphocytes and perivascular infiltrate [20]. In muscle tissue, DM primarily exhibits perimyocyte and perivascular inflammatory infiltrates. It is also accompanied by an increase in major histocompatibility complex (MHC) I class expression [21, 22]. The immune-related pathogenesis of DM remains uncertain, but studies suggest that it may be associated with complement activation and type I interferon activity. The activated complement system can lead to inflammation by dissolving endomysial capillaries [23]. The tumor microenvironment, which includes components such as the extracellular matrix, macrophages, lymphocytes, neutrophils, and endothelial cells, plays a tumor suppressor role in the early development of GC. However, under the influence of certain factors, immune tolerance occurs in the tumor microenvironment, promoting the progression of GC. Unlike other solid tumors, GC is not very responsive to immunotherapy. It is necessary to reverse the immune tolerance within the tumor microenvironment to improve the efficacy of immunotherapy in GC patients. Macrophages infiltrating the tumor microenvironment can be divided into two subgroups: M1 and M2. The M1 subgroup exhibits tumor-suppressing properties, while the M2 subgroup has the opposite effect. GC immune tolerance is mediated by the differentiation of macrophages into the M2 subgroup [24]. Cancer-associated fibroblasts (CAFs) secrete numerous cytokines and chemokines in the tumor microenvironment, exerting regulatory effects on immune cells such as T cells and macrophages [25]. Cytokines act as regulators within the GC immune-tolerant tumor microenvironment, inducing various biological processes in immune cells, fibroblasts, and endothelial cells. For example, interleukin 15 (IL-15) and serum interleukin 8 (sIL-8) promote immune escape in GC cells by upregulating PD-L1 expression on the surface of T cells [26, 27]. Tumor-associated macrophages (TAMs) inhibit NK cell killing of GC cells by secreting TGF-β1 and CHI3L1 [27, 28].
In our study, we identified a total of 8 hub genes through differential gene analysis and analysis of their interaction strengths. We analyzed their immune infiltration and found that the high expression group of hub genes exhibited increased infiltration of DCs, iDCs, macrophages, neutrophils, Th1 cells, and Th2 cells. The GO and KEGG analyses of the co-related genes and hub genes yielded similar results, with a high enrichment of immune response-related pathways, cellular components, and functions. These included MHC, cytokines, signaling receptors (ligands), and the activity and differentiation of specific immune cells. These findings suggest that inflammatory responses and immune responses play significant roles in the occurrence and development of DM and GC.
Cytokines, which include interleukins, interferons, the tumor necrosis factor superfamily, colony-stimulating factors, and chemokines, play a crucial role in the occurrence and development of DM and GC. The 8 hub genes identified in our study are closely associated with cytokines and mediate the progression of both diseases through other signaling pathways. For instance, TLR4 is a member of the Toll-like receptor (TLR) family, and its expression is stimulated by antigen-presenting cells (APCs), resulting in the production of various cytokines, chemokines, and their receptors via two pathways [29]. IL1B and IL10 belong to the interleukin cytokine family. Polymorphism in the IL1 gene cluster promotes interleukin-1-β production, which may exacerbate gastric mucosal damage and increase the risk of GC [30]. CXCL8 is a member of the CXC chemokine family and serves as a major mediator of inflammatory responses. Additionally, this protein is secreted by tumor cells to promote tumor migration, invasion, angiogenesis, and metastasis [31–33]. IFNG encodes type II interferon IFN-γ. Sánchez-Zauco et al. found that the levels of IL-1β, IL-10 and interferon-γ (IFN-γ) in the circulating blood of patients with GC were significantly higher than those of normal people [34]. The CD4 gene encodes the CD4 membrane glycoprotein of T lymphocytes, and the CD4 antigen, together with the T cell receptor on T lymphocytes, acts as a co-receptor to recognize antigens displayed by antigen-presenting cells in the context of class II MHC molecules, ultimately resulting in lymphatic Factor production and activation of T helper cells. The protein encoded by STAT3 is a member of the STAT protein family that responds to cytokines and growth factors. The CD4 gene encodes the CD4 membrane glycoprotein of T lymphocytes, and the CD4 antigen, together with the T cell receptor on T lymphocytes, acts as a co-receptor to recognize antigens displayed by antigen-presenting cells in the context of class II MHC molecules, ultimately resulting in lymphatic Factor production and activation of T helper cells. STAT3 is a constituent of the STAT protein family, which exhibits responsiveness to cytokines and growth factors. The activation and interplay of STAT3 and nuclear factor kappa-B (NF-кB) are of paramount importance in facilitating communication in TME. STAT3 helps tumor cells resist apoptosis caused by tumor surveillance and regulates angiogenesis during tumor development[35]. In GC-related studies, STAT3 was found to drive enhancer of zeste homolog 2 (EZH2) transcriptional activation, suggesting a poor prognosis in GC patients [36]. Activated STAT3 mediates autoimmune diseases by inducing differentiation of Th17 cells [37]. We found that phosphorylated STAT3 by receptor-associated kinases, pSTAT3, is significantly elevated in muscle tissue from patients with DM. Receiver characteristic curves suggest that it is a good diagnostic for DM [38].
Non-coding RNAs include miRNAs, lncRNAs and circle RNAsdo not have coding functions but play important roles in gene expression and protein function regulation. Linc-DGCR6-1 belongs to the category of lncRNAs. Linc-DGCR6-1 have been found to be capable of targeting the USP18 protein and regulating the signalling pathway of type 1 IFN. And the type 1 IFN signalling pathway is closely related to tissue injury in DM [39]. The antisense lncRNA, AL136018.1, was found to be overexpressed in the muscle tissue of DM patients. AL136018.1 could increase the transcription level of Cathepsin G (CTSG) gene, which contributed to the excessive infiltration of CD4 + T cells in DM tissues and perivascular [40, 41]. Previous studies have found that some specific non-coding RNAs can promote the differentiation of TAMs into the M2 subgroup and mediate GC immune tolerance [42]. In addition, non-coding RNA can induce drug resistance in GC cells [43]. Platinum is an extremely important drug in the chemotherapy regimen of GC. Studies have found that miR-21 can enhance the resistance of GC cells to cisplatin [44]. The regulatory network between miR-21-5p and STAT3, IL1B and TLR4 was found in the competitive endogenous RNA (ceRNA) network we established. However, the specific molecular mechanism of DM still needs comprehensive and in-depth exploration, especially the regulatory role played by non-coding RNAs other than lncRNA.
Given the close association between DM and malignant tumours, especially GC, it is necessary to explore the commonality at the genetic level between the two. This also provides reference value for our clinical diagnosis and treatment, such as for patients with DM, imaging and laboratory examination of the site of common malignant tumours can be targeted. For the symptoms of DM after diagnosis of GC, it is necessary to carefully identify whether it is paraneoplastic myositis or drug-associated myositis caused by anti-tumour therapy. And we should adopt targeted treatment for myositis symptoms caused by different etiological factors[45]. There are still limitations in our study. For example, whether different key hub genes are suggestive of disease extent at the expression level, and whether the key hub genes have molecular mechanisms that promote the progression of the two diseases, etc. Additional investigation is required to delve into the molecular pathways and ascertain possible biomarkers and therapeutic targets.
Despite the limitations of the study, the findings have significant implications for public health prevention and control of cancer. Identifying key hub genes can potentially aid in the early detection of GC in DM patients and help in improving overall patient outcomes and reducing medical costs.