Mechanism of hsa_circ_0069443 promoting early pregnancy loss through ALKBH5/FN1 axis in trophoblast cells

Bai-Xue Li; Mei-Yao Wu; Zhi-Hui Wang; Dong-Mei Zhou; Jian-Qi Li; Bing-Feng Lu; Xiao-Ling Lin; Yang Zhao; Xiu-Jie Sheng

doi:10.1016/j.isci.2024.111608

Mechanism of hsa_circ_0069443 promoting early pregnancy loss through ALKBH5/FN1 axis in trophoblast cells

iScience. 2024 Dec 16;28(1):111608. doi: 10.1016/j.isci.2024.111608. eCollection 2025 Jan 17.

Authors

Bai-Xue Li^{1

2

3

4

5

6}, Mei-Yao Wu^{1

2

3

4

7

5

6}, Zhi-Hui Wang^{1

2

3

4

5

6}, Dong-Mei Zhou^{1

2

3

4

5

6}, Jian-Qi Li^{1

2

3

4

5

6}, Bing-Feng Lu^{2

3

4

5

6}, Xiao-Ling Lin^{1

2

3

4

5

6}, Yang Zhao^{1

2

3

4

5

6}, Xiu-Jie Sheng^{1

2

3

4

5

6}

Affiliations

¹ Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China.
² Department of Gynecologic Oncology Research Office, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China.
³ Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China.
⁴ Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China.
⁵ Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China.
⁶ Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine the Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China.
⁷ Department of Gynecology, Queen Mary Hospital, Hong Kong, China.

Abstract

Studies have shown that circRNAs play an important regulatory role in trophoblast function and embryonic development. Based on sequencing and functional experiments, we found that hsa_circ_0069443 can regulate the function of trophoblast cells, and its presence is found in the exosomes secreted by trophoblast cells. It is known that exosomes mediate the interaction between the uterus and embryo, which is crucial for successful pregnancy. We found that trophoblast cell-derived exosomes overexpressing hsa_circ_0069443 promoted the migration and invasion of endometrial stromal cells as well as the EMT process of endometrial glandular epithelial cells, and this process promotes embryo implantation and adhesion, thus proving that a decrease in hsa_circ_0069443 may be the key factor leading to early pregnancy loss. This study also found that hsa_circ_0069443 can bind to the RNA-binding protein demethylase ALKBH5, affecting the overall m6A level of trophoblast cells, and hsa_circ_0069443 and ALKBH5 can regulate the expression level of FN1, verifying the role of the 0069443/ALKBH5/FN1 axis in trophoblast cells and endometrial stromal cells. In summary, this study demonstrates that hsa_circ_0069443 may be a key factor leading to early pregnancy loss, and the regulation of the hsa_circ_0069443/ALKBH5/FN1 axis may provide new insights into early diagnostic markers for early pregnancy loss.

Keywords: Cell biology; Molecular biology; Pregnancy.