Radioresistance In Cervical Cancer Research Articles

NSUN6-mediated 5-methylcytosine modification of NDRG1 mRNA promotes radioresistance in cervical cancer

BackgroundRadioresistance is the leading cause of death in advanced cervical cancer (CC). Dysregulation of RNA modification has recently emerged as a regulatory mechanism in radiation and drug resistance. We aimed to explore the biological function and clinical significance of 5-methylcytosine (m5C) in cervical cancer radiosensitivity.MethodsThe abundance of RNA modification in radiotherapy-resistant and sensitive CC specimens was quantified by liquid chromatography-tandem mass spectrometry. The essential RNA modification-related genes involved in CC radiosensitivity were screened via RNA sequencing. The effect of NSUN6 on radiosensitivity was verified in CC cell lines, cell-derived xenograft (CDX), and 3D bioprinted patient-derived organoid (PDO). The mechanisms of NSUN6 in regulating CC radiosensitivity were investigated by integrative m5C sequencing, mRNA sequencing, and RNA immunoprecipitation.ResultsWe found a higher abundance of m5C modification in resistant CC samples, and NSUN6 was the essential m5C-regulating gene concerning radiosensitivity. NSUN6 overexpression was clinically correlated with radioresistance and poor prognosis in cervical cancer. Functionally, higher NSUN6 expression was associated with radioresistance in the 3D PDO model of cervical cancer. Moreover, silencing NSUN6 increased CC radiosensitivity in vivo and in vitro. Mechanistically, NDRG1 was one of the downstream target genes of NSUN6 identified by integrated m5C-seq, mRNA-seq, and functional validation. NSUN6 promoted the m5C modification of NDRG1 mRNA, and the m5C reader ALYREF bound explicitly to the m5C-labeled NDRG1 mRNA and enhanced NDRG1 mRNA stability. NDRG1 overexpression promoted homologous recombination-mediated DNA repair, which in turn led to radioresistance in cervical cancer.ConclusionsAberrant m5C hypermethylation and NSUN6 overexpression drive resistance to radiotherapy in cervical cancer. Elevated NSUN6 expression promotes radioresistance in cervical cancer by activating the NSUN6/ALYREF-m5C-NDRG1 pathway. The low expression of NSUN6 in cervical cancer indicates sensitivity to radiotherapy and a better prognosis.

Selenium-containing metallodrug overcomes cervical cancer radioresistance by physical-chemical dual sensitization

Radiotherapy is an important treatment for cervical cancer, but the efficacy of radiotherapy is often reduced in clinical practice due to high frequency and high dose radiation leading to radiotherapy...

TRAIL-driven targeting and reversing cervical cancer radioresistance by seleno-nanotherapeutics through regulating cell metabolism

Recently, radioresistance has become a major obstacle in the radiotherapy of cervical cancer. To demonstrate enhanced radiosensitization against radioresistant cervical cancer, radioresistant cervical cancer cell line was developed and the mechanism of radioresistance was explored. Due to the overexpression of (death receptor 5, DR5) in cervical cancer, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-overexpressed cervical cancer cell membrane-camouflaged Cu2−xSe nanomedicine (CCMT) was designed. Since the CCMT was encapsulated with TRAIL-modified cell membrane, it represented high target to cervical cancer cell and immune evasion. Furthermore, Cu2−xSe had the ability to scavenge glutathione (GSH) and produce ·OH with excess H2O2 in the tumor microenvironment. The presence of CCMT combined with radiation therapy could effectively increase the 1O2 produced by X-rays. In vitro and in vivo studies elaborated that CCMT exhibited excellent radiosensitization properties to reverse radiotolerance by scavenging GSH and promoting DNA damage, apoptosis, mitochondrial membrane potential damage and metabolic disruption. Collectively, this study suggested that the development of TRAIL-overexpressed cell membrane-camouflaged Cu2−xSe nanomedicine could advance future cervical cancer treatment and minimize the disadvantages associated with radiation treatment.

