Functional roles of female sex hormones and their nuclear receptors in cervical cancer

Essays in Biochemistry ◽

10.1042/ebc20200175 ◽

2021 ◽

Author(s):

Seoung-Ae Lee ◽

Seunghan Baik ◽

Sang-Hyuk Chung

Keyword(s):

Cervical Cancer ◽

Mouse Model ◽

Estrogen Receptor Α ◽

Functional Roles ◽

Genetic Ablation ◽

Cervical Cancers ◽

Female Sex Hormones ◽

Exogenous Estrogen ◽

Valuable Treatment ◽

Hormone Sensitive

Abstract There has been little progress for several decades in modalities to treat cervical cancer. While the cervix is a hormone-sensitive tissue, physiologic roles of estrogen receptor α (ERα), progesterone receptor (PR), and their ligands in this tissue are poorly understood. It has hampered critical assessments of data in early epidemiologic and clinical studies for cervical cancer. Experimental evidence obtained from studies using mouse models has provided new insights into the molecular mechanism of ERα and PR in cervical cancer. In a mouse model expressing human papillomavirus (HPV) oncogenes, exogenous estrogen promotes cervical cancer through stromal ERα. In the same mouse model, genetic ablation of PR promotes cervical carcinogenesis without exogenous estrogen. Medroxyprogesterone acetate, a PR-activating drug, regresses cervical cancer in the mouse model. These results support that ERα and PR play opposite roles in cervical cancer. They further support that ERα inhibition and PR activation may be translated into valuable treatment for a subset of cervical cancers.

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Requirement for Estrogen Receptor α in a Mouse Model for Human Papillomavirus–Associated Cervical Cancer

Cancer Research ◽

10.1158/0008-5472.can-08-2051 ◽

2008 ◽

Vol 68 (23) ◽

pp. 9928-9934 ◽

Cited By ~ 69

Author(s):

Sang-Hyuk Chung ◽

Kerri Wiedmeyer ◽

Anny Shai ◽

Kenneth S. Korach ◽

Paul F. Lambert

Keyword(s):

Cervical Cancer ◽

Estrogen Receptor ◽

Human Papillomavirus ◽

Mouse Model ◽

Estrogen Receptor Α

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The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the Cnga3-Deficient Mouse Model of Achromatopsia

International Journal of Molecular Sciences ◽

10.3390/ijms22010052 ◽

2020 ◽

Vol 22 (1) ◽

pp. 52

Author(s):

Mirja Koch ◽

Constanze Scheel ◽

Hongwei Ma ◽

Fan Yang ◽

Michael Stadlmeier ◽

...

Keyword(s):

Protein Kinase ◽

Mouse Model ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Cone Photoreceptor ◽

Photoreceptor Degeneration ◽

Dependent Protein Kinase ◽

Genetic Ablation ◽

Cgmp Dependent Protein Kinase ◽

Dependent Protein

Mutations in the CNGA3 gene, which encodes the A subunit of the cyclic guanosine monophosphate (cGMP)-gated cation channel in cone photoreceptor outer segments, cause total colour blindness, also referred to as achromatopsia. Cones lacking this channel protein are non-functional, accumulate high levels of the second messenger cGMP and degenerate over time after induction of ER stress. The cell death mechanisms that lead to loss of affected cones are only partially understood. Here, we explored the disease mechanisms in the Cnga3 knockout (KO) mouse model of achromatopsia. We found that another important effector of cGMP, the cGMP-dependent protein kinase 2 (Prkg2) is crucially involved in cGMP cytotoxicity of cones in Cnga3 KO mice. Virus-mediated knockdown or genetic ablation of Prkg2 in Cnga3 KO mice counteracted degeneration and preserved the number of cones. Analysis of markers of endoplasmic reticulum stress and unfolded protein response confirmed that induction of these processes in Cnga3 KO cones also depends on Prkg2. In conclusion, we identified Prkg2 as a novel key mediator of cone photoreceptor degeneration in achromatopsia. Our data suggest that this cGMP mediator could be a novel pharmacological target for future neuroprotective therapies.

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The potential oncogenic and MLN4924-resistant effects of CSN5 on cervical cancer cells

Cancer Cell International ◽

10.1186/s12935-021-02078-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Huilin Zhang ◽

Ping He ◽

Qing Zhou ◽

Yan Lu ◽

Bingjian Lu

Keyword(s):

Cell Cycle ◽

Cervical Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Cancer Cell ◽

Cervical Cancer Cell ◽

Cervical Cancers ◽

Cervical Cancer Cells

Abstract Background CSN5, a member of Cop9 signalosome, is essential for protein neddylation. It has been supposed to serve as an oncogene in some cancers. However, the role of CSN5 has not been investigated in cervical cancer yet. Methods Data from TCGA cohorts and GEO dataset was analyzed to examine the expression profile of CSN5 and clinical relevance in cervical cancers. The role of CSN5 on cervical cancer cell proliferation was investigated in cervical cancer cell lines, Siha and Hela, through CSN5 knockdown via CRISPR–CAS9. Western blot was used to detect the effect of CSN5 knockdown and overexpression. The biological behaviors were analyzed by CCK8, clone formation assay, 3-D spheroid generation assay and cell cycle assay. Besides, the role CSN5 knockdown in vivo was evaluated by xenograft tumor model. MLN4924 was given in Siha and Hela with CSN5 overexpression. Results We found that downregulation of CSN5 in Siha and Hela cells inhibited cell proliferation in vitro and in vivo, and the inhibitory effects were largely rescued by CSN5 overexpression. Moreover, deletion of CSN5 caused cell cycle arrest rather than inducing apoptosis. Importantly, CSN5 overexpression confers resistance to the anti-cancer effects of MLN4924 (pevonedistat) in cervical cancer cells. Conclusions Our findings demonstrated that CSN5 functions as an oncogene in cervical cancers and may serve as a potential indicator for predicting the effects of MLN4924 treatment in the future.

