lncRNA ABHD11‐AS1, regulated by the EGFR pathway, contributes to the ovarian cancer tumorigenesis by epigenetically suppressing TIMP2

• Published in: Cancer medicine (Malden, MA) Vol. 8; no. 16; pp. 7074 - 7085
• Main Authors: Zeng, Xiang‐Yang, Jiang, Xiao‐Yan, Yong, Jia‐Hui, Xie, Hui, Yuan, Jing, Zeng, Da, Dou, Ying‐Yu, Xiao, Song‐Shu
• Format: Journal Article
• Language: English
• Published: United States John Wiley and Sons Inc 01.11.2019
• Subjects: ABHD11‐AS1; Animals; Cancer Biology; Carcinogenesis - genetics; Carcinogenesis - metabolism; Cell Line; Cell Line, Tumor; EGFR; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenesis, Genetic; epithelial ovarian cancer; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; EZH2; Female; Humans; Mice, Nude; Original Research; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Ovary - metabolism; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Signal Transduction; TIMP2; Tissue Inhibitor of Metalloproteinase-2 - metabolism; TIMP2; ABHD11-AS1; epithelial ovarian cancer; EGFR; EZH2
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.2586

Objective Epithelial ovarian cancer (EOC) is a common gynecologic malignancy characterized by extensive peritoneal metastasis and high mortality rate. ABHD11 Antisense RNA1 (ABHD11‐AS1) has recently been identified as a regulator of growth and metastasis in multiple tumors, including EOC. However, the biological function and potential mechanism of ABHD11‐AS1 in EOC remains poorly understood. Methods Immunohistochemistry, western blot, and qRT‐PCR analysis were used to determine the expression pattern of ABHD11‐AS1 and epidermal growth factor receptor (EGFR) in both EOC tissues and cell lines, respectively. Colony formation, transwell and wound healing assays were performed to evaluate the roles of EGFR and ABHD11‐AS1 on the capacity of cell proliferation, migration, and invasion. Western blot analysis was performed to measure the regulation of EGFR pathway on STAT3. Moreover, chromatin immunoprecipitation was employed to demonstrate the interaction between ABHD11‐AS1 and STAT3. RNA immunoprecipitation was subjected to prove the direct binding between ABHD11‐AS1 and EZH2. Immunofluorescence staining was performed to measure the expression and localization of TIMP2. EOC mouse model was conducted for validating the role of ABHD11‐AS1 in vivo. Results EGFR and ABHD11‐AS1 were highly expressed in EOC tissues and cell lines. Knockdown of EGFR or ABHD11‐AS1 inhibited cell growth, migration, and invasion of EOC cells. Expression of ABHD11‐AS1 was regulated by the activation of EGFR signaling pathway, mediated by STAT3. Besides, ABHD11‐AS1 was shown to silence TIMP2 by binding to chromatin‐modifying enzyme EZH2. Furthermore, inhibition of EGFR pathway or ABHD11‐AS1 repressed the tumor growth of EOC. Conclusion We defined the regulatory relationship between the EGFR signaling pathway, ABHD11‐AS1, EZH2, and TIMP2 suggesting that ABHD11‐AS1 may act as an oncogene and a potential target for antitumor therapies in ovarian cancer. EGFR and NEAT1 are upregulated in epithelial ovarian cancer. EGFR and NEAT1 promote proliferation, migration, and invasion of ovarian cancer cells. NEAT1 is upregulated by activation of EGFR signaling pathway.