LncRNA MEG3 Inhibits Tumor Progression by Modulating Macrophage Phenotypic Polarization via miR-145-5p/DAB2 Axis in Hepatocellular Carcinoma

Abstract

Background: Hepatocellular carcinoma (HCC) is the predominant histological type of primary liver cancer, which ranks sixth among the most common human tumors. Tumor-associated macrophages (TAMs) are an important component of tumor microenvironment (TME) and the M2 macrophage polarization substantially contributes to tumor growth and metastasis. Long non-coding RNA (lncRNA) MEG3 was reported to restrain HCC development. However, whether MEG3 regulates macrophage phenotypic polarization in HCC remains unclear. Methods: Bone marrow derived macrophages (BMDMs) were treated with LPS/IFNγ and IL4/IL13 to induce the M1 and M2 macrophage polarization, respectively. M2-polarized BMDMs were simultaneously transfected with adenovirus vector overexpressing MEG3 (Adv-MEG3). Subsequently, M2-polarized BMDMs were cultured for 24 h with serum-free medium, the supernatants of which were harvested as conditioned medium (CM). HCC cell line Huh7 was cultured with CM for 24 h. F4/80 + CD68 + and F4/80 + CD206 + cell percentages in M1-and M2-polarized BMDMs were calculated using flow cytometry. Huh7 cell migration, invasion and angiogenesis were determined via Transwell assay and tube formation experiment. Nude mice were implanted with Huh7 cells and Adv-MEG3-transfected M2-polarizd BMDMs, and tumor growth and M2 macrophage polarization markers were assessed. The binding between miR-145-5p and MEG3 or disabled-2 (DAB2) was verified by luciferase reporter assay. Results: MEG3 presented lower expression in HCC tissues than in normal controls, and low expression of MEG3 was correlated to poorer prognosis of HCC patients. MEG3 expression was enhanced during LPS/IFNγ-induced M1 polarization, but was reduced during IL4/IL13-induced M2 polarization. MEG3 overexpression inhibited the expression of M2 polarization markers in both M2polarized BMDMs and mice. Mechanically, MEG3 bound with miR-145-5p to regulate DAB2 expression. Overexpressing MEG3 suppressed M2 polarization-induced HCC cell metastasis and angiogenesis by upregulating DAB2 and inhibited in vivo tumor growth. Conclusion: LncRNA MEG3 curbs HCC development by repressing M2 macrophage polarization via miR-145-5p/DAB2 axis.

Decoding dynamic miRNA:ceRNA interactions unveils therapeutic insights and targets across predominant cancer landscapes

“…In addition, KLF9 has been reported to participate in coregulatory ceRNA interactions in bladder urothelial carcinomas [ 29 ]. Finally, although the anticancer effect of DAB2, which is common in all three cancer tissues, was first reported in ovarian cancer, DAB2 is regulated by non-coding RNAs in distinct cancer types [ 51 , 59 ].…”

BCAR3 and BCAR3-related competing endogenous RNA expression in hepatocellular carcinoma and their prognostic value

“…Additionally, ceRNA regulates HCC development by affecting epigenetic mechanisms, thereby interfering with cell cycle and apoptosis[ 32 ]. In particular, MEG3 affects liver cancer cell invasion by interacting with miR-145-5p to up-regulate disabled-2 expression[ 33 ]. Challenges remain in terms of clinical application despite the clear regulatory effects of these ceRNAs and networks in cell and animal models.…”

Integrating bulk and single-cell RNA sequencing data to establish necroptosis-related lncRNA risk model and analyze the immune microenvironment in hepatocellular carcinoma

“…However, there is evidence to suggest that a parallel network of necrotic apoptosis-induced CXCL1 and Mincle signals promote macrophage-induced adaptive immunosuppression, thereby promoting pancreatic ductal adenocarcinoma progression [ 53 ]. Furthermore, The lncRNA is also involved in the regulation of macrophage polarization in liver cancer [ 13 ]. The involvement of necroptosis-related lncRNAs in macrophage polarization may contribute to the immune regulation of liver cancer.…”

“…Further, lncRNAs can also influence the development of hepatocellular carcinoma by regulating immune cells. MEG3 can inhibit HCC development by inhibiting M2 macrophage polarization [ 13 ]. However, lncRNA-CRNDE can regulates M2 macrophage polarization and promotes angiogenesis in liver cancer [ 14 ].…”