RESUMEN

Cervical cancer (CC) is one of the most common cancers in women. However, copy number alteration (CNA)-driven dysregulated genes and their functions in CC are still rarely investigated. In the present study, we conducted integrative analysis of CNA and gene expression data from The Cancer Genome Atlas (TCGA) cervical cancer to identify dysregulated genes triggered by CNAs. The integration of copy number status and RNA expression revealed 763 amplified and 1,391 deleted genes significantly dysregulated by the CNAs (P-value < 1e-8). Among these CNA genes, five driver genes, including PI3KCA, PI3KCB, DVL3, WWTR1, and ERBB2, exhibited a strong association with immune cell infiltration, suggesting that the pathways that they participate in may be involved in regulating immune cell infiltration. Moreover, we also observed that the genes of immunotherapeutic targets were abundantly expressed in the wild-type samples, suggesting that immunotherapy based on these immunotherapeutic targets may be applied to wild-type samples. In addition, the two CNA driver genes, DVL3 and ERBB2, might be sensitive and resistant biomarkers for examining the tumor's response to chemoradiotherapy, respectively. Particularly, the expression of ERBB2 was also observed to be higher in responders of chemotherapy than non-responders. Furthermore, a subset of CNA genes was identified to predict the prognosis of cervical cancer. In summary, our systematic data analysis of these CNA genes not only improved our understanding of the veiled mechanism behind immune cell infiltration, but also provided the potential clinical application of these CNA genes in cervical cancer.

Asunto(s)

Genes Relacionados con las Neoplasias , Genómica , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/inmunología , Biomarcadores de Tumor/metabolismo , Variaciones en el Número de Copia de ADN/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia , Pronóstico , Factores de Riesgo , Transducción de Señal , Neoplasias del Cuello Uterino/terapia

RESUMEN

Interferon regulatory factor (IRF) 4 has been reported to modulate Toll-like receptor (TLR) signalling. Polyinosinic-polycytidylic acid (poly(I:C)) can be specifically recognised by TLR3, triggering the innate immune response and subsequently resulting in pregnancy loss. In the present study, poly(I:C) was administered to mice with or without TLR3 blockade. Chemokine (C-X-C motif) receptor 4 (CXCR4) expression was measured with or without chemokine (C-X-C motif) ligand 12 (CXCL12) inhibition. In cultured murine splenic mononuclear cells, IRF4 was knocked down by a specific short interference (si) RNA. IRF4 mRNA and protein levels and T helper (Th) 17 cell frequencies in the poly(I:C)-treated group were significantly higher than in the phosphate-buffered saline (PBS)-treated control group, and were correlated with a significantly higher embryo resorption rate. Interleukin (IL)-17A and IL-21 levels were markedly lower in the IRF4 siRNA-treated group than in the non-specific siRNA- or vehicle control-treated groups. The CXCR4+ cell frequency was significantly higher among IRF4+ uterine mononuclear and granular cells (UMGCs) compared with IRF4- cells. Inhibition of CXCL12 significantly abrogated poly(I:C)-induced increases in the frequency of IRF4+CXCR4+ cells in UMGCs. IRF4 might play a critical role in TLR3 signalling, which mediates Th17 cell activation and upregulates the expression of IL-17A and IL-21, which results in pregnancy loss. CXCL12 may modulate IRF4+CXCR4+ cell migration at the fetomaternal interface. TLR3 and IRF4 blockade could potentially prevent spontaneous abortion under certain conditions.