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

Yihao Liu; Minmin Shi; Xingfeng He; Yizhi Cao; Pengyi Liu; Fanlu Li; Siyi Zou; Chenlei Wen; Qian Zhan; Zhiwei Xu; Jiancheng Wang; Baofa Sun; Baiyong Shen

doi:10.1186/s13045-022-01272-w

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

J Hematol Oncol. 2022 May 7;15(1):52. doi: 10.1186/s13045-022-01272-w.

Authors

Yihao Liu^#^{1

2

3

4

5}, Minmin Shi^#^{1

2

4

5}, Xingfeng He^#^{1

2

4

5}, Yizhi Cao^{1

2

4

5}, Pengyi Liu^{1

2

4

5}, Fanlu Li^{1

2

4

5}, Siyi Zou^{1

2

4

5}, Chenlei Wen^{1

2

4

5}, Qian Zhan^{1

2

4

5}, Zhiwei Xu^{1

2

4

5}, Jiancheng Wang^{6

7

8

9}, Baofa Sun¹⁰, Baiyong Shen^{11

12

13

14}

Affiliations

¹ Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
² Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
³ Department of Zoology, College of Life Science, Nankai University, Tianjin, 300071, China.
⁴ State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China.
⁵ Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China.
⁶ Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. wjc10585@rjh.com.cn.
⁷ Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. wjc10585@rjh.com.cn.
⁸ State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China. wjc10585@rjh.com.cn.
⁹ Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China. wjc10585@rjh.com.cn.
¹⁰ Department of Zoology, College of Life Science, Nankai University, Tianjin, 300071, China. sunbf@nankai.edu.cn.
¹¹ Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. shenby@shsmu.edu.cn.
¹² Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. shenby@shsmu.edu.cn.
¹³ State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China. shenby@shsmu.edu.cn.
¹⁴ Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China. shenby@shsmu.edu.cn.

^# Contributed equally.

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.

Keywords: IGF2BP2; KLF12; LncRNA-PACERR; PDAC; TAMs; m6A; miR-671-3p.

MeSH terms

Carcinoma, Pancreatic Ductal* / pathology
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation / genetics
Gene Expression Regulation, Neoplastic
Humans
In Situ Hybridization, Fluorescence
Kruppel-Like Transcription Factors / genetics
Macrophages / metabolism
MicroRNAs* / genetics
Pancreatic Neoplasms* / pathology
RNA, Long Noncoding* / genetics
RNA-Binding Proteins* / genetics
Tumor Microenvironment

Substances

IGF2BP2 protein, human
KLF12 protein, human
Kruppel-Like Transcription Factors
MIRN671 microRNA, human
MicroRNAs
RNA, Long Noncoding
RNA-Binding Proteins

Abstract

MeSH terms

Substances

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