HPV post-infection microenvironment and cervical cancer

Yuan, Yi; Cai, Xiaoyan; Shen, Fu‐Ming; Ma, Feng

doi:10.1016/j.canlet.2020.10.034

Cited by 146 publications

(114 citation statements)

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“…Among them, the immune component seems to contribute more to immunotherapyresponse of CC, including the T cells, macrophages, and neutrophils (Langers et al, 2014;Krishnan et al, 2018;Chen X. J. et al, 2019;Ohno et al, 2020). Many researchers have currently investigated the correlation of the prognosis in CC patients with the critical immunological biomarkers (De Jaeghere et al, 2020;Yuan et al, 2020;Zhao et al, 2020). These studies showed significant heterogeneity of the immune component and immune response in CC patients, which might play a decisive role in the ultimate clinical outcomes of patients.…”

Section: Introductionmentioning

confidence: 99%

Integrated Bioinformatical Analysis Identifies GIMAP4 as an Immune-Related Prognostic Biomarker Associated With Remodeling in Cervical Cancer Tumor Microenvironment

Shen

2021

Front. Cell Dev. Biol.

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Tumor microenvironment (TME) is emerging as an essential part of cervical cancer (CC) tumorigenesis and development, becoming a hotspot of research these years. However, comprehending the specific composition of TME is still facing enormous challenges, especially the immune and stromal components. In this study, we downloaded the RNA-seq profiles and somatic mutation data of 309 CC cases from The Cancer Genome Atlas (TCGA) database, which were analyzed by integrative bioinformatical methods. Initially, ESTIMATE computational method was employed to calculate the amount of immune and stromal components. Then, based on the high- and low-immunity cohorts, we recognized the differentially expressed genes (DEGs) as well as the differentially mutated genes (DMGs). Additionally, we conducted an intersection analysis of DEGs and DMGs, ultimately determining an immune-related prognostic signature, GTPase, IMAP Family Member 4 (GIMAP4). Moreover, sequential analyses demonstrated that GIMAP4 was a protective factor in CC, positively correlated with the overall survival (OS) and negatively with distant metastasis. Besides, we utilized the Gene Set Enrichment Analysis (GSEA) to explore the enrichment-pathways in high and low-expression cohorts of GIMAP4. The results indicated that the genes of the high-expression cohort had a high enrichment in immune-related biological processes and metabolic activities in the low one. Furthermore, CIBERSORT analysis was applied to evaluate the proportion of tumor-infiltrating immune cells (TICs), illustrating that several activated TICs were strongly associated with GIMAP4 expression, which suggested that GIMAP4 had the potential to be an indicator for the immune state in TME of CC. Hence, GIMAP4 contributed to predicting the CC patients’ clinical outcomes, such as survival rate, distant metastasis and immunotherapy response. Moreover, GIMAP4 could serve as a promising biomarker for TME remodeling, suggesting the possible underlying mechanisms of tumorigenesis and CC progression, which may provide different therapeutic perceptions of CC, and therefore improve treatment.

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Section: Introductionmentioning

confidence: 99%

Integrated Bioinformatical Analysis Identifies GIMAP4 as an Immune-Related Prognostic Biomarker Associated With Remodeling in Cervical Cancer Tumor Microenvironment

Shen

2021

Front. Cell Dev. Biol.

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“…The long-term prognosis of CC remains poor, and the 5-year survival rate is than 10% (17). It is generally believed that human papillomavirus (HPV) infection is the main cause of CC (18). However, an increasing number of studies are reporting that HPV is not the only cause of CC development, while the limited HPVdirected therapy on CC has not been very effective (19).…”

Section: Discussionmentioning

confidence: 99%

Silencing of ITGB6 inhibits the progression of cervical carcinoma via regulating JAK/STAT3 signaling pathway

Zheng¹,

Zhu²,

Wang³

et al. 2021

Ann Transl Med

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Background: Integrin β6 (ITGB6), a key submonomer of integrin αvβ6, plays an important role in epithelial-to-mesenchymal transition (EMT), wound healing, epithelial-derived tumor growth, fibrosis, and epithelial repair. However, the role of ITGB6 in cervical carcinoma (CC) remains elusive. Methods:The expression levels of ITGB6 in CC tissues and cell lines were determined using quantitative real-time polymerase chain reaction (qRT-PCR). The cell viability, proliferation, apoptosis, migration, and invasion were evaluated by Cell Counting Kit-8 (CCK-8), colony-forming, flow cytometry, and Transwell assay, respectively. The expression of related proteins, including EMT markers and the Janus kinase/signal transducer and activator of transcription (JAK/STAT3) signaling markers, were detected using western blotting.Results: The ITGB6 expression in CC tissues and cells (C-33A, Hela, SiHa, and Caski) was remarkably higher than that in paracarcinoma tissues and ECT1/E6E7 cells. The data from The Cancer Genome Atlas (TCGA) data set suggested that patients with CC with high ITGB6 expression showed poorer overall survival (OS). Compared with the empty transfection group (si-NC), si-ITGB6 restrained the proliferation, migration, and invasion of SiHa and Hela cells, while promoting cell apoptosis. si-ITGB6 suppression decreased the expression of Snail, vimentin, and N-cadherin, while increasing E-cadherin expression. Further research showed that si-ITGB6 reduced p-JAK1/JAK1, p-JAK2/JAK2, and p-STAT3/STAT3 expression in the JAK/STAT3 signaling pathway. Interestingly, proliferation, migration, invasion, and the expressions of the molecular markers of the JAK/STAT3 signaling pathway and EMT pathway induced by ITGB6 were altered by RO8191 (JAK/STAT3 pathway activator). Furthermore, the protein expression levels of Snail, vimentin, N-cadherin, p-STAT3/STAT3, p-JAK1/JAK1, and p-JAK2/JAK2 in tumor tissues were higher than those in adjacent normal tissue, while the expression level of E-cadherin was downregulated in tumor tissues.Conclusions: Silencing of ITGB6 restrains cell proliferation, migration and invasion, and promotes apoptosis in CC by inhibiting JAK/STAT signaling pathways. Thus, ITGB6 may perhaps be a new and useful candidate target for treating CC.

