BRD4 downregulation inhibits the viability of cervical cancer cells without affecting viral oncoprotein expression

AbstractHuman papillomaviruses (HPV) are a major cause of malignancy worldwide, contributing to ~5% of all human cancers including almost all cases of cervical cancer and a growing number of ano-genital and oral cancers. HPV-induced malignancy is primarily driven by the viral oncogenes, E6 and E7, which manipulate host cellular pathways to increase cell proliferation and enhance cell survival, ultimately predisposing infected cells to malignant transformation. Consequently, a more detailed understanding of viral-host interactions in HPV-associated disease offers the potential to identify novel therapeutic targets. Here, we identify that the c-Jun N-terminal kinase (JNK) signalling pathway is activated in cervical disease and in cervical cancer. The HPV E6 oncogene induces JNK1/2 phosphorylation in a manner that requires the E6 PDZ binding motif. We show that blockade of JNK1/2 signalling using small molecule inhibitors, or knockdown of the canonical JNK substrate c-Jun, reduces cell proliferation and induces apoptosis in cervical cancer cells. We further demonstrate that this phenotype is at least partially driven by JNK-dependent activation of EGFR signalling via increased expression of EGFR and the EGFR ligands EGF and HB-EGF. JNK/c-Jun signalling promoted the invasive potential of cervical cancer cells and was required for the expression of the epithelial to mesenchymal transition (EMT)-associated transcription factor Slug and the mesenchymal marker Vimentin. Furthermore, JNK/c-Jun signalling is required for the constitutive expression of HPV E6 and E7, which are essential for cervical cancer cell growth and survival. Together, these data demonstrate a positive feedback loop between the EGFR signalling pathway and HPV E6/E7 expression, identifying a regulatory mechanism in which HPV drives EGFR signalling to promote proliferation, survival and EMT. Thus, our study has identified a novel therapeutic target that may be beneficial for the treatment of cervical cancer.

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Water-soluble amphiphilic ruthenium(ii) polypyridyl complexes as potential light-activated therapeutic agents

Chemical Communications ◽

10.1039/d0cc04397d ◽

2020 ◽

Vol 56 (65) ◽

pp. 9332-9335

Author(s):

Sandra Estalayo-Adrián ◽

Salvador Blasco ◽

Sandra A. Bright ◽

Gavin J. McManus ◽

Guillermo Orellana ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Cellular Uptake ◽

Therapeutic Agents ◽

Water Soluble ◽

Polypyridyl Complexes ◽

Cervical Cancer Cells

Two new water-soluble amphiphilic Ru(ii) polypyridyl complexes were synthesised and their photophysical and photobiological properties evaluated; both complexes showed a rapid cellular uptake and phototoxicity against HeLa cervical cancer cells.

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Antiproliferative Effects of Palmitoylethanolamide on Human Cervical Cancer Cells

10.28991/iccr-2019-020 ◽

2019 ◽

Author(s):

Laura Bonfili ◽

Valentina Cecarini ◽

Anna Maria Eleuteri

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Antiproliferative Effects ◽

Cervical Cancer Cells ◽

Human Cervical Cancer Cells ◽

Human Cervical Cancer

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The Antitumor Efficiency of Zinc Finger Nuclease Combined with Cisplatin and Trichostatin A in Cervical Cancer Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200804102300 ◽

2020 ◽

Vol 20 (17) ◽

pp. 2125-2135

Author(s):

Ci Ren ◽

Chun Gao ◽

Xiaomin Li ◽

Jinfeng Xiong ◽

Hui Shen ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Zinc Finger ◽

Hela Cells ◽

Colony Formation ◽

Trichostatin A ◽

Combined Therapy ◽

Hpv E7 ◽

Anti Cancer ◽

Cervical Cancer Cells

Background: Persistent infection with the high-risk of human papillomavirus (HR-HPVs) is the primary etiological factor of cervical cancer; HR-HPVs express oncoproteins E6 and E7, both of which play key roles in the progression of cervical carcinogenesis. Zinc Finger Nucleases (ZFNs) targeting HPV E7 induce specific shear of the E7 gene, weakening the malignant biological effects, hence showing great potential for clinical transformation. Objective: Our aim was to develop a new comprehensive therapy for better clinical application of ZFNs. We here explored the anti-cancer efficiency of HPV targeted ZFNs combined with a platinum-based antineoplastic drug Cisplatin (DDP) and an HDAC inhibitor Trichostatin A (TSA). Methods: SiHa and HeLa cells were exposed to different concentrations of DDP and TSA; the appropriate concentrations for the following experiments were screened according to cell apoptosis. Then cells were grouped for combined or separate treatments; apoptosis, cell viability and proliferation ability were measured by flow cytometry detection, CCK-8 assays and colony formation assays. The xenograft experiments were also performed to determine the anti-cancer effects of the combined therapy. In addition, the HPV E7 and RB1 expressions were measured by western blot analysis. Results: Results showed that the combined therapy induced about two times more apoptosis than that of ZFNs alone in SiHa and HeLa cells, and much more inhibition of cell viability than either of the separate treatment. The colony formation ability was inhibited more than 80% by the co-treatment, the protein expression of HPV16/18E7 was down regulated and that of RB1 was elevated. In addition, the xenografts experiment showed a synergistic effect between DDP and TSA together with ZFNs. Conclusion: Our results demonstrated that ZFNs combined with DDP or TSA functioned effectively in cervical cancer cells, and it provided novel ideas for the prevention and treatment of HPV-related cervical malignancies.

