Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2022

Open Access 01-12-2022 | Pancreatic Cancer | Research

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

Authors: 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

Published in: Journal of Hematology & Oncology | Issue 1/2022

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin 2021, 71(1).
2.
Connor AA, Gallinger S. Pancreatic cancer evolution and heterogeneity: integrating omics and clinical data. Nat Rev Cancer 2021.
3.
4.
5.
Schizas D, Charalampakis N, Kole C, Economopoulou P, Koustas E, Gkotsis E, Ziogas D, Psyrri A, Karamouzis MV. Immunotherapy for pancreatic cancer: a 2020 update. Cancer Treat Rev. 2020;86: 102016.PubMedCrossRef
6.
Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, Fearon D, Greten FR, Hingorani SR, Hunter T, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020;20(3):174–86.PubMedPubMedCentralCrossRef
7.
Ho WJ, Jaffee EM, Zheng L. The tumour microenvironment in pancreatic cancer—clinical challenges and opportunities. Nat Rev Clin Oncol. 2020;17(9):527–40.PubMedPubMedCentralCrossRef
8.
Peng J, Sun B-F, Chen C-Y, Zhou J-Y, Chen Y-S, Chen H, Liu L, Huang D, Jiang J, Cui G-S, et al. Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res. 2019;29(9):725–38.PubMedPubMedCentralCrossRef
9.
Yunna C, Mengru H, Lei W, Weidong C. Macrophage M1/M2 polarization. Eur J Pharmacol. 2020;877: 173090.PubMedCrossRef
10.
11.
Xia Y, Rao L, Yao H, Wang Z, Ning P, Chen X. Engineering macrophages for cancer immunotherapy and drug delivery. Adv Mater. 2020;32(40): e2002054.PubMedCrossRef
12.
13.
Koorstra J-BM, Karikari CA, Feldmann G, Bisht S, Rojas PL, Offerhaus GJA, Alvarez H, Maitra A. The Axl receptor tyrosine kinase confers an adverse prognostic influence in pancreatic cancer and represents a new therapeutic target. Cancer Biol Ther 2009;8(7):618–626.
14.
Song X, Wang H, Logsdon CD, Rashid A, Fleming JB, Abbruzzese JL, Gomez HF, Evans DB, Wang H. Overexpression of receptor tyrosine kinase Axl promotes tumor cell invasion and survival in pancreatic ductal adenocarcinoma. Cancer. 2011;117(4):734–43.PubMedCrossRef
15.
16.
Hua JT, Chen S, He HH. Landscape of noncoding RNA in prostate cancer. Trends Genet. 2019;35(11):840–51.PubMedCrossRef
17.
Statello L, Guo C-J, Chen L-L, Huarte M. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol 2021;22(2).
18.
Yao R-W, Wang Y, Chen L-L. Cellular functions of long noncoding RNAs. Nat Cell Biol. 2019;21(5):542–51.PubMedCrossRef
19.
Zhang G, Li S, Lu J, Ge Y, Wang Q, Ma G, Zhao Q, Wu D, Gong W, Du M, et al. LncRNA MT1JP functions as a ceRNA in regulating FBXW7 through competitively binding to miR-92a-3p in gastric cancer. Mol Cancer. 2018;17(1):87.PubMedPubMedCentralCrossRef
20.
Yi W, Li J, Zhu X, Wang X, Fan L, Sun W, Liao L, Zhang J, Li X, Ye J, et al. CRISPR-assisted detection of RNA-protein interactions in living cells. Nat Methods. 2020;17(7):685–8.PubMedCrossRef
21.
Long Y, Wang X, Youmans DT, Cech TR. How do lncRNAs regulate transcription? Sci Adv 2017;3(9):eaao2110.
22.
Qian M, Yang X, Li Z, Jiang C, Song D, Yan W, Liu T, Wu Z, Kong J, Wei H, et al. P50-associated COX-2 extragenic RNA (PACER) overexpression promotes proliferation and metastasis of osteosarcoma cells by activating COX-2 gene. Tumour Biol. 2016;37(3):3879–86.PubMedCrossRef
23.
Sun P, Quan J-C, Wang S, Zhuang M, Liu Z, Guan X, Wang G-Y, Wang H-Y, Wang X-S. lncRNA-PACER upregulates and PGE2 through the NF-κB pathway to promote the proliferation and invasion of colorectal-cancer cells. Gastroenterol Rep (Oxf). 2021;9(3):257–68.CrossRef
