LncRNA-PACERR induces pro-tumour macrophages via interacting with miR-671-3p and m6A-reader IGF2BP2 in pancreatic ductal adenocarcinoma

Abstract

Background LncRNA-PACERR plays critical role in the polarization of tissue-associated macrophages (TAMs). In this study, we found the function and molecular mechanism of PACERR in TAMs to regulate pancreatic ductal adenocarcinoma (PDAC) progression. Methods We used qPCR to analyse the expression of PACERR in TAMs and M1-tissue-resident macrophages (M1-NTRMs) which were isolated from 46 PDAC tissues. The function of PACERR on macrophages polarization and PDAC proliferation, migration and invasion were confirmed through in vivo and in vitro assays. The molecular mechanism of PACERR was discussed via fluorescence in situ hybridization (FISH), RNA pull-down, ChIP-qPCR, RIP-qPCR and luciferase assays. Results LncRNA-PACERR was high expression in TAMs and associated with poor prognosis in PDAC patients. Our finding validated that LncRNA-PACERR increased the number of M2-polarized cells and facilized cell proliferation, invasion and migration in vitro and in vivo. Mechanistically, LncRNA-PACERR activate KLF12/p-AKT/c-myc pathway by binding to miR-671-3p. And LncRNA-PACERR which bound to IGF2BP2 acts as an m6A-dependent manner to enhance the stability of KLF12 and c-myc in cytoplasm. In addition, the promoter of LncRNA-PACERR was a target of KLF12 and LncRNA-PACERR recruited EP300 to increase the acetylation of histone by interacting with KLF12 in nucleus. Conclusions This study found that LncRNA-PACERR functions as key regulator of TAMs in PDAC microenvironment and revealed the novel mechanisms in cytoplasm and in nucleus.

Identification of a novel miRNA-based recurrence and prognosis prediction biomarker for hepatocellular carcinoma

“…The accuracy of these 10 miRNAs to predict tumor recurrence after surgery or liver transplantation in patients with HCC was verified using an external validation dataset (GSE30297) and an internal validation dataset (TCGA). Multiple previous studies have shown that these 10 miRNAs are associated with multiple malignancies, including hepatocellular carcinoma, gastric cancer, and pancreatic ductal adenocarcinoma [ 12 – 14 ].…”

The role of N6-methyladenosine-modified non-coding RNAs in the pathological process of human cancer

“…In addition, recent accumulating researches reported that ncRNAs can regulate downstream target genes through interacting with m6A modulators (writers, erasers, readers). For example, PACERR, an upregulated lncRNA in pancreatic ductal adenocarcinoma (PDAC), contributes to increasing the number of M2-polarized cells and facilizing the malignant phenotype in PDAC by binding to m6A reader IGF2BP2 to increase the stability of downstream target genes KLF12 and c-myc [ 82 ].…”

Crosstalk among long non-coding RNA, tumor-associated macrophages and small extracellular vesicles in tumorigenesis and dissemination

“…PACERR acts as amiR-671-3p sponge to activate the KLF12/AKT/c-myc pathway and it also enhances the stability of KLF12 and c-myc by interacting with insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). KLF12 can directly bind to the promoter of PACERR, and KLF12-transcribed PACERR recruits histone acetyltransferase E1A binding protein p300 (EP300) to increase the acetylation of histone (H3K27) in the PACERR promoter region and enhance the transcription of PACERR in TAM ( 48 ). Notably, PTGS2 and PACERR have overlapping promoter regions, and PACERR is transcribed in the opposite direction of PTGS2; thus, PACERR functions as a cis -acting lncRNA in TAM.…”