scholarly journals Survivin Clinical Features in Cervical Cancer

2017 ◽  
Vol 1 (1) ◽  
pp. 6
Author(s):  
Miftakh Nur Rahman ◽  
Chyntia Resti Wijaya ◽  
Maria Novalentina
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Critical Role ◽  
Survivin Expression ◽  
Hpv Infection ◽  
Cytotoxic T Cell ◽  
Hpv E6 ◽  
E6 Oncoprotein ◽  
Cycle Dependent ◽  
Oncogenic Protein

Cervical cancer is the primary lethal malignancy for women worldwide, but because it develops over time, it would be one of the most preventable types of cancer. Dysregulation of apoptosis in cells plays a critical role in the malignancy development. Survivin is the smallest inhibitor apoptotic protein (IAP) which has an important part in regulating cell division and inhibitor of apoptosis. This review focused on survivin features in cervical cancer from mechanisms of malignancy relationship to human papillomavirus (HPV) infection through E6 oncogenic protein, role as a biomarker in diagnosis, prognosis, staging and prediction of metastasis, and also as a target for therapy. Regulation of survivin divided into two main groups; cell cycle dependent and cell cycle independent pathway to maintain life and death balance. Survivin expression is upregulated by E6 protein simultaneously repressing p53. Thus cancerous cervical tissue developed. Survivin is also upregulated in hypoxia, a common condition in many tumors and increased angiogenesis. Survivin plays a major role in chemotherapy and radiation resistance in many cases of cervical cancer. As a target of therapy, survivin has a promising performance, suggested very specific and no issue of resistance and also reducing resistance to chemo and radiation therapy. The goal of treatment is to lower survivin expression through transcription inhibition, immunotherapy based on cytotoxic T cell (CTL) activity and gene therapy.  Keywords: cervical cancer, survivin, HPV E6 oncoprotein, therapy

scholarly journals Role of Cdk1 in the p53-Independent Abrogation of the Postmitotic Checkpoint by Human Papillomavirus E6

2014 ◽  
Vol 89 (5) ◽  
pp. 2553-2562 ◽  
Author(s):  
Weifang Zhang ◽  
Yingwang Liu ◽  
Ning Zhao ◽  
Hanxiang Chen ◽  
Lijun Qiao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Drug Targets ◽  
Cell Cycle Checkpoints ◽  
Wild Type ◽  
Hpv E6 ◽  
E6 Oncoprotein ◽  
Shed Light

ABSTRACTSpecific types of human papillomavirus (HPV) are strongly associated with the development of cervical carcinoma. The HPV E6 oncoprotein from HPV degrades p53 and abrogates cell cycle checkpoints. Nonetheless, functional p53 has been observed in cervical cancer. We have previously identified a p53-independent function of E6 in attenuating the postmitotic G1-like checkpoint that can lead to polyploidy, an early event during cervical carcinogenesis that predisposes cells to aneuploidy. How E6 promotes cell cycle progression in the presence of p53 and its target, p21, remains a mystery. In this study, we examined the expression of cell cycle-related genes in cells expressing wild-type E6 and the mutant that is defective in p53 degradation but competent in abrogating the postmitotic checkpoint. Our results demonstrated an increase in the steady-state levels of G1- and G2-related cyclins/Cdks in E6-expressing keratinocytes. Interestingly, only Cdk1 remained active in E6 mutant-expressing cells while bypassing the postmitotic checkpoint. Furthermore, the downregulation of Cdk1 impaired the ability of both wild-type and mutant E6 to induce polyploidy. Our study thus demonstrated an important role for Cdk1, which binds p21 with lower affinity than Cdk2, in abrogating the postmitotic checkpoint in E6-expressing cells. We further show that E2F1 is important for E6 to upregulate Cdk1. Moreover, reduced nuclear p21 localization was observed in the E6 mutant-expressing cells. These findings shed light on the mechanisms by which HPV induces genomic instability and hold promise for the identification of drug targets.IMPORTANCEHPV infection is strongly associated with the development of cervical carcinoma. HPV encodes an E6 oncoprotein that degrades the tumor suppressor p53 and abrogates cell cycle checkpoints. Nonetheless, functional p53 has been observed in cervical cancer. We have recently demonstrated a p53-independent abrogation of the postmitotic checkpoint by HPV E6 that induces polyploidy. However, the mechanism is not known. In this study, we provide evidence that Cdk1 plays an important role in this process. Previously, Cdk2 was thought to be essential for the G1/S transition, while Cdk1 only compensated its function in the absence of Cdk2. Our studies have demonstrated a novel role of Cdk1 at the postmitotic G1-like checkpoint in the presence of Cdk2. These findings shed light on the mechanisms by which HPV induces genomic instability and hold promise for the identification of drug targets.