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Involvement of MCH-oxytocin neural relay within the hypothalamus in murine nursing behavior

Scientific Reports ◽

10.1038/s41598-021-82773-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yoko Kato ◽

Harumi Katsumata ◽

Ayumu Inutsuka ◽

Akihiro Yamanaka ◽

Tatsushi Onaka ◽

...

Keyword(s):

Mammalian Species ◽

Virgin Female ◽

Essential Elements ◽

Hypothalamic Nucleus ◽

Male Mice ◽

Hypothalamic Area ◽

Functional Roles ◽

Genetic Ablation ◽

Optogenetic Stimulation ◽

Stimulation Of

AbstractMultiple sequential actions, performed during parental behaviors, are essential elements of reproduction in mammalian species. We showed that neurons expressing melanin concentrating hormone (MCH) in the lateral hypothalamic area (LHA) are more active in rodents of both sexes when exhibiting parental nursing behavior. Genetic ablation of the LHA-MCH neurons impaired maternal nursing. The post-birth survival rate was lower in pups born to female mice with congenitally ablated MCH neurons under control of tet-off system, exhibiting reduced crouching behavior. Virgin female and male mice with ablated MCH neurons were less interested in pups and maternal care. Chemogenetic and optogenetic stimulation of LHA-MCH neurons induced parental nursing in virgin female and male mice. LHA-MCH GABAergic neurons project fibres to the paraventricular hypothalamic nucleus (PVN) neurons. Optogenetic stimulation of PVN induces nursing crouching behavior along with increasing plasma oxytocin levels. The hypothalamic MCH neural relays play important functional roles in parental nursing behavior in female and male mice.

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Recovery strategies following COVID-19 disruption to cervical cancer screening and their impact on excess diagnoses

British Journal of Cancer ◽

10.1038/s41416-021-01275-3 ◽

2021 ◽

Author(s):

Alejandra Castanon ◽

Matejka Rebolj ◽

Francesca Pesola ◽

Peter Sasieni

Keyword(s):

Cervical Cancer ◽

Cancer Screening ◽

Cervical Cancer Screening ◽

Intraepithelial Neoplasia ◽

Cervical Cancers ◽

Screening Interval ◽

Recovery Strategies ◽

Screening Services ◽

The Impact ◽

Published Research

Abstract Background The COVID-19 pandemic has disrupted cervical cancer screening services. Assuming increases to screening capacity are unrealistic, we propose two recovery strategies: one extends the screening interval by 6 months for all and the other extends the interval by 36/60 months, but only for women who have already missed being screened. Methods Using routine statistics from England we estimate the number of women affected by delays to screening. We used published research to estimate the proportion of screening age women with high-grade cervical intraepithelial neoplasia and progression rates to cancer. Under two recovery scenarios, we estimate the impact of COVID-19 on cervical cancer over one screening cycle (3 years at ages 25–49 and 5 years at ages 50–64 years). The duration of disruption in both scenarios is 6 months. In the first scenario, 10.7 million women have their screening interval extended by 6 months. In the second, 1.5 million women (those due to be screened during the disruption) miss one screening cycle, but most women have no delay. Results Both scenarios result in similar numbers of excess cervical cancers: 630 vs. 632 (both 4.3 per 100,000 women in the population). However, the scenario in which some women miss one screening cycle creates inequalities—they would have much higher rates of excess cancer: 41.5 per 100,000 delayed for screened women compared to those with a 6-month delay (5.9 per 100,000). Conclusion To ensure equity for those affected by COVID-19 related screening delays additional screening capacity will need to be paired with prioritising the screening of overdue women.

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Role of Immune Checkpoint Inhibitors in Cervical Cancer: From Preclinical to Clinical Data

Cancers ◽

10.3390/cancers13092089 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2089

Author(s):

Simona Duranti ◽

Antonella Pietragalla ◽

Gennaro Daniele ◽

Camilla Nero ◽

Francesca Ciccarone ◽

...

Keyword(s):

Cervical Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Hpv Infection ◽

Phase Iii ◽

Screening Programs ◽

Cervical Cancers ◽

Relapsed Disease

Human papillomavirus (HPV) infection is the recognized cause of almost all cervical cancers. Despite the reduction in incidence due to a wide use of screening programs and a specific vaccine, the prognosis of cervical cancer remains poor, especially for late-stage and relapsed disease. Considering the elevated rates of PD-L1 expression in up to 80% of cervical cancers, a strong rationale supports the use of immunotherapy to restore the immune response against tumor. The aim of this review is to analyze the possible role of immune checkpoint inhibitors in cervical cancer treatment, with a particular focus on the rationale and on the results of phase I and II clinical trials. An overview of ongoing phase III studies with possible future areas of development is also provided.

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