Background: AURKA, Aurora kinase A encoding gene, is an important signaling hub gene for mitosis. In recent years, AURKA has been implicated in the occurrence and development of several cancers. However, its relationship with the tumor microenvironment in skin cutaneous melanoma (SKCM) and the molecular mechanisms underlying its effects are still unclear. Method：We adopted a variety of bioinformatics methods to comprehensively analyze the potential carcinogenesis of AURKA in SKCM, and constructed a prognostic nomogram model. We also dentified an inhibitor targeting AURKA and verified its therapeutic effects against SKCM using the molecular docking technology. Results:We found that abnormally high expression of AURKA was responsible for driving the occurrence and development of SKCM, and affected various pathological factors in SKCM. In addition, AURKA was established as an independent marker of poor SKCM prognosis. We also characterized the potential mechanisms by which AURKA manifests its effects in SKCM and found that AURKA inhibits the infiltration of CD8+ T cells and promotes hypoxia by activating the TGF-β signaling pathway. At the same time, the high AURKA expression group had higher tumor stemness index and promoted cell proliferation and metastasis. Finally, the small molecule compound ZNC97018978 targeting AURKA screened by molecular docking technology can inhibit the proliferation, invasion and metastasis of SKCM. The possible mechanism is that ZNC97018978 induces apoptosis by arresting the cell cycle, thereby inhibiting cell proliferation. Conclusion:AURKA is the core hub gene driving the occurrence and development of SKCM, and its expression is regulated by epigenetic modifications. AURKA can regulate the infiltration level of various immune cells in the tumor microenvironment, reshape the immunosuppressive tumor microenvironment, and apoptosis, and hypoxia. Thus, it is a prognostic biomarker and potential therapeutic target in SKCM. ZNC97018978 is an effective and safe inhibitor of AURKA in vitro; its safety and effectiveness in vivo as a potential treatment for cutaneous melanoma should be further determined.

Skin cutaneous melanoma (SKCM) has a low early detection rate and a high mortality rate. There are many problems such as side effects and drug resistance in existing therapeutic drugs. Current studies have confirmed that SKCM pathogenesis-related genes promote the invasion and metastasis of cutaneous melanoma, but their roles in the tumor microenvironment (TME) remain unclear. Network pharmacology provides new opportunities for drug repurposing and repositioning, and is a fast, safe, and inexpensive drug discovery method to find new drugs for the treatment of SKCM. In this study, based on 3 databases (KEGG, OMIM, and Genotype) to obtain SKCM-related genes, and TCGA SKCM dataset, SKCM differential genes in GSE3189 and GSE46517 were intersected to identify SKCM pathogenesis-related differential genes, and the differential genes were immune infiltration and analysis, For survival analysis, a prognostic nomogram risk model was constructed based on the results of multivariate Cox regression analysis for risk stratification and prognosis prediction, then focused on the differential expression of ZC3H12A and its effect on TME. Finally, the protein interaction network method was used to quantify the similarity between 684 drug targets and skin melanoma, and to screen out drugs similar to skin melanoma. Based on 3 databases of KEGG, OMIM, and Genotype, 294 SKCM-related genes and 18 SKCM pathogenesis-related differential genes were obtained, and 18 SKCM pathogenesis-related differential genes were significantly correlated with TME. The constructed prognostic nomogram risk model predicted performance better and provided valuable information for immunotherapy. Multivariate Cox regression analysis and K-M analysis showed that ZC3H12A was a differentially expressed gene affecting the prognosis of SKCM and promoted the infiltration of anti-tumor immune cells CD8 + T cells, B cells, and DC cells. Based on the analysis of the protein interaction network method, 43 drugs were found to have high potential in the treatment of SKCM, and the literature search of these 43 drugs was carried out, and 21 drugs were found to have experimental verification for the treatment of SKCM. Taken together, the differential genes associated with the pathogenesis of SKCM have important roles in the tumor immune microenvironment, clinicopathological features, and prognosis, especially ZC3H12A has a potential role in identifying early SKCM patients. At the same time, it provides a new strategy for the drug development of SKCM and provides a basis for the reuse of SKCM drugs. Supplementary Information The online version contains supplementary material available at 10.1007/s00210-023-02461-1.

