Full Text | PDF

Share on tweeters Share on facebook Share on linkedin Share on googleplus

Theranostics 2023; 13(2):833-848. doi:10.7150/thno.77441 This issue Cite

Research Paper

ALKBH5 activates FAK signaling through m6A demethylation in ITGB1 mRNA and enhances tumor-associated lymphangiogenesis and lymph node metastasis in ovarian cancer

Rui Sun#, Lin Yuan#, Yi Jiang, Yicong Wan, Xiaolling Ma, Jing Yang, Guodong Sun, Shulin Zhou, Hui Wang, Jiangnan Qiu, Lin Zhang✉, Wenjun Cheng✉

Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
# These authors contributed equally.

✉ Corresponding authors: Lin Zhang: feilin1915com; Wenjun Cheng: chengwenjunorg.cn

Citation:
Sun R, Yuan L, Jiang Y, Wan Y, Ma X, Yang J, Sun G, Zhou S, Wang H, Qiu J, Zhang L, Cheng W. ALKBH5 activates FAK signaling through m6A demethylation in ITGB1 mRNA and enhances tumor-associated lymphangiogenesis and lymph node metastasis in ovarian cancer. Theranostics 2023; 13(2):833-848. doi:10.7150/thno.77441. https://www.thno.org/v13p0833.htm
Other styles

File import instruction

Abstract

Graphic abstract

Background: Lymph node (LN) metastasis is common in patients with epithelial ovarian cancer (EOC) and is associated with poor prognosis. Tumor-associated lymphangiogenesis is the first stage of LN metastasis. Research on lymphangiogenesis and lymph node metastases can help develop new anti-LN-targeted therapies. Aberrant N6-methyladenosine (m6A) modifications have been reported to be linked to LN metastasis in several cancers, however, their role in EOC lymphangiogenesis and LN metastasis remains unclear.

Methods: m6A levels in EOC tissues with or without LN metastases were evaluated by dot blot analysis. Real-time polymerase chain reaction (PCR) and immunofluorescence were used to examine the expression of m6A-related enzymes. Additionally, in vitro and in vivo functional studies were performed to discover the importance of the AlkB homolog 5 (ALKBH5) gene in EOC lymphatic metastasis. To identify the downstream target genes regulated by ALKBH5, we performed RNA pulldown, RNA-binding protein immunoprecipitation-quantitative PCR, co-immunoprecipitation, m6A-modified RNA immunoprecipitation-quantitative PCR, and luciferase reporter assays.

Results: m6A modification was reduced in ovarian cancers with LN metastases. ALKBH5 overexpression increased tumor-associated lymphangiogenesis and LN metastasis both in vitro and in vivo. ALKBH5 overexpression also reversed the m6A modification in ITGB1 mRNA and suppressed the YTHDF2 protein-mediated m6A-dependent ITGB1 mRNA degradation, which resulted in increased expression of ITGB1 and phosphorylation of the focal adhesion kinase (FAK) and Src proto-oncogene proteins, thereby increasing LN metastasis. Furthermore, hypoxia induced the expression of hypoxia inducible factor 1 subunit alpha, which increased ALKBH5 expression and enhanced LN metastasis in EOC.

Conclusions: The ALKBH5/m6A-ITGB1/FAK signalling axis is important in ovarian cancer lymphangiogenesis and LN metastasis. Antibodies that block ITGB1 and FAK kinase-inhibitors are promising anti-metastatic agents.

Keywords: lymphatic metastasis, epithelial ovarian cancer, N6-methyladenosine, ALKBH5, ITGB1

Citation styles

APA
Sun, R., Yuan, L., Jiang, Y., Wan, Y., Ma, X., Yang, J., Sun, G., Zhou, S., Wang, H., Qiu, J., Zhang, L., Cheng, W. (2023). ALKBH5 activates FAK signaling through m6A demethylation in ITGB1 mRNA and enhances tumor-associated lymphangiogenesis and lymph node metastasis in ovarian cancer. Theranostics, 13(2), 833-848. https://doi.org/10.7150/thno.77441.

ACS
Sun, R.; Yuan, L.; Jiang, Y.; Wan, Y.; Ma, X.; Yang, J.; Sun, G.; Zhou, S.; Wang, H.; Qiu, J.; Zhang, L.; Cheng, W. ALKBH5 activates FAK signaling through m6A demethylation in ITGB1 mRNA and enhances tumor-associated lymphangiogenesis and lymph node metastasis in ovarian cancer. Theranostics 2023, 13 (2), 833-848. DOI: 10.7150/thno.77441.

NLM
Sun R, Yuan L, Jiang Y, Wan Y, Ma X, Yang J, Sun G, Zhou S, Wang H, Qiu J, Zhang L, Cheng W. ALKBH5 activates FAK signaling through m6A demethylation in ITGB1 mRNA and enhances tumor-associated lymphangiogenesis and lymph node metastasis in ovarian cancer. Theranostics 2023; 13(2):833-848. doi:10.7150/thno.77441. https://www.thno.org/v13p0833.htm

CSE
Sun R, Yuan L, Jiang Y, Wan Y, Ma X, Yang J, Sun G, Zhou S, Wang H, Qiu J, Zhang L, Cheng W. 2023. ALKBH5 activates FAK signaling through m6A demethylation in ITGB1 mRNA and enhances tumor-associated lymphangiogenesis and lymph node metastasis in ovarian cancer. Theranostics. 13(2):833-848.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Popup Image

©2024 Ivyspring International Publisher. Terms of use