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

Hypoxia-induced exosomal circPDK1 promotes pancreatic cancer glycolysis via c-myc activation by modulating miR-628-3p/BPTF axis and degrading BIN1

Authors: Jiewei Lin, Xinjing Wang, Shuyu Zhai, Minmin Shi, Chenghong Peng, Xiaxing Deng, Da Fu, Jiancheng Wang, Baiyong Shen

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

Login to get access

Abstract

Background

circRNA has been established to play a pivotal role in tumorigenesis development in a variety of cancers; nevertheless, the biological functions and molecular mechanisms of hypoxia-induced exosomal circRNAs in pancreatic cancer remain largely unknown.

Methods

Differentially expressed circRNAs in exosomes between hypoxic exosomes and normoxic exosomes in PC cells were verified by RNA sequencing. The expression of circPDK1 in PC tumors and PC patients was evaluated by qRT-PCR and ISH, and the biological functions of circPDK1 in PC were verified through a series of in vitro and in vivo experiments. Using Western blotting, Co-IP, RNA pull-down, ChIP, RIP, dual-luciferase assays, and rescue experiments, the underlying mechanism of circPDK1 was verified.

Results

CircPDK1 was highly abundant in PC tumor tissues and serum exosomes and was associated with poor survival. Exosomal circPDK1 significantly promoted PC cell proliferation, migration, and glycolysis both in vitro and in vivo. Mechanistically, circPDK1 could be activated by HIF1A at the transcriptional level and sponges miR-628-3p to activate the BPTF/c-myc axis. In addition, circPDK1 serves as a scaffold that enhances the interaction between UBE2O and BIN1, inducing the UBE2O-mediated degradation of BIN1.