Aldolase A promotes cervical cancer cell radioresistance by regulating the glycolysis and DNA damage after irradiation

ABSTRACT Radioresistance is the major obstacle that affects the efficacy of radiotherapy which is an important treatment for cervical cancer. By analyzing the databases, we found that aldolase A (ALDOA), which is a key enzyme in metabolic reprogramming, has a higher expression in cervical cancer patients and is associated with poor prognosis. We detected the expression of ALDOA in the constructed cervical cancer radioresistance (RR) cells by repetitive irradiation and found that it was upregulated compared to the control cells. Functional assays were conducted and the results showed that the knockdown of ALDOA in cervical cancer RR cells inhibited the proliferation, migration, and clonogenic abilities by regulating the cell glycolysis. In addition, downregulation of ALDOA enhanced radiation-induced apoptosis and DNA damage by causing G2/M phase arrest and further promoted radiosensitivity of cervical cancer cells. The functions of ALDOA in regulating tumor radiosensitivity were also verified by the mouse tumor transplantation model in vivo. Therefore, our study provides new insights into the functions of ALDOA in regulating the efficacy of radiotherapy and indicates that ALDOA might be a promising target for enhancing radiosensitivity in treating cervical cancer patients.

Hypoxic tumor cell-derived small extracellular vesicle miR-152-3p promotes cervical cancer radioresistance through KLF15 protein

BackgroundRadiotherapy is widely used in treating cervical cancer patients, however, radioresistance unavoidably occurs and seriously affects the treatment effect. It is well known that hypoxia plays an important role in promoting radioresistance in tumor microenvironment, yet our understanding of the effect of small extracellular vesicles miRNA on cervical cancer radiosensitivity in hypoxic environment is still limited.MethodsSmall extracellular vesicles extracted from hypoxic and normoxic cultured cervical cancer cells were evaluated for their effects on radioresistance. miR-152-3p was found to be a potential effector in hypoxia-derived extracellular vesicles by searching the GEO database. Its downstream substrate was confirmed by double luciferase report, which was KLF15. The role of miR-152-3p and KLF15 in regulating cervical cancer radioresistance was detected by cell activity assays. The findings were confirmed in vivo by animal models. The expression of miR-152-3p was quantified by qRT-PCR and its prognostic significance was evaluated.ResultsHypoxic environment promoted the secretion of small extracellular vesicles, and reduced the apoptosis and DNA damage caused by radiation, accompanied by increased expression of small extracellular vesicles miR-152-3p from hypoxic cervical cancer cells. Furthermore, small extracellular vesicles miR-152-3p promoted Hela xenograft growth and reduced the radiosensitivity vivo. Mechanism studies revealed that KLF15 protein was the downstream target of miR-152-3p in regulating radioresistance.ConclusionOur findings suggest that small extracellular vesicles miR-152-3p affects the therapeutic effect of radiotherapy and holds potential as a biomarker or therapeutic target for cervical cancer prognosis and improving radiotherapy.

Defining new biomarkers for overcoming therapeutical resistance in cervical cancer using lncRNA.

Despite improvements in cervical cancer diagnosis and treatment, the prognosis for cervical cancer patients remains dismal due to the development of drug resistance, metastasis, and invasion resulting leading to treatment failure. Long non-coding RNAs (lncRNAs), a class of RNA transcripts have been reported in mediating carcinogenesis as well as drug, and radio-resistance in tumor cells. These lncRNAs regulate various cancer hallmarks and contribute to the development of therapeutic resistance. They regulates multiple signalling pathways, recruits polycomb group, function as miRNA sponge and scaffolds. Additionally, lncRNAs can act as oncogenes or tumor suppressors in cervical cancer. This comprehensive review outlines the biogenesis of lncRNA and its role in cancer development. It delves into the mechanisms through which various lncRNAs mediate chemoresistance and radioresistance in cervical cancer. By shedding into the light of mechanism, this review will also aids researchers in understanding lncRNAs as biomarkers and latest advancements in clinically targeting them with the help of Artificial Intelligence for overcoming chemoresistance and radioresistance, thereby improving cervical cancer treatment.