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Genistein Induces Alterations of Epigenetic Modulatory Signatures in Human Cervical Cancer Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520617666170918142114 ◽

2018 ◽

Vol 18 (3) ◽

pp. 412-421 ◽

Cited By ~ 24

Author(s):

Madhumitha Kedhari Sundaram ◽

Mohammad Zeeshan Ansari ◽

Abdullah Al Mutery ◽

Maryam Ashraf ◽

Reem Nasab ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

In Silico ◽

Tumour Suppressor Genes ◽

Dietary Polyphenols ◽

In Silico Studies ◽

Genistein Treatment ◽

Cervical Cancer Cells ◽

Human Cervical Cancer Cells ◽

Human Cervical Cancer

Introduction: Epidemiological studies indicate that diet rich in fruits and vegetables is associated with decreased cancer risk thereby indicating that dietary polyphenols can be potential chemo-preventive agents. The reversible nature of epigenetic modifications makes them a favorable target for cancer prevention. Polyphenols have been shown to reverse aberrant epigenetic patterns by targeting the regulatory enzymes, DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). In vitro and in silico studies of DNMTs and HDACs were planned to examine genistein’s role as a natural epigenetic modifier in human cervical cancer cells, HeLa. Methods: Expression of the tumour suppressor genes (TSGs) [MGMT, RARβ, p21, E-cadherin, DAPK1] as well the methylation status of their promoters were examined alongwith the activity levels of DNMT and HDAC enzymes after treatment with genistein. Expression of DNMTs and HDACs was also studied. In-silico studies were performed to determine the interaction of genistein with DNMTs and HDACs. Results: Genistein treatment significantly reduced the expression and enzymatic activity of both DNMTs and HDACs in a time-dependent way. Molecular modeling data suggest that genistein can interact with various members of DNMT and HDAC families and support genistein mediated inhibition of their activity. Timedependent exposure of genistein reversed the promoter region methylation of the TSGs and re-established their expression. Conclusions: In this study, we find that genistein is able to reinstate the expression of the TSGs studied by inhibiting the action of DNMTs and HDACs. This shows that genistein could be an important arsenal in the development of epigenetic based cancer therapy.

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MicroRNA-96-5p Facilitates the Viability, Migration, and Invasion and Suppresses the Apoptosis of Cervical Cancer Cells byNegatively Modulating SFRP4

Technology in Cancer Research & Treatment ◽

10.1177/1533033820934132 ◽

2020 ◽

Vol 19 ◽

pp. 153303382093413 ◽

Cited By ~ 1

Author(s):

Huiling Zhang ◽

Ruxin Chen ◽

Jinyan Shao

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Clinical Stage ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Related Protein ◽

Siha Cells ◽

Gene Assay ◽

Cervical Cancer Cells ◽

Cancer Tissues

Purpose: The current study was intended to research the functional role and regulatory mechanism of microRNA-96-5p in the progression of cervical cancer. Methods: MicroRNA-96-5p expression in cervical cancer tissues was assessed by quantitative real-time polymerase chain reaction. The association between microRNA-96-5p expression and clinicopathological features of patients with cervical cancer was analyzed. MTT, flow cytometry, wound healing, and transwell assay were performed to evaluate the viability, apoptosis, migration, and invasion of Hela and SiHa cells. Targetscan, dual-luciferase reporter gene assay, and RNA pull-down analysis were constructed to evaluate the target relationship between microRNA-96-5p and secreted frizzled-related protein 4. Results: MicroRNA-96-5p was overexpressed in cervical cancer tissues, and microRNA-96-5p expression was markedly associated with the clinical stage and lymph node metastasis of patients with cervical cancer. Overexpressed microRNA-96-5p facilitated the viability, migration, invasion, and inhibited the apoptosis of Hela and SiHa cells, whereas suppression of microRNA-96-5p exerted the opposite trend. Secreted frizzled-related protein 4 was proved to be a target of microRNA-96-5p. Silencing of secreted frizzled-related protein 4 eliminated the anti-tumor effect of microRNA-96-5p on cervical cancer cells. Conclusions: MicroRNA-96-5p facilitated the viability, migration, and invasion and inhibited the apoptosis of cervical cancer cells via negatively regulating secreted frizzled-related protein 4.

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Near‐infrared emissive polymer coated IR ‐820 nanoparticles assisted photo‐thermal therapy for cervical cancer cells

Journal of Biophotonics ◽

10.1002/jbio.202100117 ◽

2021 ◽

Author(s):

Lijun Zhu ◽

Jianjun Chen ◽

Ting Yan ◽

Alimu Gulinigaer ◽

Xueliang Zhang ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Near Infrared ◽

Thermal Therapy ◽

Cervical Cancer Cells

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Retraction: Down-regulation of the radiation-induced pEGFRThr654 mediated activation of DNA-PK by Cetuximab in cervical cancer cells

RSC Advances ◽

10.1039/d1ra90037d ◽

2021 ◽

Vol 11 (9) ◽

pp. 5021-5021

Author(s):

Laura Fisher

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Down Regulation ◽

Cervical Cancer Cells ◽

Radiation Induced

Retraction of ‘Down-regulation of the radiation-induced pEGFRThr654 mediated activation of DNA-PK by Cetuximab in cervical cancer cells’ by Yunxiang Qi et al., RSC Adv., 2020, 10, 1132–1141, DOI: 10.1039/C9RA04962B.

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