LncRNA AGAP2 antisense RNA 1 stabilized by insulin-like growth factor 2 mRNA binding protein 3 promotes macrophage M2 polarization in clear cell renal cell carcinoma through regulation of the microRNA-9-5p/THBS2/PI3K-Akt pathway

Peng Xu; Da-Xiong Feng; Jun Wang; Yao-Dong Wang; Gang Xie; Bin Zhang; Xiao-Han Li; Jia-Wei Zeng; Jia-Fu Feng

doi:10.1186/s12935-023-03173-5

LncRNA AGAP2 antisense RNA 1 stabilized by insulin-like growth factor 2 mRNA binding protein 3 promotes macrophage M2 polarization in clear cell renal cell carcinoma through regulation of the microRNA-9-5p/THBS2/PI3K-Akt pathway

Cancer Cell Int. 2023 Dec 18;23(1):330. doi: 10.1186/s12935-023-03173-5.

Authors

Peng Xu^#^{1

2}, Da-Xiong Feng^#³, Jun Wang^#⁴, Yao-Dong Wang^{1

5}, Gang Xie^{1

6}, Bin Zhang^{1

2}, Xiao-Han Li⁷, Jia-Wei Zeng^{8

9}, Jia-Fu Feng^{10

11}

Affiliations

¹ NHC Key Laboratory of Nuclear Technology Medical Transformation (MIANYANG CENTRAL HOSPITAL), Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 12 Changjia Lane, Jingzhong Street, Mianyang, Sichuan, 621000, People's Republic of China.
² Department of Clinical Laboratory, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, People's Republic of China.
³ Department of Spine Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People's Republic of China.
⁴ Department of Laboratory Medicine, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu, 610045, People's Republic of China.
⁵ Department of Urology Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, People's Republic of China.
⁶ Department of Pathology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, People's Republic of China.
⁷ Department of Medical Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People's Republic of China.
⁸ NHC Key Laboratory of Nuclear Technology Medical Transformation (MIANYANG CENTRAL HOSPITAL), Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 12 Changjia Lane, Jingzhong Street, Mianyang, Sichuan, 621000, People's Republic of China. [email protected].
⁹ Department of Clinical Laboratory, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, People's Republic of China. [email protected].
¹⁰ NHC Key Laboratory of Nuclear Technology Medical Transformation (MIANYANG CENTRAL HOSPITAL), Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 12 Changjia Lane, Jingzhong Street, Mianyang, Sichuan, 621000, People's Republic of China. [email protected].
¹¹ Department of Clinical Laboratory, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, People's Republic of China. [email protected].

^# Contributed equally.

Abstract

Background: Increasing evidence highlights the potential role of long non-coding RNAs (lncRNAs) in the biological behaviors of renal cell carcinoma (RCC). Here, we explored the mechanism of AGAP2-AS1 in the occurrence and development of clear cell RCC (ccRCC) involving IGF2BP3/miR-9-5p/THBS2.

Methods: The expressions of AGAP2-AS1, IGF2BP3, miR-9-5p, and THBS2 and their relationship were analyzed by bioinformatics. The targeting relationship between AGAP2-AS1 and miR-9-5p and between miR-9-5p and THBS2 was evaluated with their effect on cell biological behaviors and macrophage polarization assayed. Finally, we tested the effect of AGAP2-AS1 on ccRCC tumor formation in xenograft tumors.

Results: IGF2BP3 could stabilize AGAP2-AS1 through m6A modification. AGAP2-AS1 was highly expressed in ccRCC tissues and cells. The lentivirus-mediated intervention of AGAP2-AS1 induced malignant behaviors of ccRCC cells and led to M2 polarization of macrophages. In addition, THBS2 promoted M2 polarization of macrophages by activating the PI3K/AKT signaling pathway. AGAP2-AS1 could directly bind with miR-9-5p and promote the expression of THBS2 downstream of miR-9-5p. These results were further verified by in vivo experiments.

Conclusion: AGAP2-AS1 stabilized by IGF2BP3 competitively binds to miR-9-5p to up-regulate THBS2, activating the PI3K/AKT signaling pathway and inducing macrophage M2 polarization, thus facilitating the development of RCC.

Keywords: AGAP2-AS1; IGF2BP3; Long non-coding RNA; M2 polarization; N6-methyladenosine; PI3K/AKT; Renal cell carcinoma; THBS2; miR-9-5p.

Grants and funding

2019YJ0701/the Science and Technology Department of Sichuan Province