PAX1 hypomethylation as a prognostic biomarker for radioresistance of cervical cancer

BackgroundPAX1 gene methylation plays an important role in the development of cervical cancer. However, its prognostic value after radiotherapy for locally advanced cervical cancer is unknown, so this study aimed to investigate the value of PAX1 gene methylation for predicting the sensitivity of radiotherapy for cervical cancer.MethodsWe selected 125 patients with primary cervical cancer who underwent concurrent chemo-radiotherapy as the study population, quantitative methylation-specific polymerase chain reaction (QMSP) was used for detecting PAX1 methylation status of cervical exfoliated cells. Logistic regression model was used to analyze the risk factors associated with the short-term efficacy and to establish a prediction model of radiotherapy sensitivity based on PAX1 gene methylation. Cell viability after radiation of Hela and SiHa cells transfected with PAX1 or control vector was evaluated by CCK8. Furthermore, RNA-Seq analyses identified different expressed genes (DEGs) in PAX1 overexpressed SiHa cells. Gene Ontology (GO) and pathway enrichment analysis was carried out to determine the biological function of DEGs.ResultsPAX1 methylation level was associated with HPV16/18-positive rate. PAX1 hypomethylation was found to be a risk factor for tumor residual after chemo-radiotherapy. A nomogram containing the risk factors for PAX1 methylation status, lymph node metastasis, pathological type and tumor size was further constructed to predict the probability of tumor residual after chemo-radiotherapy (AUC = 0.823, 95% CI 0.736–0.910). High PAX1 protein level was more likely to cause radioresistance in both Hela and SiHa cells. Transcriptomic sequencing of PAX1 overexpressed and control cells identified 615 differentially expressed genes, and GO enrichment analysis suggested that PAX1 may be involved in the regulation of signaling receptor activity and response to viruses.ConclusionPAX1 hypomethylation status could be used as a promising biomarker to predict radioresistance in cervical cancer. This further provides a new idea for the individualized treatment strategy of simultaneous radiotherapy for cervical cancer.

CircRNF13, a novel N6-methyladenosine-modified circular RNA, enhances radioresistance in cervical cancer by increasing CXCL1 mRNA stability

BackgroundCircular RNAs (circRNAs) and N6-methyladenosine (m6A) have been shown to play an increasingly critical role in the development of different cancers. However, there is limited evidence on how circRNAs and m6A interact to affect the radiosensitivity of cervical cancer (CC). This study provides a mechanistic understanding of the novel m6A-regulated circRNF13 in enhancing radioresistance in CC.MethodsDifferentially expressed circRNAs were identified from radiosensitive and radioresistant CC tissues. Meanwhile, these circRNAs were subjected to methylated RNA immunoprecipitation (Me-RIP). Finally, the effects of these circRNAs on radiosensitivity were characterized.ResultsCircRNF13 was poorly expressed in CC patients that were sensitive to concurrent radiochemotherapy. Experiments conducted both in vitro and in vivo confirmed that the knockdown of circRNF13 potentiated the radiosensitivity of CC cells. Further mechanistic studies revealed that METTL3/YTHDF2 promoted the degradation of circRNF13 and subsequently affected the stability of CXC motif chemokine ligand 1 (CXCL1), ultimately enhancing the radiosensitivity of CC cells.ConclusionThis study identified circRNF13 as a novel m6A-modified circRNA and validated the METTL3/YTHDF2/circRNF13/CXCL1 axis as a potential target for CC radiotherapy.

Retraction: LncRNA NEAT1 enhances the radio-resistance of cervical cancer via miR-193b-3p/CCND1 axis.

// Dongmei Han 1 , Jianfeng Wang 1 and Guanghui Cheng 1 1 Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China Correspondence to: Guanghui Cheng, email: guanghuicheng_ghc@163.com Keywords: Received: RECEIVED_DATE     Accepted: ACCEPTED_DATE     Published: April 24, 2023 Copyright: © 2023 Han et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Cancer-Associated Fibroblasts Exposed to High-Dose Ionizing Radiation Promote M2 Polarization of Macrophages, Which Induce Radiosensitivity in Cervical Cancer