scholarly journals Cell Cycle-Dependent Expression of Mammalian E2-C Regulated by the Anaphase-Promoting Complex/Cyclosome

2000 ◽  
Vol 11 (8) ◽  
pp. 2821-2831 ◽  
Author(s):  
Atsushi Yamanaka ◽  
Shigetsugu Hatakeyama ◽  
Kin-ichiro Kominami ◽  
Masatoshi Kitagawa ◽  
Masaki Matsumoto ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Substrate Specificity ◽  
Critical Role ◽  
Anaphase Promoting Complex ◽  
Polyubiquitin Chain ◽  
M Phase ◽  
Ubiquitin Conjugating Enzyme ◽  
Recognition Motifs ◽  
Cycle Dependent ◽  
Conjugating Enzyme

Progression through mitosis requires the precisely timed ubiquitin-dependent degradation of specific substrates. E2-C is a ubiquitin-conjugating enzyme that plays a critical role with anaphase-promoting complex/cyclosome (APC/C) in progression of and exit from M phase. Here we report that mammalian E2-C is expressed in late G2/M phase and is degraded as cells exit from M phase. The mammalian E2-C shows an autoubiquitinating activity leading to covalent conjugation to itself with several ubiquitins. The ubiquitination of E2-C is strongly enhanced by APC/C, resulting in the formation of a polyubiquitin chain. The polyubiquitination of mammalian E2-C occurs only when cells exit from M phase. Furthermore, mammalian E2-C contains two putative destruction boxes that are believed to act as recognition motifs for APC/C. The mutation of this motif reduced the polyubiquitination of mammalian E2-C, resulting in its stabilization. These results suggest that mammalian E2-C is itself a substrate of the APC/C-dependent proteolysis machinery, and that the periodic expression of mammalian E2-C may be a novel autoregulatory system for the control of the APC/C activity and its substrate specificity.

scholarly journals E2F activity is regulated by cell cycle-dependent changes in subcellular localization.

1997 ◽  
Vol 17 (12) ◽  
pp. 7268-7282 ◽  
Author(s):  
R Verona ◽  
K Moberg ◽  
S Estes ◽  
M Starz ◽  
J P Vernon ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Subcellular Localization ◽  
Nuclear Localization ◽  
Mammalian Cells ◽  
Critical Role ◽  
Biological Properties ◽  
Dependent Manner ◽  
Restriction Point ◽  
Cycle Dependent ◽  
Almost All

E2F directs the cell cycle-dependent expression of genes that induce or regulate the cell division process. In mammalian cells, this transcriptional activity arises from the combined properties of multiple E2F-DP heterodimers. In this study, we show that the transcriptional potential of individual E2F species is dependent upon their nuclear localization. This is a constitutive property of E2F-1, -2, and -3, whereas the nuclear localization of E2F-4 is dependent upon its association with other nuclear factors. We previously showed that E2F-4 accounts for the majority of endogenous E2F species. We now show that the subcellular localization of E2F-4 is regulated in a cell cycle-dependent manner that results in the differential compartmentalization of the various E2F complexes. Consequently, in cycling cells, the majority of the p107-E2F, p130-E2F, and free E2F complexes remain in the cytoplasm. In contrast, almost all of the nuclear E2F activity is generated by pRB-E2F. This complex is present at high levels during G1 but disappears once the cells have passed the restriction point. Surprisingly, dissociation of this complex causes little increase in the levels of nuclear free E2F activity. This observation suggests that the repressive properties of the pRB-E2F complex play a critical role in establishing the temporal regulation of E2F-responsive genes. How the differential subcellular localization of pRB, p107, and p130 contributes to their different biological properties is also discussed.

scholarly journals Effect of modified neoadjuvant chemotherapy on levels of E6 oncoprotein in HPV-infected cervical tumor tissue

2021 ◽  
Vol 67 (4) ◽  
pp. 531-537
Author(s):  
Elena Frantsiyants ◽  
Anna Menshenina ◽  
Tatiana Moiseenko ◽  
Natalia Ushakova ◽  
Ekaterina Verenikina ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Hpv Infection ◽  
Main Group ◽  
Control Group ◽  
Cervical Tumor ◽  
E6 Oncoprotein ◽  
Tumor Tissues ◽  
Group 2 ◽  
Group 1

