N 6-methyladenosine modification ofCENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistanceN 6-methyladenosine modification ofCENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance- 解放军医学杂志（英文版） 2022年9卷第5期 页码：576-591
- Affiliations：
1.Departments of Gynecology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fujian Medical University, Fuzhou 350014, China
2.Department of Radiation Oncology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fujian Medical University, Fuzhou 350014, China
3.Shenzhen Key Laboratory of Immunity and Inflammatory Diseases, Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, Guangdong, China
4.Outpatient Department, Fujian Hospital of People’s Armed Police, Fujian Medical University, Fuzhou 350014, China
- Author bio：
* ccb@fjmu.edu.cn;
xuqinfj@163.com
- Funds：the Joint Funds for the Innovation of Science and Technology Program of Fujian Province, China(2018Y9110);the Natural Science Foundation of Fujian Province, China(2020J011126);the China Postdoctoral Science Foundation(2021T140468)
DOI：10.1186/s40779-022-00378-z
中图分类号：-
纸质出版：2022-10
- Accepted：
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N 6-methyladenosine modification ofCENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance[J]. 解放军医学杂志（英文版）, 2022,9(5):576-591.Lin X, Wang F, Chen J, Liu J, Lin YB, Li L, et al. N6-methyladenosine modification of CENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance. Mil Med Res. 2022;9(1):19.
N 6-methyladenosine modification ofCENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance[J]. 解放军医学杂志（英文版）, 2022,9(5):576-591. DOI： 10.1186/s40779-022-00378-z.Lin X, Wang F, Chen J, Liu J, Lin YB, Li L, et al. N6-methyladenosine modification of CENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance. Mil Med Res. 2022;9(1):19. DOI： 10.1186/s40779-022-00378-z.
摘要
Abstract
Background:
2
Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis. In the current study
we determined the relevant players and role of
N
6
-methyladenine (m
6
A) RNA methylation in cervical cancer progression.
Methods:
2
The roles of m
6
A RNA methylation and centromere protein K (CENPK) in cervical cancer were analyzed using bioinformatics analysis. Methylated RNA immunoprecipitation was adopted to detect m
6
A modification of
CENPK
mRNA. Human cervical cancer clinical samples
cell lines
and xenografts were used for analyzing gene expression and function. Immunofluorescence staining and the tumorsphere formation
clonogenic
MTT
and EdU assays were performed to determine cell stemness
chemoresistance
migration
invasion
and proliferation in HeLa and SiHa cells
respectively. Western blotting analysis
co-immunoprecipitation
chromatin immunoprecipitation
and luciferase reporter
cycloheximide chase
and cell fractionation assays were performed to elucidate the underlying mechanism.
Results:
2
Bioinformatics analysis of public cancer datasets revealed firm links between m
6
A modification patterns and cervical cancer prognosis
especially through ZC3H13-mediated m
6
A modification of
CENPK
mRNA. CENPK expression was elevated in cervical cancer
associated with cancer recurrence
and independently predicts poor patient prognosis [hazard ratio=1.413
95% confidence interval=1.078–1.853
P
=0.012]. Silencing of
CENPK
prolonged the overall survival time of cervical cancer-bearing mice and improved the response of cervical cancer tumors to chemotherapy
in vivo
(
P
<
0.001). We also showed that CENPK was directly bound to SOX6 and disrupted the interactions of CENPK with β-catenin
which promoted β-catenin expression and nuclear translocation
facilitated p53 ubiquitination
and led to activation of Wnt/β-catenin signaling
but suppression of the p53 pathway. This dysregulation ultimately enhanced the tumorigenic pathways required for cell stemness
DNA damage repair pathways necessary for cisplatin/carboplatin resistance
epithelial-mesenchymal transition involved in metastasis
and DNA replication that drove tumor cell proliferation.
Conclusions:
2
CENPK was shown to have an oncogenic role in cervical cancer and can thus serve as a prognostic indicator and novel target for cervical cancer treatment.
关键词
Keywords
references
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