METTL3 facilitates immunosurveillance by inhibiting YTHDF2-mediated NLRC5 mRNA degradation in endometrial cancer

被引：18

作者：

Zhan, Lei ^{[1
,2
,3
,4
,5
,6
,7
]}

Zhang, Jing ^{[2
]}

Zhang, Jun-Hui ^{[1
,3
,4
,5
,6
,7
]}

Liu, Xiao-Jing ^{[2
]}

Guo, Bao ^{[2
]}

Chen, Jia-Hua ^{[2
]}

Tang, Zhen-Hai ^{[8
]}

Wang, Wen-Yan ^{[2
]}

Wang, Qing-Yuan ^{[2
]}

Wei, Bing ^{[2
]}

Cao, Yun-Xia ^{[1
,3
,4
,5
,6
,7
]}

机构：

[1] Anhui Med Univ, Affiliated Hosp 1, Dept Obstet & Gynecol, 218 Jixi Rd, Hefei 230022, Anhui, Peoples R China

[2] Anhui Med Univ, Affiliated Hosp 2, Dept Obstet & Gynecol, 678 Furong Rd, Hefei 230601, Anhui, Peoples R China

[3] Anhui Med Univ, NHC Key Lab Study Abnormal Gametes & Reprod Tract, 81 Meishan Rd, Hefei 230032, Anhui, Peoples R China

[4] Anhui Med Univ, Key Lab Populat Hlth Life Cycle, Minist Educ Peoples Republ China, 81 Meishan Rd, Hefei 230032, Anhui, Peoples R China

[5] Anhui Prov Key Lab Reprod Hlth & Genet, 81 Meishan Rd, Hefei 230032, Anhui, Peoples R China

[6] Anhui Prov Engn Res Ctr Biopreservat & Artificial, 81 Meishan Rd, Hefei 230032, Anhui, Peoples R China

[7] Anhui Prov Inst Translat Med, 81 Meishan Rd, Hefei 230032, Anhui, Peoples R China

[8] Ctr Sci Res Anhui Med Univ, 218 Jixi Rd, Hefei 230022, Anhui, Peoples R China

来源：

BIOMARKER RESEARCH | 2023年 / 11卷 / 01期

关键词：

Endometrial cancer; N6-methyladenosine; N6-adenosine-methyltransferase-like; 3; YTH domain-containing family 2; NLR family CARD domain-containing 5; Immunosurveillance; Biomarker; Immunotherapy;

D O I：

10.1186/s40364-023-00479-4

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background N6-methyladenosine (m6A) methylation is the most abundant chemical posttranscriptional modification of mRNA, and it is associated with the regulation of the immune response to tumors. However, the function of m6A modification in the immune response to endometrial cancer (EC) remains unknown. Our study investigated the immunological role of methyltransferase-like 3 (METTL3) in EC and the underlying molecular mechanism. Methods We investigated the correlation between the expression of METTL3 and CD8 by using an endometrial tissue microarray cohort. Next, we investigated the role and mechanism of METTL3 in the immune response to EC using a mouse tumor model and a CD8(+) T cell-EC cell coculture system after METTL3 overexpression or depletion. Additionally, RNA immunoprecipitation (RIP), methylated RIP, and RNA stability experiments were used to investigate the mechanism underlying the function of METTL3 in immunosurveillance of EC. Results METTL3 levels were downregulated in EC patients, low levels of METTL3 were correlated with poor prognosis in EC patients. There was a positive correlation between METTL3 expression and CD8 expression. Overexpression of METTL3 in the EC cell and CD8(+) T cell coculture system inhibited EC cell proliferation, migration, and promoted CD8(+) T-cell proliferation, and in vivo, METTL3 overexpression increased CD8(+) T cell proportions and inhibited EC progression; however, genetic depletion of METTL3 exerted the opposite effects. NLR family CARD domain-containing 5 (NLRC5) was identified as a target of METTL3-mediated m6A modification. The degradation of NLRC5 was increased by YTH domain-containing family 2 (YTHDF2). Conclusions Overall, METTL3, YTHDF2, and NLRC5 have potential to be the diagnostic and prognostic biomarkers for EC. METTL3 facilitated the m6A modifications of NLRC5 and inhibited its degradation through a YTHDF2-dependent mechanism in EC. Genetic overexpression of METTL3 attenuated the immune evasion of EC by promoting NLRC5-mediated immunosurveillance, suggesting that the METTL3/YTHDF2/NLRC5 axis is a promising target of immunotherapy in EC.

引用

页数：5