. Background. Human papillomavirus (HPV) has been established to be the etiological factor of cervical cancer (CC). HPV infection and CC progression involve the direct participation of the E6 oncoprotein. Aim. An analysis of the E6 oncoprotein levels in tissues of the tumor and its perifocal area in HPV-associated cervical squamous cell cancer as an objective indicator of the effect of treatment depending on preoperative chemotherapy. Material and methods. The study included clinical and laboratory data of 237 patients with high-risk HPV infection of the cervix. The patients were divided into 4 groups: two main groups (CC T2а2–2bN0–1M0) and two control groups. Patients in the main group 1 (n=84) received standard neoadjuvant chemotherapy (NACT), in the main group 2 (n=93) — modified NACT with prior plasmapheresis session and a parallel course of nonspecific immunotherapy with Allokin-alpha. Control group 1 (n=40) included patients with CC T1b2–2a1N0–1M0, surgical treatment; control group 2 (n=20) — HPV-positive patients without CC. Levels of E6 were measured in samples of the cervical tumor and perifocal tissues. Results. The lowest levels of the E6 oncoprotein were registered in the group of HPV-positive patients without CC. After modified NACT, E6 levels in tumor tissues remained 4.6 times higher than in intact tissues, and even so, these patients demonstrated minimal E6 levels compared to other CC patients. E6 in tumor tissues was significantly lower than in main group 1 (by 3.3 times) and 8 times lower than in control group 1. E6 levels in the perifocal tissues of patients in main group 2 were 1.9 times lower than in the corresponding tissues of patients in main group 1 and 2.2 times lower than in control group 1. Conclusions. Inclusion of plasmapheresis and inducers of endogenous interferonogenesis into neoadjuvant treatment for cervical cancer can be considered pathogenetically justified, since it affects the key unit of cervical carcinogenesis.

Role of molecular biomarker human papilloma virus (HPV) E6 oncoprotein in cervical cancer screening

2020 ◽  
Vol 158 (3) ◽  
pp. 590-596
Author(s):  
Rifat Ara ◽  
Sabera Khatun ◽  
Shahana Pervin ◽  
Munira Jahan ◽  
Umme Shahera ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Screening ◽  
Human Papilloma Virus ◽  
Cervical Cancer Screening ◽  
Molecular Biomarker ◽  
Papilloma Virus ◽  
Hpv E6 ◽  
E6 Oncoprotein

scholarly journals The Human Papillomavirus (HPV) E6 Oncoprotein Regulates CD40 Expression via the AT-Hook Transcription Factor AKNA

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 521 ◽  
Author(s):  
Joaquin Manzo-Merino ◽  
Alfredo Lagunas-Martínez ◽  
Carla Contreras-Ochoa ◽  
Marcela Lizano ◽  
Leonardo Castro-Muñoz ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
High Risk ◽  
Immune Surveillance ◽  
Dependent Manner ◽  
Hpv E6 ◽  
E6 Oncoprotein ◽  
Inflammatory State ◽  
Cervical Cancer Development ◽  
Carcinogenic Process

Persistent infection with high-risk Human Papillomavirus (HR-HPV) is the main requisite for cervical cancer development. Normally, HPV is limited to the site of infection and regulates a plethora of cellular elements to avoid the immune surveillance by inducing an anti-inflammatory state, allowing the progress through the viral cycle and the carcinogenic process. Recent findings suggest that the AT-hook transcriptional factor AKNA could play a role in the development of cervical cancer. AKNA is strongly related to the expression of co-stimulatory molecules such CD40/CD40L to achieve an anti-tumoral immune response. To date, there is no evidence demonstrating the effect of the HPV E6 oncoprotein on the AT-hook factor AKNA. In this work, minimal expression of AKNA in cervical carcinoma compared to normal tissue was found. We show the ability of E6 from high-risk HPVs 16 and 18 to interact with and down-regulate AKNA as well as its co-stimulatory molecule CD40 in a proteasome dependent manner. We also found that p53 interacts with AKNA and promotes AKNA expression. Our results indicate that the de-regulation of CD40 and AKNA is induced by the HPV E6 oncoprotein, and this event involves the action of p53 suggesting that the axis E6/p53A/AKNA might play an important role in the de-regulation of the immune system during the carcinogenic process induced by HR-HPV.

Association between Toll-like Receptor and Tumor Necrosis Factor Immunological Pathways in Uterine Cervical Neoplasms

2016 ◽  
Vol 103 (1) ◽  
pp. 81-86 ◽  
Author(s):  
Lucas G.G. de Matos ◽  
Eduardo B. Cândido ◽  
Paula V.T. Vidigal ◽  
Polyanna H.C. Bordoni ◽  
Rivia M. Lamaita ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Tumor Necrosis ◽  
Critical Role ◽  
Immunological Response ◽  
Intraepithelial Neoplasia ◽  
Hpv Infection ◽  
Membrane Receptors ◽  
Premalignant Lesions ◽  
Cervical Lesions ◽  
Tnf Α