24.
Xiong D-D, Chen H, He R-Q, Lan A-H, Zhong J-C, Chen G, Feng Z-B, Wei K-L. MicroRNA-671-3p inhibits the development of breast cancer: A study based on in vitro experiments, in-house quantitative polymerase chain reaction and bioinformatics analysis. Int J Oncol. 2018;52(6):1801–14.PubMedPubMedCentral
25.
Mao S, Lu Z, Zheng S, Zhang H, Zhang G, Wang F, Huang J, Lei Y, Wang X, Liu C, et al. Exosomal miR-141 promotes tumor angiogenesis via KLF12 in small cell lung cancer. J Exp Clin Cancer Res. 2020;39(1):193.PubMedPubMedCentralCrossRef
26.
He Z, Guo X, Tian S, Zhu C, Chen S, Yu C, Jiang J, Sun C. MicroRNA-137 reduces stemness features of pancreatic cancer cells by targeting KLF12. J Exp Clin Cancer Res. 2019;38(1):126.PubMedPubMedCentralCrossRef
27.
Liu Y, Liang L, Ji L, Zhang F, Chen D, Duan S, Shen H, Liang Y, Chen Y. Potentiated lung adenocarcinoma (LUAD) cell growth, migration and invasion by lncRNA DARS-AS1 via miR-188-5p/ KLF12 axis. Aging (Albany NY). 2021;13(19):23376–92.CrossRef
28.
Huang H, Weng H, Chen J. mA modification in coding and non-coding RNAs: roles and therapeutic implications in cancer. Cancer Cell. 2020;37(3):270–88.PubMedPubMedCentralCrossRef
29.
Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, Zhao BS, Mesquita A, Liu C, Yuan CL, et al. Recognition of RNA N-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20(3):285–95.PubMedPubMedCentralCrossRef
30.
Jiang X, Guo S, Wang S, Zhang Y, Chen H, Wang Y, Liu RL, Niu Y-J, Xu Y: EIF4A3-induced circARHGAP29 promotes aerobic glycolysis in docetaxel-resistant prostate cancer through IGF2BP2/c-Myc/LDHA signaling. Cancer Res 2021.
31.
Zhai S, Xu Z, Xie J, Zhang J, Wang X, Peng C, Li H, Chen H, Shen B, Deng X. Epigenetic silencing of LncRNA LINC00261 promotes c-myc-mediated aerobic glycolysis by regulating miR-222-3p/HIPK2/ERK axis and sequestering IGF2BP1. Oncogene. 2021;40(2):277–91.PubMedCrossRef
32.
Xie J, Xing S, Shen B-Y, Chen H-T, Sun B, Wang Z-T, Wang J-W, Lu X-X. PIWIL1 interacting RNA piR-017061 inhibits pancreatic cancer growth via regulating EFNA5. Hum Cell. 2021;34(2):550–63.PubMedCrossRef
33.
Lin J, Xu Z, Xie J, Deng X, Jiang L, Chen H, Peng C, Li H, Zhang J, Shen B. Oncogene APOL1 promotes proliferation and inhibits apoptosis via activating NOTCH1 signaling pathway in pancreatic cancer. Cell Death Dis. 2021;12(8):760.PubMedPubMedCentralCrossRef
34.
Chen S, Yang C, Wang Z-W, Hu J-F, Pan J-J, Liao C-Y, Zhang J-Q, Chen J-Z, Huang Y, Huang L, et al. CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer. J Hematol Oncol. 2021;14(1):60.PubMedPubMedCentralCrossRef
35.
Zou Y, Lu P, Shi J, Liu W, Yang M, Zhao S, Chen N, Chen M, Sun Y, Gao A, et al. IRX3 promotes the browning of white adipocytes and its rare variants are associated with human obesity risk. EBioMedicine. 2017;24:64–75.PubMedPubMedCentralCrossRef
36.
37.
Liu Y, Wang X, Zhu Y, Cao Y, Wang L, Li F, Zhang Y, Li Y, Zhang Z, Luo J, et al. The CTCF/LncRNA-PACERR complex recruits E1A binding protein p300 to induce pro-tumour macrophages in pancreatic ductal adenocarcinoma via directly regulating PTGS2 expression. Clin Transl Med. 2022;12(2): e654.PubMedPubMedCentralCrossRef
38.
Wen C-L, Huang K, Jiang L-L, Lu X-X, Dai Y-T, Shi M-M, Tang X-M, Wang Q-B, Zhang X-D, Wang P-H, et al. An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma. Proc Natl Acad Sci USA. 2019;116(46):23264–73.PubMedPubMedCentralCrossRef
39.
He Z, Yang D, Fan X, Zhang M, Li Y, Gu X, Yang M. The roles and mechanisms of lncRNAs in liver fibrosis. Int J Mol Sci 2020;21(4).
40.