Backgrounds: Absent in melanoma 2 (AIM2) is a crucial developmental regulator for innate immune responses and recent reports suggest its vital function in the process of cancer development and progression, however, the mutations, copy number variations (CNV), methylation, and relationship with the tumor microenvironment (TME), along with the underlying molecular biological processes, remain unclear. Methods: the mutations, CNVs, and methylation patterns of AIM2 in patients with skin cutaneous melanoma (SKCM) were systematically analyzed in this study. Its effects on TME, immunotherapy, and prognoses of SKCM patients were also investigated. According to the findings of the multifactorial Cox regression analysis, a prognostic alignment diagram-based model was constructed. Results: The findings showed that AIM2 expression differed significantly in patients with SKCM. The CNVs and gene methylation patterns affected the level of AIM2 expression, and genetic alterations could influence the tumor immunophenotype. The prognostic alignment diagram model had better predictive efficacy and may improve survival rates in patients. The elevated expression of AIM2 led to enhanced immune responses in SKCM patients and could induce cellular pyroptosis, apoptosis, and necrosis. AIM2 could promote CD8+ T-cell infiltration by activating the PANoptosis pathway and M1 macrophage polarization., and this may be a possible mechanism of its action. In addition, significant associations of AIM2 expression with hot tumor, tumor mutational burden (TMB), immune checkpoint-related genes, and microsatellite instability (MSI), were observed. Conclusions:AIM2 is associated with increased abundance of effector CD8+ T-cells, positive responses to immune checkpoint blockade (ICB) treatment, and improved prognoses. Therefore, it could be a putative enhancer and prognostic biomarker for the treatment of SKCM.

Background: AURKA, Aurora kinase A encoding gene, is an important signaling hub gene for mitosis. In recent years, AURKA has been implicated in the occurrence and development of several cancers. However, its relationship with the tumor microenvironment in skin cutaneous melanoma (SKCM) and the molecular mechanisms underlying its effects are still unclear. Method：We adopted a variety of bioinformatics methods to comprehensively analyze the potential carcinogenesis of AURKA in SKCM, and constructed a prognostic nomogram model. We also dentified an inhibitor targeting AURKA and verified its therapeutic effects against SKCM using the molecular docking technology. Results: We found that abnormally high expression of AURKA was responsible for driving the occurrence and development of SKCM, and affected various pathological factors in SKCM. In addition, AURKA was established as an independent marker of poor SKCM prognosis. We also characterized the potential mechanisms by which AURKA manifests its effects in SKCM and found that AURKA inhibits the infiltration of CD8+ T cells and promotes hypoxia by activating the TGF-β signaling pathway. At the same time, the high AURKA expression group had higher tumor stemness index and promoted cell proliferation and metastasis. Finally, the small molecule compound ZNC97018978 targeting AURKA screened by molecular docking technology can inhibit the proliferation, invasion and metastasis of SKCM. The possible mechanism is that ZNC97018978 induces apoptosis by arresting the cell cycle, thereby inhibiting cell proliferation. Conclusion: AURKA is the core hub gene driving the occurrence and development of SKCM, and its expression is regulated by epigenetic modifications. AURKA can regulate the infiltration level of various immune cells in the tumor microenvironment, reshape the immunosuppressive tumor microenvironment, and apoptosis, and hypoxia. Thus, it is a prognostic biomarker and potential therapeutic target in SKCM. ZNC97018978 is an effective and safe inhibitor of AURKA in vitro; its safety and effectiveness in vivo as a potential treatment for cutaneous melanoma should be further determined.

Backgrounds:Absent in melanoma 2 (AIM2) is a crucial developmental regulator for innate immune responses and recent reports suggest its vital function in the process of cancer development and progression, however, the mutations, copy number variations (CNV), methylation, and relationship with the tumor microenvironment (TME), along with the underlying molecular biological processes, remain unclear. Methods: the mutations, CNVs, and methylation patterns of AIM2 in patients with skin cutaneous melanoma (SKCM) were systematically analyzed in this study. Its effects on TME, immunotherapy, and prognoses of SKCM patients were also investigated. According to the findings of the multifactorial Cox regression analysis, a prognostic alignment diagram-based model was constructed. Results: The findings showed that AIM2 expression differed significantly in patients with SKCM. The CNVs and gene methylation patterns affected the level of AIM2 expression, and genetic alterations could influence the tumor immunophenotype. The prognostic alignment diagram model had better predictive efficacy and may improve survival rates in patients. The elevated expression of AIM2 led to enhanced immune responses in SKCM patients and could induce cellular pyroptosis, apoptosis, and necrosis. AIM2 could promote CD8+ T-cell infiltration by activating the PANoptosis pathway and M1 macrophage polarization., and this may be a possible mechanism of its action. In addition, significant associations of AIM2 expression with hot tumor, tumor mutational burden (TMB), immune checkpoint-related genes, and microsatellite instability (MSI), were observed. Conclusions:AIM2 is associated with increased abundance of effector CD8+ T-cells, positive responses to immune checkpoint blockade (ICB) treatment, and improved prognoses. Therefore, it could be a putative enhancer and prognostic biomarker for the treatment of SKCM.