Enhancer of mRNA Decapping protein 4 (EDC4) interacts with replication protein a (RPA) and contributes to Cisplatin resistance in cervical Cancer by alleviating DNA damage

Abstract Background Cervical cancer (CC) is the third most common gynecological malignancy around the world. Cisplatin is an effective drug, but cisplatin resistance is a vital factor limiting the clinical usage of cisplatin. Enhancer of mRNA decapping protein 4 (EDC4) is a known regulator of mRNA decapping, which was related with genome stability and sensitivity of drugs. This research was to investigate the mechanism of EDC4 on cisplatin resistance in CC. Two human cervical cancer cell lines, HeLa and SiHa, were used to investigate the role of EDC4 on cisplatin resistance in vitro. The knockdown or overexpression of EDC4 or replication protein A (RPA) in HeLa or SiHa cells was performed by transfection. Cell viability was analyzed by MTT assay. The growth of cancer cells was evaluated by colony formation assay. DNA damage was measured by γH2AX (a sensitive DNA damage response marker) immunofluorescent staining. The binding of EDC4 and RPA was analyzed by immunoprecipitation. Results EDC4 knockdown in cervical cancer cells (HeLa and SiHa) enhanced cisplatin sensitivity and cisplatin induced cell growth inhibition and DNA damage. EDC4 overexpression reduced DNA damage caused by cisplatin and enhanced cell growth of cervical cancer cells. EDC4 could interact with RPA and promote RPA phosphorylation. RPA knockdown reversed the inhibitory effect of EDC4 on cisplatin-induced DNA damage. Conclusion The present results indicated that EDC4 is responsible for the cisplatin resistance partly through interacting with RPA in cervical cancer by alleviating DNA damage. This study indicated that EDC4 or RPA may be novel targets to combat chemotherapy resistance in cervical cancer. Graphical abstract

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Insights of Cisplatin Resistance in Cervical Cancer: A Decision Making for Cellular Survival

10.5772/intechopen.98489 ◽

2021 ◽

Author(s):

Elizabeth Mahapatra ◽

Salini Das ◽

Souvick Biswas ◽

Archismaan Ghosh ◽

Debomita Sengupta ◽

...

Keyword(s):

Cervical Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Cisplatin Resistance ◽

Platinum Resistance ◽

Cellular Survival ◽

Repair Enzymes ◽

Damage Repair ◽

Cervical Cancer Cells ◽

The Impact

The clinical scenario of acquired cisplatin resistance is considered as a major impediment in cervical cancer treatment. Bulky drug-DNA adducts formed by cisplatin elicits DNA damage response (DDR) which either subsequently induces apoptosis in the cervical cancer cells or enables them to adapt with drug assault by invigorating pro-survival molecular cascades. When HPV infected cervical cancer cells encounter cisplatin, a complex molecular interaction between deregulated tumor suppressors, DNA damage-repair enzymes, and prosurvival molecules get initiated. Ambiguous molecular triggers allow cancer cells to cull apoptosis by opting for a survival fate. Overriding of the apoptotic cues by the pro-survival cues renders a cisplatin resistant phenotype in the tumor microenvironment. The present review undrapes the impact of deregulated signaling nexus formed due to crosstalk of the key molecules related to cell survival and apoptosis in orchestrating platinum resistance in cervical cancer.

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Replication Protein A Availability during DNA Replication Stress Is a Major Determinant of Cisplatin Resistance in Ovarian Cancer Cells

Cancer Research ◽

10.1158/0008-5472.can-18-0618 ◽

2018 ◽

Vol 78 (19) ◽

pp. 5561-5573 ◽

Cited By ~ 21

Author(s):

François Bélanger ◽

Emile Fortier ◽

Maxime Dubé ◽

Jean-François Lemay ◽

Rémi Buisson ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Replication ◽

Cancer Cells ◽

Cisplatin Resistance ◽

Protein A ◽

Replication Stress ◽

Replication Protein A ◽

Replication Protein ◽

Ovarian Cancer Cells ◽

Dna Replication Stress

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Oncogenic role of ALX3 in cervical cancer cells through KDM2B-mediated histone demethylation of CDC25A

BMC Cancer ◽

10.1186/s12885-021-08552-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jinhong Qi ◽

Li Zhou ◽

Dongqing Li ◽

Jingyuan Yang ◽

He Wang ◽

...

