Because of the continued lack of significant declines in its incidence, mortality, or disability rates, cervical cancer is becoming an increasingly serious public health concern. While there have been some studies on the causes of cervical cancer, it is important to comprehend its pathogenesis and inducers, which include immunological microenvironment, environmental variables, and genetic factors, given the multifaceted character of cervical cancer. Although a wide range of topics have been studied in the present study on this illness, our knowledge of these mechanisms is still extremely diverse. Consequently, a critical component of the creative development of cervical treatment in the future will be the thorough investigation of the underlying concept26.
This research involved examining the TCGA database to assess the transcriptomic variances in telomere genes between cervical cancer specimens and control samples. Through analysis and validation using R software, we identified 327 genes with telomere differences primarily linked to CC, noting that their expression levels may increase or decrease in CC. Through PPI, GO, and KEGG enrichment analysis, the functioning of these crucial genes was examined, leading to the exclusion of 16 key gene composition and prognosis models and an assessment of how changes in telomere genes affect cervical cancer patient survival rates. It was also discovered that they have a close connection to the immune system's response. When integrated with immune cells, this confirmation facilitates additional studies on telomeres in cervical cancer27.
The enrichment analysis of core genes associated with telomeres revealed that these genes are mostly engaged in cell cycle regulation, double-strand break repair, aging of cells, and catalytic activity and replication of DNA. According to research, telomeres eventually deteriorate and exhibit a randomly diminishing pattern during the course of several cell divisions. Telomere shortening frequently results in cell cycle arrest, which sets off the apoptotic process. As a result, research on telomeres is crucial for treating tumors. Previous research has shown that certain age-related processes and human aging illnesses have higher total telomere shortening12,28.
A malfunction in the telomere nucleoprotein complex could expose free chromosome ends to DNA double-strand breaks (DSBS) repair, leading to the fusion of telomere and non-telomere loci. Such irregularities could contribute to the emergence of tumors. The development of cancer is attributed to the stability of replicated telomere arrays, aiding tissue cells in attaining immortality29. Attaining this objective is possible through the activation of telomerase or by triggering different telomere elongation (ALT) routes. Consequently, the reduction in telomere length may be viewed as a strategy to inhibit tumors. Alterations in telomeres, triggered by genetics, either elevate or diminish the likelihood and advancement of cancer in distinct manners30,31. For example, the mechanism of telomere progression in liver cancer has been detailed in the literature.
Accumulating research uncovers a process aligning the cell's destiny with the telomere's condition. This paper delves into the destiny of telomeric RNA within cells and the processes contributing to its initial growth32.
Cervical cancer development is significantly influenced by the immune microenvironment. Presently, it's theorized that tumor cells play a role in various distinct molecules that regulate autoimmune responses. The E7 oncoprotein is capable of diminishing the pro-inflammatory immune signaling route through the interruption of toll-like receptor 9 TLR9 and cGAS-STING pathways. Studies indicate that E6 and E7 disrupt interferon signaling, diminishing the NF-kB pathway and interleukin1β production, all contributing to harm to the host's natural immune response33. Oncoproteins are further involved in the downregulation of major histocompatibility complex (MHC) class I by binding to MHC I promoters33. This increases the likelihood that the HPV virus linked to cervical cancer may infiltrate the body, which is also a major contributing cause to the dismal prognosis of head and neck cancer. The levels of CCL20 may be lowered by blocking these inflammatory pathways. By inhibiting or lessening the aforementioned pathways, it may be possible to avoid or mitigate tumor spread and recurrence during treatment. As a chemokine, CCL20 helps to prevent infection, hemostasis, cell proliferation, and remodeling. It also attracts antigens in the form of delivery cells, such as Langerhans cells, to the virus-infected area34. Immunoinfiltrating data showed that telomere core genes associated with cervical cancer were associated with Mast cells resting, Dendritic cells resting, T cells regulatory (Tregs), T cells CD8, Mast cells activated, Macrophages, Neutrophils, B cells memory, T cells gamma delta, Monocytes and other immune cells were significantly correlated. It has been documented that mast cells contribute to the expansion of blood vessels during the creation and discharge of histamine, a biogenic amine, in various pathological conditions, including allergic responses and conjunctivitis. Histamine may intensify inflammation, leading to heightened capillary permeability and disorders of lymph reflux. Elevated histamine concentrations are linked to multiple tumor types such as cervical, ovarian, vaginal, uterine, vulvar, and colorectal cancers, aiding in the suppression of their proliferation35.
The role of Tregs in HPV infection is to protect tissue from immune-mediated damage at different anatomical subsites36. In addition, macrophages play a key role in the tumor microenvironment, where they have significant effects on blood vessel formation, extracellular matrix remodeling, cancer cell growth, metastasis, and immunosuppressive synergies, as well as on chemotherapeutic drugs and checkpoint blocking immunotherapy resistance. Studies have shown that macrophages have phagocytic function and can produce cytokines such as antibodies, and these immune responses are closely related to the body's immune system. Macrophages have the function of mediating cancer cell phagocytosis and cytotoxic tumor killing, so they have become the main target of cancer therapy37. Neutrophils play a significant function in the tumor immunological microenvironment. The body uses neutrophils as its first line of defense against infections and reacts to many inflammatory symptoms, including cancer38. In the context of cancer, neutrophils might be reclassified as agents that encourage cancer, suggesting their adaptability and ability to control their activity in diverse inflammatory settings. Latest studies have revealed a complex and nuanced interplay between cancerous cells and healthy cells39.