Conclusions

We found that circPDK1 was activated by HIF1A at the transcriptional level by modulating the miR-628-3p/BPTF axis and degrading BIN1. Exosomal circPDK1 is a promising biomarker for PC diagnosis and prognosis and represents a potential therapeutic target for PC.
Appendix
Available only for authorised users
Literature
1.
2.
Chiorean EG, Coveler AL. Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies. Drug Des Dev Ther. 2015;9:3529–45.CrossRef
3.
4.
5.
Kucharzewska P, Christianson HC, Welch JE, Svensson KJ, Fredlund E, Ringnér M, et al. Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc Natl Acad Sci U S A. 2013;110:7312–7.PubMedPubMedCentralCrossRef
6.
Li J, Liao T, Liu H, Yuan H, Ouyang T, Wang J, et al. Hypoxic glioma stem cell-derived exosomes containing Linc01060 promote progression of glioma by regulating the MZF1/c-Myc/HIF1α axis. Cancer Res. 2021;81:114–28.PubMedCrossRef
7.
8.
Shih JW, Chiang WF, Wu ATH, Wu MH, Wang LY, Yu YL, et al. Long noncoding RNA LncHIFCAR/MIR31HG is a HIF-1α co-activator driving oral cancer progression. Nat Commun. 2017;8:15874.PubMedPubMedCentralCrossRef
9.
10.
Zhou R, Chen KK, Zhang J, Xiao B, Huang Z, Ju C, et al. The decade of exosomal long RNA species: an emerging cancer antagonist. Mol Cancer. 2018;17:75.PubMedPubMedCentralCrossRef
11.
Wang X, Luo G, Zhang K, Cao J, Huang C, Jiang T, et al. Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic cancer metastasis. Cancer Res. 2018;78:4586–98.PubMedCrossRef
12.
Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019;20:675–91.PubMedCrossRef
13.
Chen S, Huang V, Xu X, Livingstone J, Soares F, Jeon J, et al. Widespread and functional RNA circularization in localized prostate cancer. Cell. 2019;176:831-843.e822.PubMedCrossRef
14.
Li P, Xu Z, Liu T, Liu Q, Zhou H, Meng S, et al. Circular RNA sequencing reveals serum exosome circular RNA panel for high-grade astrocytoma diagnosis. Clin Chem. 2021;68:332–43.CrossRef
15.
Wang S, Zhang K, Tan S, Xin J, Yuan Q, Xu H, et al. Circular RNAs in body fluids as cancer biomarkers: the new frontier of liquid biopsies. Mol Cancer. 2021;20:13.PubMedPubMedCentralCrossRef
16.
Chen LL. The expanding regulatory mechanisms and cellular functions of circular RNAs. Nat Rev Mol Cell Biol. 2020;21:475–90.PubMedCrossRef
17.
Xie M, Yu T, Jing X, Ma L, Fan Y, Yang F, et al. Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation. Mol Cancer. 2020;19:112.PubMedPubMedCentralCrossRef
18.
Hua K, Deng X, Hu J, Ji C, Yu Y, Li J, et al. Long noncoding RNA HOST2, working as a competitive endogenous RNA, promotes STAT3-mediated cell proliferation and migration via decoying of let-7b in triple-negative breast cancer. J Exp Clin Cancer Res. 2020;39:58.PubMedPubMedCentralCrossRef
19.
Li B, Zhu L, Lu C, Wang C, Wang H, Jin H, et al. circNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity. Nat Commun. 2021;12:295.PubMedPubMedCentralCrossRef
20.
Townshend RJL, Eismann S, Watkins AM, Rangan R, Karelina M, Das R, et al. Geometric deep learning of RNA structure. Science. 2021;373:1047–51.PubMedCrossRef
21.
Wang J, Zhao Y, Zhu C, Xiao Y. 3dRNAscore: a distance and torsion angle dependent evaluation function of 3D RNA structures. Nucleic Acids Res. 2015;43: e63.PubMedPubMedCentralCrossRef
22.
Tuszynska I, Bujnicki JM. DARS-RNP and QUASI-RNP: new statistical potentials for protein-RNA docking. BMC Bioinform. 2011;12:348.CrossRef
23.
Vaupel P, Mayer A, Höckel M. Tumor hypoxia and malignant progression. Methods Enzymol. 2004;381:335–54.PubMedCrossRef
24.
Sorg BS, Hardee ME, Agarwal N, Moeller BJ, Dewhirst MW. Spectral imaging facilitates visualization and measurements of unstable and abnormal microvascular oxygen transport in tumors. J Biomed Opt. 2008;13:014026.PubMedCrossRef
25.
Vaupel P, Höckel M, Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal. 2007;9:1221–35.PubMedCrossRef
26.
27.
Li L, Li C, Wang S, Wang Z, Jiang J, Wang W, et al. Exosomes derived from hypoxic oral squamous cell carcinoma cells deliver miR-21 to normoxic cells to elicit a prometastatic phenotype. Cancer Res. 2016;76:1770–80.PubMedCrossRef
28.
Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J, et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 2015;25:981–4.PubMedPubMedCentralCrossRef
29.
Boeckel JN, Jaé N, Heumüller AW, Chen W, Boon RA, Stellos K, et al. Identification and characterization of hypoxia-regulated endothelial circular RNA. Circ Res. 2015;117:884–90.PubMedCrossRef
30.
Zeng Z, Zhao Y, Chen Q, Zhu S, Niu Y, Ye Z, et al. Hypoxic exosomal HIF-1α-stabilizing circZNF91 promotes chemoresistance of normoxic pancreatic cancer cells via enhancing glycolysis. Oncogene. 2021;40:5505–17.PubMedCrossRef