Radiotherapy, including brachytherapy, is a major therapeutic regimen for cervical cancer. Radioresistance is a decisive factor in radiation treatment failure. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor microenvironment are critical factors in the curative effects of cancer therapies. However, the interactions between TAMs and CAFs in the context of ionizing radiation are not fully understood. This study was undertaken to investigate whether M2 macrophages induce radioresistance in cervical cancer and to explore the TAMs' phenotypic transformation after IR and its underlying mechanisms. The radioresistance of cervical cancer cells was enhanced after being co-cultured with M2 macrophages. TAMs tended to undergo M2 polarization after high-dose irradiation, which was strongly associated with CAFs in both mouse models and patients with cervical cancer. Additionally, cytokine and chemokine analysis was performed to find that high-dose irradiated CAFs promoted macrophage polarization towards the M2 phenotype through chemokine (C-C motif) ligand 2. Collectively, our results highlight the crucial role that high-dose irradiated CAFs play in the regulation of M2 phenotype polarization, which ultimately induces radioresistance in cervical cancer.

The PIK3CA-E545K-SIRT4 signaling axis reduces radiosensitivity by promoting glutamine metabolism in cervical cancer

The mutation of glutamic acid 545 to lysine (E545K) in PIK3CA, as the most common missense mutation of this gene in various cancer types, is frequently observed in cervical cancer and has been shown to reduce cervical cancer radiosensitivity. However, the underlying mechanisms remain unclear. Here, we implicate the alterations of glutamine metabolism in PIK3CA-E545K-mediated radioresistance of cervical cancer. Specifically, PIK3CA mutation negatively regulated the expression of SIRT4 via the epigenetic regulator EP300 independently of the canonical mTORC1 pathway. PIK3CA-E545K-induced SIRT4 downregulation promoted cell proliferation, migration, and radiation-induced DNA repair and apoptosis, while SIRT4 overexpression reversed the radioresistance phenotype mediated by PIK3CA mutation. Mechanistically, SIRT4 modulated glutamine metabolism and thus cellular apoptosis by negatively regulating a glutamate pyruvate transaminase GPT1. Moreover, the PI3K inhibitor BYL719, but not mTOR inhibitors, exerted remarkable synergistic effects with radiotherapy by inhibiting glutamine metabolism in vitro and in vivo. Collectively, this study reveals the role of PIK3CA-E545K-SIRT4 axis in regulating glutamine metabolism and the radioresistance in cervical cancer, which provides a necessary preliminary basis for clinical research of PI3K inhibitors as radiosensitizing agents.

YTHDF3 mediates HNF1α regulation of cervical cancer radio-resistance by promoting RAD51D translation in an m6A-dependent manner.

Radiotherapy, as an important primary treatment, has effectively improved the survival of patients with cervical cancer (CC). Some patients, however, do not benefit optimally from radiotherapy because of radio-resistance. Therefore, identifying radio-resistance biomarkers and unravelling the underlying mechanisms is of critical importance for these patients. In the present study, we found significant upregulation of hepatocyte nuclear factor 1-alpha (HNF1α) expression in radio-resistant cervical cancer tissues and cell lines. Depletion of HNF1α reduced and overexpression of HNF1α promoted the resistance of CC cells to irradiation invitro and invivo. HNF1α positively regulated DNA repair protein RAD51 homologue 4 (RAD51D) at the protein level but not at the mRNA level. Mechanistically, upregulation of HNF1α enhanced YTH domain-containing family protein 3 (YTHDF3) transcription, which in turn promoted RAD51D mRNA N6 -methyladenosine (m6A) modification. YTHDF3 mediates HNF1α regulation of cervical cancer radio-resistance by promoting RAD51D translation in an m6A-dependent manner. The HFN1α/YTHDF3/RAD51D regulatory axis was found to play a critical role in conferring radio-resistance of CC cells. In conclusion, dysregulation of the HFN1α/YTHDF3/RAD51D axis may promote the radio-resistance of CC cells. Blocking this pathway may provide therapeutic benefits against CC radio-resistance.

Aspirin Restores Radiosensitivity in Cervical Cancer Cells by Inducing Mitotic Catastrophe through Downregulating G2/M Effectors.

