| BackgroundMeningioma is a common primary tumor of the central nervous system.Although most meningiomas are benign tumors and have a good prognosis after surgical resection,for highly invasive high-grade meningiomas,complete surgical resection is difficult,and the postoperative recurrence rate is high and the prognosis is poor.Even in meningiomas completely removed by surgery,the total tumor recurrence rate 15 years after operation is as high as 60%.With the increasing improvement of people’s living standards and the extension of average life expectancy,the number of meningioma patients will be more and more.At present,there is no specific targeted drug for the treatment of meningiomas.Clinically,adjuvant radiotherapy after surgical resection is still the classic scheme for the treatment of high-grade meningiomas.In addition,for meningiomas located in functional areas with complex intracranial anatomical structures,total resection is usually impossible,and the choice of adjuvant radiotherapy is particularly critical.As an important means of meningioma treatment,radiotherapy is of great significance to improve the survival and prognosis of patients.However,most meningioma patients will have different degrees of radiation resistance during radiotherapy,and the effect of radiotherapy is poor.In the field of radiotherapy for meningiomas,especially for highgrade meningiomas,radiotherapy resistance is the main problem.Therefore,to explore new targets of radiosensitization for high-grade meningiomas and effectively reduce radiotherapy resistance is an urgent problem to be solved in the treatment of meningiomas.The main mechanism of radiotherapy is DNA damage of tumor cells.Whether tumor tissues are sensitive to radiation mainly depends on the DNA damage repair ability of target cells.It has been confirmed that there are many repair pathways related to DNA damage response in tumor cells.Among them,cell cycle regulation mechanism occupies an important part of DNA damage repair,mainly focusing on the regulation of Cyclindependent Kinases(CDK)and cell cycle checkpoint.Therefore,there may be a new target of abnormal activation of DNA damage repair in the cell cycle regulation pathway.Clarifying the regulation mechanism of this target is of great significance to reduce tumor radiation resistance.Cyclin B1(CCNB1),as an important member of cyclin family,is an important regulatory factor related to G2 / M checkpoint.Studies have shown that CCNB1,as an important molecule involved in the process of cell cycle regulation in the DNA damage repair pathway,is related to the occurrence and development of a variety of tumors and radiosensitivity.In the early stage,our research group conducted a large number of literature review in combination with the clinical data of meningioma patients,and finally screened the differential gene CCNB1 related to the poor prognosis of meningioma patients.Through the preparation of high-throughput tissue microarray and the follow-up of clinical data for survival correlation analysis and verification,we further discussed its role in radiation sensitization of meningioma at the level of cell phenotype,The radiosensitivity mechanism was preliminarily explored.Contents and Method1.Correlation between CCNB1 expression and prognosis of meningioma patientsThe research group first collected 87 meningioma samples and 9 normal dural tissue samples,prepared them into tissue microarray for immunohistochemical interpretation,then made statistical analysis,and analyzed the survival of 42 meningioma patients with complete follow-up data.Then,the relevant clinical data of meningioma patients in GEO database were downloaded for further survival analysis.2.Role of CCNB1 in radiosensitivity of high-grade meningioma cellsThe malignant meningioma cell line IOMM-Lee was selected to construct CCNB1 knockdown and overexpression stable cell lines.Through the experimental methods of tumor cell migration,proliferation,clone formation,apoptosis,cell cycle and DNA damage repair pathway protein detection,the role of CCNB1 in meningioma radiosensitivity was further clarified,and its effect on DNA damage repair pathway induced by ionizing radiation was explored.Results1.The expression of CCNB1 was significantly correlated with the prognosis of meningioma patientsIn the first part,the results of tissue microarray showed that the expression of CCNB1 was significantly up-regulated in high-grade cell tumors;Subsequent survival analysis showed that the expression of CCNB1 was significantly correlated with the prognosis of meningioma patients;Further Cox multivariate analysis showed that the expression level of CCNB1 was an independent prognostic risk factor in patients with meningioma;Finally,the survival analysis results of meningioma cases downloaded from GEO database are consistent with the above clinical results.2.CCNB1 knockdown significantly increased the radiosensitivity of high-grade meningioma cellsIn the second part,the cell scratch experiment showed that CCNB1 knockdown significantly inhibited the migration of high-grade tumor cells;The proliferation experiment showed that CCNB1 knockdown significantly inhibited the proliferation of high-grade tumor cells;Further clone formation rate showed that CCNB1 knockdown could significantly reduce the survival rate of high-grade meningioma cells after irradiation;Apoptosis experiment showed that CCNB1 knockdown significantly promoted the apoptosis process of high-grade tumor cells after irradiation;Cell cycle test showed that CCNB1 knockdown significantly aggravated the G2/M phase arrest of high-grade meningioma cells after irradiation;The verification of DNA damage repair related proteins suggested that CCNB1 knockdown significantly inhibited the activation of DNA damage repair pathway in high-grade meningioma cells after irradiation.ConclusionFirstly,through the tissue microarray and clinical data of clinical samples,this study confirmed that the expression of CCNB1 was up-regulated in high-grade meningiomas,which was significantly correlated with the prognosis of meningiomas.Further,through the cell phenotype experiment,it was clear for the first time that CCNB1 knockdown had a significant radiosensitization effect on high-grade meningiomas cells,and preliminarily explored its mechanism,which may be related to the regulation of DNA damage repair pathway by CCNB1.Combined with the above research results,CCNB1 is expected to be a new target for radiation sensitization therapy of meningioma. |
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