Introduction The immune system plays a critical role in the defense against human papillomavirus (HPV) infection and its persistence. Toll-like receptors (TLRs) are membrane receptors responsible for activation of the innate immune response, and an association between TLR expression and uterine cervical cancer has been shown. Tumor necrosis factors (TNFs) are among the main mediators of skin and mucosa inflammation. The aim of this study was to demonstrate the association between TLR and TNF immune expression and cervical cancer and premalignant cervical lesions. Methods A total of 64 embedded tissues were obtained from gynecological procedures, including 35 specimens with cervical intraepithelial neoplasia (CIN) and 10 specimens with cervical squamous cell carcinoma (CSCC) as well as 19 normal cervical samples. The expression of TLR2, TLR3, TLR4, TNF-α and TNF-β was measured by immunohistochemistry and graded into low and high levels of expression. Results There was an association between the expression levels of TLR2 and those of TNF-α and TNF-β (p = 0.01 and p = 0.021, respectively) in the cervical cancer and CIN groups. TLR4 expression was associated with TNF-α and TNF-β expression (p = 0.016 and p = 0.025, respectively) in these 2 groups. By contrast, TLR3 was not statistically associated with TNF-α or TNF-β in any of the groups. Conclusions There might be an association of the TLR2 and TLR4 pathways with the immunological response of TNF-α and TNF-β in cervical cancer. These markers are also expressed at higher levels in cervical cancer and premalignant lesions compared to normal controls.

Cell cycle-dependent regulation of TIAP/m-survivin expression

2000 ◽  
Vol 1493 (1-2) ◽  
pp. 188-194 ◽  
Author(s):  
Masayuki Otaki ◽  
Masahiko Hatano ◽  
Koichi Kobayashi ◽  
Takeshi Ogasawara ◽  
Takayuki Kuriyama ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Survivin Expression ◽  
Cycle Dependent

scholarly journals In Silico Approaches: A Way to Unveil Novel Therapeutic Drugs for Cervical Cancer Management

2021 ◽  
Vol 14 (8) ◽  
pp. 741
Author(s):  
Diana Gomes ◽  
Samuel Silvestre ◽  
Ana Paula Duarte ◽  
Aldo Venuti ◽  
Christiane P. Soares ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Small Molecules ◽  
In Silico ◽  
Access To Health Services ◽  
Cancer Management ◽  
Hpv E6 ◽  
Therapeutic Drugs ◽  
E6 Oncoprotein ◽  
Access To Health ◽  
E6 And E7

Cervical cancer (CC) is the fourth most common pathology in women worldwide and presents a high impact in developing countries due to limited financial resources as well as difficulties in monitoring and access to health services. Human papillomavirus (HPV) is the leading cause of CC, and despite the approval of prophylactic vaccines, there is no effective treatment for patients with pre-existing infections or HPV-induced carcinomas. High-risk (HR) HPV E6 and E7 oncoproteins are considered biomarkers in CC progression. Since the E6 structure was resolved, it has been one of the most studied targets to develop novel and specific therapeutics to treat/manage CC. Therefore, several small molecules (plant-derived or synthetic compounds) have been reported as blockers/inhibitors of E6 oncoprotein action, and computational-aided methods have been of high relevance in their discovery and development. In silico approaches have become a powerful tool for reducing the time and cost of the drug development process. Thus, this review will depict small molecules that are already being explored as HR HPV E6 protein blockers and in silico approaches to the design of novel therapeutics for managing CC. Besides, future perspectives in CC therapy will be briefly discussed.

scholarly journals Extracellular Vesicles in Cervical Cancer and HPV Infection

Membranes ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 453
Author(s):  
Víctor Acevedo-Sánchez ◽  
Ruth M. Rodríguez-Hernández ◽  
Sergio R. Aguilar-Ruíz ◽  
Honorio Torres-Aguilar ◽  
María de los A. Romero-Tlalolini
Keyword(s):  
Cervical Cancer ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Current Knowledge ◽  
Hpv Infection ◽  
Dna And Rna ◽  
Cell Structures ◽  
Infected Cells ◽  
And Function ◽  
Oncogenic Protein

Since their description, extracellular vesicles (EVs) have shown growing relevance in cancer progression. These cell structures contain and transfer molecules such as nucleic acids (including DNA and RNA), proteins, and lipids. Despite the rising information about EVs’ relationship with cancer, there is still scarce evidence about their content and function in cervical cancer. Interestingly, the composition and purposes of some cellular molecules and the expression of oncogenic proteins packaged in EVs seem modified in HPV-infected cells; and, although only the E6 oncogenic protein has been detected in exosomes from HPV-positive cells, both E6/E7 oncogenes mRNA has been identified in EVs; however, their role still needs to be clarified. Given that EVs internalizing into adjacent or distant cells could modify their cellular behavior or promote cancer-associated events like apoptosis, proliferation, migration, or angiogenesis in receptor cells, their comprehensive study will reveal EV-associated mechanisms in cervical cancer. This review summarizes the current knowledge in composition and functions of cervical cancer and HPV Infection-derived EVs.

Sign in / Sign up

Export Citation Format

Share Document