Keyword(s):

Cell Cycle ◽

Cervical Cancer ◽

Cell Growth ◽

Cancer Cells ◽

Cell Cycle Progression ◽

Cervical Squamous Cell Carcinoma ◽

Cycle Progression ◽

Normal Tissues ◽

Positive Regulator ◽

Cervical Cancer Cells

Abstract Background Cell division cycle 25A (CDC25A) is a well-recognized regulator of cell cycle progression and is involved in cancer development. This work focused on the function of CDC25A in cervical cancer cell growth and the molecules involved. Methods A GEO dataset GSE63514 comprising data of cervical squamous cell carcinoma (CSCC) tissues was used to screen the aberrantly expressed genes in cervical cancer. The CDC25A expression in cancer and normal tissues was predicted in the GEPIA database and that in CSCC and normal cells was determined by RT-qPCR and western blot assays. Downregulation of CDC25A was introduced in CSCC cells to explore its function in cell growth and the cell cycle progression. The potential regulators of CDC25A activity and the possible involved signaling were explored. Results CDC25A was predicted to be overexpressed in CSCC, and high expression of CDC25A was observed in CSCC cells. Downregulation of CDC25A in ME180 and C33A cells reduced cell proliferation and blocked cell cycle progression, and it increased cell apoptosis. ALX3 was a positive regulator of CDC25A through transcription promotion. It recruited a histone demethylase, lysine demethylase 2B (KDM2B), to the CDC25A promoter, which enhanced CDC25A expression through demethylation of H3k4me3. Overexpression of ALX3 in cells blocked the inhibitory effects of CDC25A silencing. CDC25A was found as a positive regulator of the PI3K/Akt signaling pathway. Conclusion This study suggested that the ALX3 increased CDC25A expression through KDM2B-mediated demethylation of H3K4me3, which induced proliferation and cell cycle progression of cervical cancer cells.

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Replication Protein A phosphorylation and the cellular response to DNA damage

DNA Repair ◽

10.1016/j.dnarep.2004.03.028 ◽

2004 ◽

Vol 3 (8-9) ◽

pp. 1015-1024 ◽

Cited By ~ 194

Author(s):

Sara K. Binz ◽

Anne M. Sheehan ◽

Marc S. Wold

Keyword(s):

Dna Damage ◽

Cellular Response ◽

Protein A ◽

Replication Protein A ◽

Replication Protein

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CYT-Rx20 Inhibits Cervical Cancer Cell Growth and Migration Through Oxidative Stress-Induced DNA Damage, Cell Apoptosis, and Epithelial-to-Mesenchymal Transition Inhibition

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000001033 ◽

2017 ◽

Vol 27 (7) ◽

pp. 1306-1317

Author(s):

Yen-Yun Wang ◽

Pei-Wen Hsieh ◽

Yuk-Kwan Chen ◽

Stephen Chu-Sung Hu ◽

Ya-Ling Hsu ◽

...

Keyword(s):

Cervical Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Apoptosis ◽

Cervical Cancer Cell ◽

Ros Generation ◽

Mesenchymal Transition ◽

Cervical Cancer Cells

ObjectiveThe β-nitrostyrene family has been reported to possess anticancer properties. However, the anticancer activity of β-nitrostyrenes on cervical cancer cells and the underlying mechanisms involved remain unexplored. In this study, a β-nitrostyrene derivative CYT-Rx20 (3′-hydroxy-4′-methoxy-β-methyl-β-nitrostyrene) was synthesized, and its anticancer activity on cervical cancer cells and the mechanisms involved were investigated.MethodsThe effect of CYT-Rx20 on human cervical cancer cell growth was evaluated using cell viability assay. Reactive oxygen species (ROS) generation and annexin V staining were detected by flow cytometry. The protein expression levels of cleaved caspase-3, cleaved caspase-9, cleaved poly (ADPribose) polymerase, γH2AX, β-catenin, Vimentin, and Twist were measured by Western blotting. DNA double-strand breaks were determined by γ-H2AX foci formation and neutral comet assay. Migration assay was used to determine cancer cell migration. Nude mice xenograft was used to investigate the antitumor effects of CYT-Rx20 in vivo.ResultsCYT-Rx20 induced cytotoxicity in cervical cancer cells by promoting cell apoptosis via ROS generation and DNA damage. CYT-Rx20-induced cell apoptosis, ROS generation, and DNA damage were reversed by thiol antioxidants. In addition, CYT-Rx20 inhibited cervical cancer cell migration by regulating the expression of epithelial-to-mesenchymal transition markers. In nude mice, CYT-Rx20 inhibited cervical tumor growth accompanied by increased expression of DNA damage marker γH2AX and decreased expression of mesenchymal markers β-catenin and Twist.ConclusionsCYT-Rx20 inhibits cervical cancer cells in vitro and in vivo and has the potential to be further developed into an anti-cervical cancer drug clinically.

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Hexokinase 2 Promotes Cell Growth and Tumor Formation Through the Raf/MEK/ERK Signaling Pathway in Cervical Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.581208 ◽

2020 ◽

Vol 10 ◽

Author(s):

Nan Cui ◽

Lu Li ◽

Qian Feng ◽

Hong-mei Ma ◽

Dan Lei ◽

...

Keyword(s):

Cervical Cancer ◽

Cell Growth ◽

Cancer Cells ◽

Signaling Pathway ◽

Hela Cells ◽

Tumor Formation ◽

Erk Signaling ◽

Cyclin A1 ◽

Hexokinase 2 ◽

Cervical Cancer Cells

Hexokinase 2 (HK2) is a member of the hexokinases (HK) that has been reported to be a key regulator during glucose metabolism linked to malignant growth in many types of cancers. In this study, stimulation of HK2 expression was observed in squamous cervical cancer (SCC) tissues, and HK2 expression promoted the proliferation of cervical cancer cells in vitro and tumor formation in vivo by accelerating cell cycle progression, upregulating cyclin A1, and downregulating p27 expression. Moreover, transcriptome sequencing analysis revealed that MAPK3 (ERK1) was upregulated in HK2-overexpressing HeLa cells. Further experiments found that the protein levels of p-Raf, p-MEK1/2, ERK1/2, and p-ERK1/2 were increased in HK2 over-expressing SiHa and HeLa cells. When ERK1/2 and p-ERK1/2 expression was blocked by an inhibitor (FR180204), reduced cyclin A1 expression was observed in HK2 over-expressing cells, with induced p27 expression and inhibited cell growth. Therefore, our data demonstrated that HK2 promoted the proliferation of cervical cancer cells by upregulating cyclin A1 and down-regulating p27 expression through the Raf/MEK/ERK signaling pathway.

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Upregulation of miR-205 induces CHN1 expression, which is associated with the aggressive behaviour of cervical cancer cells and correlated with lymph node metastasis

BMC Cancer ◽

10.1186/s12885-020-07478-w ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Jianbing Liu ◽

Yunfeng Li ◽

Xihua Chen ◽

Xiangbo Xu ◽

Haoqi Zhao ◽

...

Keyword(s):

Cervical Cancer ◽

Lymph Node ◽

High Risk ◽

Cell Growth ◽

Lymph Node Metastasis ◽

Cancer Cells ◽

Migration And Invasion ◽

Node Metastasis ◽

Cervical Cancer Cells ◽

Human Cervical Cancer

Abstract Background Cervical cancer is the leading cause of cancer-related death in women worldwide. However, the mechanisms mediating the development and progression of cervical cancer are unclear. In this study, we aimed to elucidate the roles of microRNAs and a1-chimaerin (CHN1) protein in cervical cancer progression. Methods The expression of miR-205 and CHN1 protein was investigated by in situ hybridisation and immunohistochemistry. We predicted the target genes of miR-205 using software prediction and dual luciferase assays. The expression of mRNAs and proteins was tested by qRT-PCR and western blotting respectively. The ability of cell growth, migration and invasion was evaluated by CCK-8 and transwell. Cell apoptosis was analysed by flow cytometry analysis. Results We found that miR-205 and CHN1 were highly expressed in human cervical cancer tissue compared with paired normal cervical tissues. The CHN1 gene was shown to be targeted by miR-205 in HeLa cells. Interestingly, transfection with miR-205 mimic upregulated CHN1 mRNA and protein, while miR-205 inhibitor downregulated CHN1 in high-risk and human papilloma virus (HPV)-negative human cervical cancer cells in vitro,. These data suggested that miR-205 positively regulated the expression of CHN1. Furthermore, the miR-205 mimic promoted cell growth, apoptosis, migration, and invasion in high-risk and HPV-negative cervical cancer cells, while the miR-205 inhibitor blocked these biological processes. Knockdown of CHN1 obviously reduced the aggressive cellular behaviours induced by upregulation of miR-205, suggesting that miR-205 positively regulated CHN1 to mediate these cell behaviours during the development of cervical cancer. Furthermore, CHN1 was correlated with lymph node metastasis in clinical specimens. Conclusions Our findings showed that miR-205 positively regulated CHN1 to mediate cell growth, apoptosis, migration, and invasion during cervical cancer development, particularly for high-risk HPV-type cervical cancer. These findings suggested that dysregulation of miR-205 and subsequent abnormalities in CHN1 expression promoted the oncogenic potential of human cervical cancer.

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