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“…In recent years, a significant amount of data have accumulated, indicating that many malignant neoplasms arise as a result of prolonged infection, and as a consequence of a chronic inflammatory process that forms the tumor microenvironment through various pathways [ 203 ]. Numerous triggers of chronic inflammation increase the risk of malignancy development and progression ( Figure 7 ), including (1) infections of various origins, for example, the main risk factor for stomach cancer and mucosa-associated lymphoma is bacterium Helicobacter pylori, which leads to a significant formation of nitric oxide that damages the host nucleotide DNA and alters the regulation of transcription through the activity of DNA methyltransferase [ 204 , 205 , 206 , 207 ], the Candida fungi increase the risk of hematological malignancies, cancers of the oral cavity, lips, pancreas, skin, and thyroid gland [ 208 , 209 , 210 ], an infection with Trichomonas vaginalis correlates with an increase in the cervical cancer incidence [ 211 ] and prostate cancer [ 212 ], and cells infected with Human papillomavirus that release various cytokines create an inflammatory environment, which leads to the activation of pro-oncogenic signaling pathways that contribute to the development of cervical carcinoma [ 213 , 214 , 215 , 216 , 217 ]; (2) autoimmune diseases—inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis are associated with an increased risk of intestinal adenocarcinoma [ 218 , 219 , 220 , 221 ]; and (3) inflammatory conditions of uncertain origin, for example, prostatitis in prostate cancer [ 222 , 223 ]. Chronic inflammation has been proven to be associated with various stages of tumor formation, including cellular transformation, promotion, survival, proliferation, invasion, angiogenesis, metastasis, and drug resistance ( Figure 8 ) [ 224 , 225 ].…”

Section: Role Of Inflammation In Cancer Progressionmentioning

confidence: 99%

Therapeutic Influence on Important Targets Associated with Chronic Inflammation and Oxidative Stress in Cancer Treatment

Neganova

Liu

Aleksandrova

et al. 2021

Cancers

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Chronic inflammation and oxidative stress are the interconnected pathological processes, which lead to cancer initiation and progression. The growing level of oxidative and inflammatory damage was shown to increase cancer severity and contribute to tumor spread. The overproduction of reactive oxygen species (ROS), which is associated with the reduced capacity of the endogenous cell defense mechanisms and/or metabolic imbalance, is the main contributor to oxidative stress. An abnormal level of ROS was defined as a predisposing factor for the cell transformation that could trigger pro-oncogenic signaling pathways, induce changes in gene expression, and facilitate accumulation of mutations, DNA damage, and genomic instability. Additionally, the activation of transcription factors caused by a prolonged oxidative stress, including NF-κB, p53, HIF1α, etc., leads to the expression of several genes responsible for inflammation. The resulting hyperactivation of inflammatory mediators, including TNFα, TGF-β, interleukins, and prostaglandins can contribute to the development of neoplasia. Pro-inflammatory cytokines were shown to trigger adaptive reactions and the acquisition of resistance by tumor cells to apoptosis, while promoting proliferation, invasion, and angiogenesis. Moreover, the chronic inflammatory response leads to the excessive production of free radicals, which further aggravate the initiated reactions. This review summarizes the recent data and progress in the discovery of mechanisms that associate oxidative stress and chronic inflammation with cancer onset and metastasis. In addition, the review provides insights for the development of therapeutic approaches and the discovery of natural substances that will be able to simultaneously inhibit several key oncological and inflammation-related targets.

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HPV post-infection microenvironment and cervical cancer

Cited by 146 publications

References 111 publications

Integrated Bioinformatical Analysis Identifies GIMAP4 as an Immune-Related Prognostic Biomarker Associated With Remodeling in Cervical Cancer Tumor Microenvironment

Integrated Bioinformatical Analysis Identifies GIMAP4 as an Immune-Related Prognostic Biomarker Associated With Remodeling in Cervical Cancer Tumor Microenvironment

Silencing of ITGB6 inhibits the progression of cervical carcinoma via regulating JAK/STAT3 signaling pathway

Therapeutic Influence on Important Targets Associated with Chronic Inflammation and Oxidative Stress in Cancer Treatment

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