AURKA is a prognostic potential therapeutic target in skin cutaneous melanoma modulating the tumor microenvironment, apoptosis, and hypoxia

Abstract

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.

Comprehensive pan-cancer analysis and the regulatory mechanism of AURKA, a gene associated with prognosis of ferroptosis of adrenal cortical carcinoma in the tumor micro-environment

“…We next chose 12 malignancies to investigate the association between AURKA and immune cells in them, finding that all immune cells except Th2 cells were adversely connected with AURKA. Previous research ( Bustos-Moran et al, 2019 ; Sun et al, 2021 ; Long and Zhang, 2022 ) has shown that AURKA may impact T cells, reshape the immunosuppressive tumor microenvironment, apoptosis, and hypoxia and hence contribute to immunological control, particularly CD8 + T cells that govern Th1 regulation. For example, studies ( Han et al, 2020 ) suggest that decreasing Aurora-A activity or deleting the AURKA gene might boost IL10-induced infiltration and growth of CD8 + T cells in malignancies.…”

Bioinformatics Analysis of Programmed Cell Death in Spinal Cord Injury

“…In addition, Cdk1 can also mediate phosphorylation of Ulk1 and Atg13, thus promoting autophagy 55 . Except Cdk1, other hub genes have not been studied in SCI, but they all have the functions of regulating cell cycle, promoting cell proliferation and inhibiting apoptosis, necroptosis, pyroptosis and ferroptosis in other diseases [57][58][59][60][61][62][63][64][65][66][67] .…”

Characteristics and significance of programmed cell death‐related gene expression signature in skin cutaneous melanoma

“…In SKCM, the dysregulation of PCD pathways significantly contributes to multiple facets of tumorigenesis, encompassing tumor initiation, progression, and therapeutic responsiveness 11,12 . Apoptosis is particularly relevant in SKCM, since alterations in the expression of pro‐apoptotic and anti‐apoptotic proteins disrupt the delicate balance between cell survival and death, promoting tumor cell evasion of programmed death and facilitating tumor growth and metastasis 13,14 . Moreover, mounting evidence suggests the implication of alternative PCD mechanisms in SKCM, including pyroptosis and ferroptosis 15,16 .…”

“… 11 , 12 Apoptosis is particularly relevant in SKCM, since alterations in the expression of pro‐apoptotic and anti‐apoptotic proteins disrupt the delicate balance between cell survival and death, promoting tumor cell evasion of programmed death and facilitating tumor growth and metastasis. 13 , 14 Moreover, mounting evidence suggests the implication of alternative PCD mechanisms in SKCM, including pyroptosis and ferroptosis. 15 , 16 Pyroptosis has been implicated in promoting inflammation and fostering the progression of SKCM.…”