Wang L, Cho KB, Li Y, Tao G, Xie Z, Guo B: Long noncoding RNA (lncRNA)-mediated competing endogenous RNA networks provide novel potential biomarkers and therapeutic targets for colorectal cancer. Int J Mol Sci 2019;20(22).
41.
Ding L, Ding Y, Kong X, Wu J, Fu J, Yan G, Zhou H. Dysregulation of Krüppel-like factor 12 in the development of endometrial cancer. Gynecol Oncol. 2019;152(1):177–84.PubMedCrossRef
42.
Godin-Heymann N, Brabetz S, Murillo MM, Saponaro M, Santos CR, Lobley A, East P, Chakravarty P, Matthews N, Kelly G, et al. Tumour-suppression function of KLF12 through regulation of anoikis. Oncogene. 2016;35(25):3324–34.PubMedCrossRef
43.
Grossi E, Raimondi I, Goñi E, González J, Marchese FP, Chapaprieta V, Martín-Subero JI, Guo S, Huarte M. A lncRNA-SWI/SNF complex crosstalk controls transcriptional activation at specific promoter regions. Nat Commun. 2020;11(1):936.PubMedPubMedCentralCrossRef
44.
Wang C, Li Y, Yan S, Wang H, Shao X, Xiao M, Yang B, Qin G, Kong R, Chen R, et al. Interactome analysis reveals that lncRNA HULC promotes aerobic glycolysis through LDHA and PKM2. Nat Commun. 2020;11(1):3162.PubMedPubMedCentralCrossRef
45.
46.
Li T, Hu P-S, Zuo Z, Lin J-F, Li X, Wu Q-N, Chen Z-H, Zeng Z-L, Wang F, Zheng J, et al. METTL3 facilitates tumor progression via an mA-IGF2BP2-dependent mechanism in colorectal carcinoma. Mol Cancer. 2019;18(1):112.PubMedPubMedCentralCrossRef
47.
Zhu Y, Herndon JM, Sojka DK, Kim K-W, Knolhoff BL, Zuo C, Cullinan DR, Luo J, Bearden AR, Lavine KJ et al. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 2017;47(2).
48.
49.
Yao Y, Zhou Y, Fu X. miR-671-3p is downregulated in non-small cell lung cancer and inhibits cancer progression by directly targeting CCND2. Mol Med Rep. 2019;19(3):2407–12.PubMed
50.
Xu X, Yu Y, Zong K, Lv P, Gu Y. Up-regulation of IGF2BP2 by multiple mechanisms in pancreatic cancer promotes cancer proliferation by activating the PI3K/Akt signaling pathway. J Exp Clin Cancer Res. 2019;38(1):497.PubMedPubMedCentralCrossRef
51.
Wang Y, Lu J-H, Wu Q-N, Jin Y, Wang D-S, Chen Y-X, Liu J, Luo X-J, Meng Q, Pu H-Y, et al. LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer. Mol Cancer. 2019;18(1):174.PubMedPubMedCentralCrossRef
52.
Hu X, Peng W-X, Zhou H, Jiang J, Zhou X, Huang D, Mo Y-Y, Yang L. IGF2BP2 regulates DANCR by serving as an N6-methyladenosine reader. Cell Death Differ. 2020;27(6):1782–94.PubMedCrossRef
Metadata
Title
LncRNA-PACERR induces pro-tumour macrophages via interacting with miR-671-3p and m6A-reader IGF2BP2 in pancreatic ductal adenocarcinoma
Authors
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
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2022
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-022-01272-w

Other articles of this Issue 1/2022

Journal of Hematology & Oncology 1/2022 Go to the issue

Review

The mitochondrial unfolded protein response (UPRmt): shielding against toxicity to mitochondria in cancer

Review

Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets

Research

Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2)

Research

CXCL13 chemokine is a novel player in multiple myeloma osteolytic microenvironment, M2 macrophage polarization, and tumor progression

Review

Immune checkpoint modulators in cancer immunotherapy: recent advances and emerging concepts

Research

Mesenchymal stromal cells plus basiliximab, calcineurin inhibitor as treatment of steroid-resistant acute graft-versus-host disease: a multicenter, randomized, phase 3, open-label trial
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits