Stat1 confers sensitivity to radiation in cervical cancer cells by controlling Parp1 levels: a new perspective for Parp1 inhibition

AbstractCervical cancer (CC) is the fourth most common cause of cancer-related death in women. According to international guidelines, a standard treatment for locally advanced cervical cancer (LACC) consists of exclusive concurrent chemoradiation treatment (CRT). However, chemoradioresistance and subsequent relapse and metastasis of cancer occur in many patients, and survival for these women has generally remained poor. Therefore, strategies to overcome resistance are urgently needed. We have recently reported a radiosensitizing effect of the signal transducer and activator of transcription 1 (STAT1) in CC, associated with the control of [Poly(ADP-ribose) polymerase −1] PARP1 levels, a key factor in cell response to DNA damage induced by radiation. Here, we sought to decipher the underlying mechanism of STAT1-mediated control of PARP1, elucidating its role as a radiosensitizer in CC. Functional and molecular biology studies demonstrated that STAT1 may act at both transcriptional and posttranscriptional levels to modulate PARP1 expression in CC cells. In light of these results, we tested the effect of Olaparib in sensitizing CC cells to radiation and investigated signaling pathways involved in the activity observed. Results showed that PARP1 inhibition, at clinically achievable doses, may indeed selectively improve the sensitivity of resistant CC cells to DNA-damaging treatment. The translational relevance of our findings was supported by preliminary results in a limited patient cohort, confirming that higher PARP1 levels are significantly associated with a radioresistant phenotype. Finally, bioinformatics analysis of GEPIA and TCGA databases, demonstrated that PARP1 mRNA is higher in CC than in normal tissues and that increased PARP1 mRNA expression levels are associated with poor prognosis of LACC patients. Overall, our data open new opportunities for the development of personalized treatments in women diagnosed with CC.

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ZNF582 Methylation Predicts Better Radiotherapy Response of Cervical Cancer and ZNF582 Overexpression Reduces Radiosensitivity by Arresting the Cell Cycle in S Phase

10.21203/rs.3.rs-990658/v1 ◽

2021 ◽

Author(s):

Nayiyuan Wu ◽

Xiaoyun Zhang ◽

Miaochen Zhu ◽

Chao Fang ◽

Xiaoting Liu ◽

...

Keyword(s):

Cell Cycle ◽

Cervical Cancer ◽

Cell Cycle Arrest ◽

Locally Advanced ◽

Underlying Mechanism ◽

S Phase ◽

Cycle Arrest ◽

Cervical Cancer Cells ◽

Pre Treatment ◽

The Relationship

Abstract Purpose: Our previous studies identified ZNF582 methylation (ZNF582m) level as a useful biomarker for cervical cancer screening, detection, and prognosis. The purpose of this study is to investigate the relationship between ZNF582m level and cervical cancer radiotherapy sensitivity and its underlying mechanism.Patients and Methods: This was a prospective multicenter clinical study, included two independent cohorts locally advanced cervical cancer patients. Exfoliated cervical cancer cells were collected pre-treatment and during treatment (after 24, 30, 36, 48, and 64 Gy) to test ZNF582m level, radiotherapy response evaluated according to RECIST Version. Results: In the first cohort, 22 cases achieved satisfied response, 28 exhibited modest response. Radiotherapy reduced ZNF582m level among all patients. Baseline ZNF582m was significantly higher in the satisfied response cases than in modest response cases, also, patients with high baseline ZNF582m (ZNF582m-high, n = 21) were more sensitive to radiotherapy than ZNF582m-low patients (n = 29), as evidenced by greater satisfied response rate (76.2% vs. 20.7%). An independent cohort confirmed above results. The magnitude of ZNF582m reduction was associated with a radiotherapeutic response, a subset of ZNF582m-low patients (5 of 28) exhibiting a transient increase in ZNF582m demonstrated greater radiosensitivity than other ZNF582m-low patients. ZNF582 overexpression induced cell cycle arrest in S phase.Conclusion: High ZNF582m level predicts better cervical cancer radiosensitivity, ZNF582 overexpression reduces radiosensitivity by cell cycle arrest.

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Influence of icariin on inflammation, apoptosis, invasion, and tumor immunity in cervical cancer by reducing the TLR4/MyD88/NF-κB and Wnt/β-catenin pathways

Cancer Cell International ◽

10.1186/s12935-021-01910-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chunyang Li ◽

Shuangqing Yang ◽

Huaqing Ma ◽

Mengjia Ruan ◽

Luyan Fang ◽

...

Keyword(s):

Cervical Cancer ◽

Underlying Mechanism ◽

Tissue Growth ◽

Migration And Invasion ◽

Dependent Manner ◽

Antitumor Effects ◽

Siha Cells ◽

Cervical Cancer Cells

Abstract Background Cervical cancer is a type of the most common gynecology tumor in women of the whole world. Accumulating data have shown that icariin (ICA), a natural compound, has anti-cancer activity in different cancers, including cervical cancer. The study aimed to reveal the antitumor effects and the possible underlying mechanism of ICA in U14 tumor-bearing mice and SiHa cells. Methods The antitumor effects of ICA were investigated in vivo and in vitro. The expression of TLR4/MyD88/NF-κB and Wnt/β-catenin signaling pathways were evaluated. Results We found that ICA significantly suppressed tumor tissue growth and SiHa cells viability in a dose-dependent manner. Also, ICA enhanced the anti-tumor humoral immunity in vivo. Moreover, ICA significantly improved the composition of the microbiota in mice models. Additionally, the results clarified that ICA significantly inhibited the migration, invasion capacity, and expression levels of TGF-β1, TNF-α, IL-6, IL-17A, IL-10 in SiHa cells. Meanwhile, ICA was revealed to promote the apoptosis of cervical cancer cells by down-regulating Ki67, survivin, Bcl-2, c-Myc, and up-regulating P16, P53, Bax levels in vivo and in vitro. For the part of mechanism exploration, we showed that ICA inhibits the inflammation, proliferation, migration, and invasion, as well as promotes apoptosis and immunity in cervical cancer through impairment of TLR4/MyD88/NF-κB and Wnt/β-catenin pathways. Conclusions Taken together, ICA could be a potential supplementary agent for cervical cancer treatment.

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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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Effects of LncRNA HOX Transcript Antisense RNA Targeting miRNA-761 on Cervical Cancer Cell Proliferation and Apoptosis

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2021.2725 ◽

2021 ◽

Vol 11 (10) ◽

pp. 2081-2086

Author(s):

Bin Qiu ◽

Hui Zhong ◽

Shenqiu Ming ◽

Chunxia Zhu

Keyword(s):

Cervical Cancer ◽

Cell Proliferation ◽

Cell Apoptosis ◽

Control Group ◽

Normal Tissues ◽

Cell Clones ◽

Cervical Cancer Cells ◽

Set Up ◽

Cancer Tissues ◽

Lncrna Hotair

Abnormal LncRNA HOTAIR level is correlated with various cancers and miR-761 can inhibit cancers. LncRNA HOTAIR targets miR-761 by StarBase 2.0 analysis. Our study investigated whether LncRNA HOTAIR can affect cervical cancer cells by regulating miR-761. The control group (NC group), LncRNA HOTAIR group and LncRNA HOTAIR + miR-761 Mimics group were set up to measure LncRNA HOTAIR and miR-761 level by qRT-PCR. Dual fluorescein reporter assay assessed whether miR-761 binds LncRNA HOTAIR. Western blot was used to measure Cyclin D1, Bcl-2 and Tubulin expression and clone formation assay was to assess cell proliferation and Annexin VFITC/PI staining was to detect cell apoptosis. Compared with normal tissues, LncRNA HOTAIR level was significantly higher in cervical cancer tissues, while miR-761 was lower (P < 0.01). LncRNA HOTAIR targets miR-761. Compared with NC group, CyclinD1 and Bcl-2 in LncRNA HOTAIR group were significantly increased (P < 0.01), which were significantly lower in LncRNA HOTAIR + miR-761 Mimics group (P < 0.05). Compared to NC group, miR-761 in LncRNA HOTAIR group was significantly reduced (P < 0.01) and elevated by miR-761 Mimics. In addition, compared to NC group, the number of cell clones in LncRNA HOTAIR group was increased, cell proliferation was increased, and number of apoptotic cells was decreased, which were all reversed in the LncRNA HOTAIR + miR-761 Mimics group. LncRNA HOTAIR targets miR-761, promotes cell proliferation and reduces cell apoptosis. miR-761 mimics can partially prevent the effects of LncRNA HOTAIR.

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The Impacts of Bone Marrow Mesenchymal Stem Cells (BMSCs)-Derived Periostin on Epithelial-Mesenchymal Transition (EMT) of Cervical Cancer Cells

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2022.2958 ◽

2022 ◽

Vol 12 (4) ◽

pp. 820-826

Author(s):

Chengyong Wu ◽

Weifeng Wei ◽

Jing Li ◽

Shenglin Peng

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Signal Transduction Pathway ◽

Underlying Mechanism ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Essential Components ◽

Cervical Cancer Cells ◽

E Cadherin

Epithelial-mesenchymal transition (EMT) is closely related to the migrating and invading behaviors of cells. Periostin is one of the essential components in the extracellular matrix and can induce EMT of cells and their sequential metastasis. But its underlying mechanism is unclear. The Hela and BMSC cell lines were assigned into Periostin-mimic group, Periostin-Inhibitor group and Periostin-NC group followed by analysis of cell migration and invasion, expression of E-Cadherin, Vimentin, β-Catenin, Snail, MMP-2, MMP-9, PTEN, and p-PTEN. Cells in Periostin-mimic group exhibited lowest migration, least number of invaded cells, as well as lowest levels of Vimentin, β-Catenin, Snail, MMP-2, MMP-9, p-PTEN, Akt, p-Akt, p-GSK-3β, p-PDK1 and p-cRcf, along with highest levels of E-cadherin and PTEN. Moreover, cells in Periostin-NC group had intermediate levels of these above indicators, while, the Periostin-Inhibitor group exhibited the highest migration rate, the most number of invaded cells, and the highest levels of these proteins (P < 0.05). In conclusion, BMSCs-derived Periostin can influence the EMT of cervical cancer cells possibly through restraining the activity of the PI3K/AKT signal transduction pathway, indicating that Periostin might be a target of chemotherapy in clinics for the treatment of cervical cancer.

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Oncothermia in HIV-Positive and -Negative Locally Advanced Cervical Cancer Patients in South Africa

Conference Papers in Medicine ◽

10.1155/2013/293968 ◽

2013 ◽

Vol 2013 ◽

pp. 1-3

Author(s):

Carrie A. Strauss ◽

Jeffrey A. Kotzen ◽

Ans Baeyens ◽

Irma Maré

Keyword(s):

South Africa ◽

Cervical Cancer ◽

Cancer Patients ◽

Standard Treatment ◽

Locally Advanced ◽

External Beam Radiation ◽

Hiv Positive ◽

Advanced Cervical Cancer ◽

Treatment Toxicity ◽

Locally Advanced Cervical Cancer

Aim. Investigate the clinical, economic, and cellular effects of the addition of oncothermia to standard treatment for HIV-positive and -negative locally advanced cervical cancer patients in public healthcare in South Africa. Objectives. Evaluate the effect that the addition of oncothermia has on local disease control, progression-free survival, overall survival at 2 years, treatment toxicity, quality of life, economic impact, and HIV status of participants. Radiobiology investigations will evaluate thermoradiosensitivity and the molecular markers for thermoradiosensitivity. Methodology. Phase III randomised clinical trial involving 236 HIV-negative and -positive stage IIb-III locally advanced cervical cancer patients. Treatment includes cisplatin, external beam radiation, and brachytherapy. The study group will receive oncothermia treatments. Participants will be monitored for two years after completion of treatment. Hypothesis. The addition of oncothermia to standard treatment protocols will result in improved clinical response without increasing treatment toxicity in HIV-positive patients or raising healthcare costs.

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Simultaneously Integrated Boost (SIB) Improves Sparing of Normal Tissues in Locally Advanced Cervical Cancer While Reducing Overall Treatment Time

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2014.05.2635 ◽

2014 ◽

Vol 90 (1) ◽

pp. S931

Author(s):

H. Feng ◽

Y. Hasan ◽

M. Kopec ◽

H.A. Al-Hallaq

Keyword(s):

Cervical Cancer ◽

Treatment Time ◽

Locally Advanced ◽

Advanced Cervical Cancer ◽

Overall Treatment Time ◽

Normal Tissues ◽

Locally Advanced Cervical Cancer ◽

Integrated Boost

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Expression of Nup93 is associated with the proliferation, migration and invasion capacity of cervical cancer cells

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmz131 ◽

2019 ◽

Vol 51 (12) ◽

pp. 1276-1285

Author(s):

Xiaolan Ouyang ◽

Xiaoming Hao ◽

Shuaibin Liu ◽

Jianguo Hu ◽

Lina Hu

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Underlying Mechanism ◽

Tumor Formation ◽

Cellular Migration ◽

Migration And Invasion ◽

Nuclear Pore ◽

Cervical Cancer Cells ◽

Invasion Capacity

Abstract Cervical cancer is a prevalent and devastating malignancy in females worldwide. Nucleoporin 93 (Nup93), a member of the nuclear pore complex, plays an important role in transport across the nuclear pore. Several nucleoporins have been linked to cancer. However, the oncogenic role and underlying mechanism of Nup93 in cervical cancer development have not been reported. In this study, the expression of Nup93 was analyzed by quantitative real-time polymerase chain reaction (qPCR), western blot analysis, and immunohistochemical staining in cervical cancer tissues and cell lines. We found that the expression of Nup93 was higher in cervical cancer samples, compared to normal cervical samples. The knockdown of Nup93 inhibited cell proliferation, migration, and invasion capacity of cervical cancer cells. At the same time, we also found that silencing of Nup93 could inhibit cellular migration and invasion by regulating cytoskeleton actin and Rho family proteins. Nup93 also participated in the IL-6/STAT3 signaling pathway. In addition, down-regulation of Nup93 prevented tumor formation in mice in vivo. Thus, Nup93 may be a carcinogenic gene and serve as a potential therapeutic target for cervical cancer.

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