Most human papillomavirus infections are readily cleared by the host immune response. However, in some individuals, human papillomavirus can establish a persistent infection. The persistence of high-risk human papillomavirus infection is the major risk factor for cervical cancer development. These viruses have developed mechanisms to evade the host immune system, which is an important step in persistence and, ultimately, in tumor development. Several cell types, receptors, transcription factors and inflammatory mediators involved in the antiviral immune response are viral targets and contribute to tumorigenesis. These targets include antigen-presenting cells, macrophages, natural killer cells, Toll-like receptors, nuclear factor kappa B and several cytokines and chemokines, such as interleukins, interferon and tumor necrosis factor. In the present review, we address both the main innate immune response mechanisms involved in HPV infection clearance and the viral strategies that promote viral persistence and may contribute to cancer development. Finally, we discuss the possibility of exploiting this knowledge to develop effective therapeutic strategies.
OBJECTIVES: Oxidative stress results from an imbalance between the generation and elimination of oxidant species. This condition may result in DNA, RNA and protein damage, leading to the accumulation of genetic alterations that can favor malignant transformation. Persistent infection with high-risk human papillomavirus types is associated with inflammatory responses and reactive oxygen species production. In this context, oxidative stress, chronic inflammation and high-risk human papillomavirus can act in a synergistic manner. To counteract the harmful effects of oxidant species, protective molecules, known as antioxidant defenses, are produced by cells to maintain redox homeostasis. In recent years, the use of natural antioxidants as therapeutic strategies for cancer treatment has attracted the attention of the scientific community. This review discusses specific molecules and mechanisms that can act against or together with oxidative stress, presenting alternatives for cervical cancer prevention and treatment.
Protein kinase C (PKC) plays a regulatory role in key pathways in cancer. However, since phosphorylation is a step for classical PKC (cPKC) maturation and does not correlate with activation, there is a lack of tools to detect active PKC in tissue samples. Here, a structure-based rational approach was used to select a peptide to generate an antibody that distinguishes active from inactive cPKC. A peptide conserved in all cPKCs, C2Cat, was chosen since modeling studies based on a crystal structure of PKCβ showed that it is localized at the interface between the C2 and catalytic domains of cPKCs in an inactive kinase. Anti-C2Cat recognizes active cPKCs at least two-fold better than inactive kinase in ELISA and immunoprecipitation assays, and detects the temporal dynamics of cPKC activation upon receptor or phorbol stimulation. Furthermore, the antibody is able to detect active PKC in human tissue. Higher levels of active cPKC were observed in the more aggressive triple negative breast cancer tumors as compared to the less aggressive estrogen receptor positive tumors. Thus, this antibody represents a reliable, hitherto unavailable and a valuable tool to study PKC activation in cells and tissues. Similar structure-based rational design strategies can be broadly applied to obtain active-state specific antibodies for other signal transduction molecules.
High superoxide dismutase 2 (SOD2) expression is associated with a poor prognosis at many cancer sites, the presence of metastases, and more advanced cervical cancer. This study aims to determine whether SOD2 protein expression is associated with the prognosis of stage IIIB cervical carcinoma. Methods: sixty-three patients with stage IIIB squamous cell cervical carcinoma were included. The evaluation of SOD2 expression by immunohistochemistry was based on a positive cell ratio score and the staining intensity score. Taking disease recurrence and death as endpoints, receiver operating characteristic curves were used to discriminate between high and low SOD2 expression. Results: high SOD2 expression was associated with recurrence (p = 0.001), distant recurrence (p = 0.002), and death (p = 0.005). A multivariate analysis showed that patients with high SOD2 expression had a threefold increased risk for recurrence (HR = 3.16; 1.33–7.51) and death (HR = 2.98; 1.20–7.40) compared with patients who had low SOD2 expression. Patients with high SOD2 expression had shorter disease-free survival (p = 0.001) and overall survival (p = 0.003) than patients with low SOD2 expression. Conclusion: high SOD2 expression is a strong prognostic factor for stage IIIB squamous cell carcinoma of the cervix and could be used as a prognostic marker in women with cervical carcinoma.
It is suggested that HPV-18 variants from the A lineage have higher oncogenic potential compared to B variants. Some studies show uneven distribution of HPV-18 variants in cervical adenocarcinomas and squamous cell carcinomas. Regarding HPV-18 variants’ functions, the few studies reported focus on E6, and none were performed using natural host cells. Here, we immortalized primary human keratinocytes (PHKs) with E6/E7 of HPV-18 A1 and B1 sublineages and functionally characterized these cells. PHK18A1 reached immortalization significantly faster than PHK18B1 and formed a higher number of colonies in monolayer and 3D cultures. Moreover, PHK18A1 showed greater invasion ability and higher resistance to apoptosis induced by actinomycin-D. Nevertheless, no differences were observed regarding morphology, proliferation after immortalization, migration, or epithelial development in raft cultures. Noteworthy, our study highlights qualitative differences among HPV-18 A1 and B1 immortalized PHKs: in contrast to PHK18A1, which formed more compact colonies and spheroids of firmly grouped cells and tended to invade and migrate as clustered cells, morphologically, PHK18B1 colonies and spheroids were looser, and migration and invasion of single cells were observed. Although these observations may be relevant for the association of these variants with cervical cancer of different histological subtypes, further studies are warranted to elucidate the mechanisms behind these findings.
Oxidative stress reflects an imbalance in the maintenance of the intracellular redox state resulting in the accumulation of oxidant species that may contribute to tumorigenesis. The superoxide dismutase 2 protein (SOD2) contributes to cell homeostasis by catalyzing the dismutation of superoxide anion radicals in oxygen and hydrogen peroxide, preventing the direct inactivation of biomolecules. SOD2 protein can be induced by the activation of the NF-kB pathway in several cell types following treatment with interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNFα), both proinflammatory cytokines. In addition, previous studies from the group have shown a direct correlation between increased levels of SOD2 protein and severity of uterine cervix lesions. The aim of this study is to elucidate the involvement of SOD2 in the pathogenesis associated with HPV and in the effect of proinflammatory cytokines. Methods: Primary human keratinocytes transduced with HPV16 oncogenes and cervical cancer derived cell lines were treated with the proinflammatory cytokines TNFα, and IL-1beta. The expression of SOD2 protein involved in IL-1 β and TNFα signaling pathways was determined by Western blot and ELISA. Results: Preliminary results suggest the presence of higher levels of SOD2 expression in uterine cervix-derived tumor cell lines when compared to normal primary keratinocytes. Treatment with IL-1β and TNFα induces SOD2 protein accumulation in in the HPV16 positive cervical-derived tumor line, SiHa. On the other hand, no SOD2 induction was observed in the HPV-negative cervical cancer derived cell line C33. Further replications and additional experiments are needed for conclusions. Citation Format: Gabriela Ávila Fernandes Silva, Rafaella Almeida Lima Nunes, Enrique Boccardo, Luisa Lina Villa, Lara Termini. Study of superoxide dismutase-2 protein in HPV-mediated cell transformation [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B69.
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