Compromised cell-cycle checkpoint is a major obstacle for rendering radiotherapeutic success of radioresistant cells. Aspirin (ASA), an anti-inflammatory agent was repurposed previously for improving radiotherapy by limiting radiation toxicity. However, the underlying mechanism was unclear. The present study aimed to identify the mechanism of ASA mediated reversal of radioresistance in cervical cancer cells. Radioresistant subline SiHa/RR was developed from parental cervical squamous carcinoma cell line SiHa by chronic fractionated irradiation (IR). The radioresistance property of SiHa/RR was confirmed by clonogenic assay. Alteration in cell-cycle by ASA was determined by flow cytometry. ASA induced nuclear damage as consequence of mitotic catastrophe was confirmed by microscopic observation. The interaction between ASA and G2/M regulators was explored through in silico docking analysis and expressional change of them was affirmed by western blotting. Immunofluorescence study to examine Aurora Kinase A localization in presence and absence of ASA treatment was conducted. Finally the radiosensitizing ability of ASA was verified by apoptotic parameters (flow cytometrically and by western blotting). Higher colony forming ability of SiHa/RR compared to SiHa became restrained upon ASA (5μM) treatment prior to IR. Flow cytometric analysis of ASA treated cells showed increased G2/M population followed by enlargement of cells displaying giant multinucleated morphology; typical characteristics of mitotic catastrophe. Underlying noteworthy mechanisms involved decreased expressions of G2/M regulatory proteins (Cyclin B1, CDK1, Aurora A Kinase, pAurora A Kinase) in IR/ASA along with inhibiting nuclear localization of Aurora Kinase A in SiHa/RR. Docking results also supported the findings. Prolonged treatment (12 h) with ASA led to apoptosis by altering expressions of Bcl2, Bax and Cytochrome C; which was achieved through the event of mitotic catastrophe. This work established that G2/M arrest and mitotic catastrophe can be considered as the principle mechanism of restoration of radiosensitivity in SiHa/RR by ASA pretreatment.

Recent progress of the tumor microenvironmental metabolism in cervical cancer radioresistance.

Radiotherapy is widely used as an indispensable treatment option for cervical cancer patients. However, radioresistance always occurs and has become a big obstacle to treatment efficacy. The reason for radioresistance is mainly attributed to the high repair ability of tumor cells that overcome the DNA damage caused by radiotherapy, and the increased self-healing ability of cancer stem cells (CSCs). Accumulating findings have demonstrated that the tumor microenvironment (TME) is closely related to cervical cancer radioresistance in many aspects, especially in the metabolic processes. In this review, we discuss radiotherapy in cervical cancer radioresistance, and focus on recent research progress of the TME metabolism that affects radioresistance in cervical cancer. Understanding the mechanism of metabolism in cervical cancer radioresistance may help identify useful therapeutic targets for developing novel therapy, overcome radioresistance and improve the efficacy of radiotherapy in clinics and quality of life of patients.

Statement of Retraction: Elevation of microRNA-512-5p inhibits MUC1 to reduce radioresistance in cervical cancer

This article refers to:RETRACTED ARTICLE: Elevation of microRNA-512-5p inhibits MUC1 to reduce radioresistance in cervical cancer

KLK5 is associated with the radioresistance, aggression, and progression of cervical cancer

ObjectiveThe role of kallikrein-related peptidase 5 (KLK5) has been studied in several diseases, including skin and ovarian cancers. However, its role in cervical cancer remains unclear, particularly in regulating the radiation resistance and growth of cervical cancer cells. Radiation resistance of cervical cancer is associated with local recurrence, distant metastasis, and reduced survival. MethodsWe first analyzed radiotherapy-naive samples and relevant clinical data from patients with cervical cancer who received radiotherapy without surgery or other antitumor treatment from 2014 to 2016. Subsequently, biopsied tissues, in vitro cells, and transplanted tumors in nude mice were investigated. ResultsGene sequencing and clinical data analysis showed that KLK5 overexpression was associated with a poor prognosis post-radiotherapy. In in vitro cell and tumor transplantation experiments, KLK5 overexpression significantly increased radiation resistance. However, downregulating KLK5 expression increased radiosensitivity. ConclusionOur results confirm that KLK5 is vital to the radioresistance of cervical cancer, and provide a new target and marker for the treatment of radioresistance in cervical cancer.

CircCASC15-miR-100-mTOR may influence the cervical cancer radioresistance

BackgroundCervical cancer has ranked the top one in gynecological malignancies for incidence. Radioresistance is now becoming a leading reason of recurrence.MethodsOur microRNA array data indicated that the miRNA-100 level decreased significantly during radioresistance. In this study, we up-regulated miR-100 in Hela and Siha cells by using miR-100 mimics and observed proliferation and invasion.ResultsIt turned out that with overexpression of miR-100, the cells had less invasiveness as well as proliferation. It may target gene mTOR, and it deed reduced EMT. To examine the role of miR-100 in radioresistance, there was no significant result showed by BSP. While the circCASC15 has been identified with sponge function according to RNA pull down and ISH.ConclusionThe conclusions indicate miR-100 is a tumor suppressor gene and could be a therapeutic target in radio-resistant cervical cancers.

SND1 Promotes Radioresistance in Cervical Cancer Cells by Targeting the DNA Damage Response.

Background: Radiotherapy is one of the most effective therapeutic strategies for cervical cancer patients, although radioresistance-mediated residual and recurrent tumors are the main cause of treatment failure. However, the mechanism of tumor radioresistance is still elusive. DNA damage response pathways are key determinants of radioresistance. The purpose of this study was to investigate the role and mechanism of SND1 in radioresistance of cervical cancer. Methods: A stable HeLa cell line with SND1 knockout (HeLa-KO) was generated through a modified CRISPR/Cas9 double-nicking gene editing system. The stable CaSki cell lines with SND1 knockdown (CaSki-Ctrl, CaSki-SND1-sh-1, CaSki-SND1-sh-2) were constructed through lentivirus transfection with the pSil-SND1-sh-1 and pSil-SND1-sh-2 plasmids. Results: It was observed that SND1 deficiency significantly increased the radiosensitivity of cervical cancer cells. It was also found that silencing SND1 promotes radiation-induced apoptosis. Significantly, the cells with a loss of SND1 function exhibited inefficient ataxia telangiectasia mutated pathway activation, subsequently impairing DNA repair and G2/M checkpoint arrest. In addition, threonine 103 is an important phosphorylation site of SND1 under DNA damaging stress. Conclusion: Collectively, the results of this study reveal a potent radiosensitizing effect of silencing SND1 or T103 mutation on cervical cancer cells, providing novel insights into potential therapeutic strategies for cervical cancer treatment.

USP21 regulates Hippo signaling to promote radioresistance by deubiquitinating FOXM1 in cervical cancer.

The ectopic expression of ubiquitin-specific peptidase 21 (USP21) is common in different types of cancer. However, its relationship with radio-sensitivity in cervical cancer (CC) remains unclear. In this study, we aimed to uncover the effect of USP21 on CC radio-resistance and its underlying mechanism. Our results showed that the expression of USP21 was markedly increased in CC tissues of radio-resistant patients and CC cells treated with radiation. Besides, knockdown of USP21 restrained the survival fractions, and facilitated apoptosis of CC cells in the absence or presence of radiation. Additionally, USP21 in combination with FOXM1 regulated the stability and ubiquitination of FOXM1. However, FOXM1 reversed the effects of USP21 knockdown on the radio-resistance of CC cells. Furthermore, FOXM1 knockdown activated the Hippo pathway by inhibiting the nuclear translocation of Yes-associated protein 1 (YAP1), and FOXM1 knockdown attenuated the radio-resistance of CC cells via inhibiting the Hippo-YAP1 pathway. USP21 activated the Hippo pathway by mediating FOXM1. Knockdown of USP21 enhanced the radio-sensitivity of CC cells in vivo. In summary, USP21 contributed to the radio-resistance of CC cells via FOXM1/Hippo signaling, and may serve as a promising target for radio-sensitizers in the radiotherapy of CC.

Novel Therapy and Diagnosis of Cervical Cancer Radio Resistance for the Future Development

Novel Therapy and Diagnosis of Cervical Cancer Radio Resistance for the Future Development