31.
32.
Zhou R, Wu Y, Wang W, Su W, Liu Y, Wang Y, et al. Circular RNAs (circRNAs) in cancer. Cancer Lett. 2018;425:134–42.PubMedCrossRef
33.
Richart L, Carrillo-de Santa Pau E, Río-Machín A, de Andrés MP, Cigudosa JC, Lobo VJS, et al. BPTF is required for c-MYC transcriptional activity and in vivo tumorigenesis. Nat Commun. 2016;7:10153.PubMedPubMedCentralCrossRef
34.
Chen Q, Li J, Shen P, Yuan H, Yin J, Ge W, et al. Biological functions, mechanisms, and clinical significance of circular RNA in pancreatic cancer: a promising rising star. Cell Biosci. 2022;12:97.PubMedPubMedCentralCrossRef
35.
Hormaechea-Agulla D, Kim Y, Song MS, Song SJ. New insights into the role of E2s in the pathogenesis of diseases: lessons learned from UBE2O. Mol Cells. 2018;41:168–78.PubMedPubMedCentral
36.
Ge Y, Schuster MB, Pundhir S, Rapin N, Bagger FO, Sidiropoulos N, et al. The splicing factor RBM25 controls MYC activity in acute myeloid leukemia. Nat Commun. 2019;10:172.PubMedPubMedCentralCrossRef
37.
Kinney EL, Tanida S, Rodrigue AA, Johnson JK, Tompkins VS, Sakamuro D. Adenovirus E1A oncoprotein liberates c-Myc activity to promote cell proliferation through abating Bin1 expression via an Rb/E2F1-dependent mechanism. J Cell Physiol. 2008;216:621–31.PubMedCrossRef
38.
39.
Yang R, Chen H, Xing L, Wang B, Hu M, Ou X, et al. Hypoxia-induced circWSB1 promotes breast cancer progression through destabilizing p53 by interacting with USP10. Mol Cancer. 2022;21:88.PubMedPubMedCentralCrossRef
40.
Semba H, Takeda N, Isagawa T, Sugiura Y, Honda K, Wake M, et al. HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity. Nat Commun. 2016;7:11635.PubMedPubMedCentralCrossRef
41.
Peng F, Wang JH, Fan WJ, Meng YT, Li MM, Li TT, et al. Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia. Oncogene. 2018;37:1062–74.PubMedCrossRef
42.
Xie F, Huang Q, Liu CH, Lin XS, Liu Z, Liu LL, et al. MiR-1271 negatively regulates AKT/MTOR signaling and promotes apoptosis via targeting PDK1 in pancreatic cancer. Eur Rev Med Pharmacol Sci. 2018;22:678–86.PubMed
43.
Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3:177–85.PubMedCrossRef
44.
Pan J, Li M, Yu F, Zhu F, Wang L, Ning D, et al. Up-Regulation of p53/miR-628-3p Pathway, a Novel Mechanism of Shikonin on Inhibiting Proliferation and Inducing Apoptosis of A549 and PC-9 Non-Small Cell Lung Cancer Cell Lines. Front Pharmacol. 2021;12:766165.PubMedPubMedCentralCrossRef
45.
Wang T, Mao P, Feng Y, Cui B, Zhang B, Chen C, et al. Blocking hsa_circ_0006168 suppresses cell proliferation and motility of human glioblastoma cells by regulating hsa_circ_0006168/miR-628-5p/IGF1R ceRNA axis. Cell Cycle. 2021;20:1181–94.PubMedPubMedCentralCrossRef
46.
Green AL, DeSisto J, Flannery P, Lemma R, Knox A, Lemieux M, et al. BPTF regulates growth of adult and pediatric high-grade glioma through the MYC pathway. Oncogene. 2020;39:2305–27.PubMedCrossRef
47.
Zhang C, Chen L, Liu Y, Huang J, Liu A, Xu Y, et al. Downregulated METTL14 accumulates BPTF that reinforces super-enhancers and distal lung metastasis via glycolytic reprogramming in renal cell carcinoma. Theranostics. 2021;11:3676–93.PubMedPubMedCentralCrossRef
48.
Wang J, Jia Y, Zhao S, Zhang X, Wang X, Han X, et al. BIN1 reverses PD-L1-mediated immune escape by inactivating the c-MYC and EGFR/MAPK signaling pathways in non-small cell lung cancer. Oncogene. 2017;36:6235–43.PubMedCrossRef
49.
Liu X, Ma F, Liu C, Zhu K, Li W, Xu Y, et al. UBE2O promotes the proliferation, EMT and stemness properties of breast cancer cells through the UBE2O/AMPKα2/mTORC1-MYC positive feedback loop. Cell Death Dis. 2020;11:10.PubMedPubMedCentralCrossRef
50.
Huang Y, Yang X, Lu Y, Zhao Y, Meng R, Zhang S, et al. UBE2O targets Mxi1 for ubiquitination and degradation to promote lung cancer progression and radioresistance. Cell Death Differ. 2021;28:671–84.PubMedCrossRef
Metadata
Title
Hypoxia-induced exosomal circPDK1 promotes pancreatic cancer glycolysis via c-myc activation by modulating miR-628-3p/BPTF axis and degrading BIN1
Authors
Jiewei Lin
Xinjing Wang
Shuyu Zhai
Minmin Shi
Chenghong Peng
Xiaxing Deng
Da Fu
Jiancheng Wang
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/s13045-022-01348-7

Other articles of this Issue 1/2022

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

Letter to the Editor

The global landscape of neoadjuvant and adjuvant anti-PD-1/PD-L1 clinical trials

Research

SARS-CoV-2 vaccine response and rate of breakthrough infection in patients with hematological disorders

Rapid communication

Determinants of SARS-CoV-2 waning immunity in allogeneic hematopoietic stem cell transplant recipients

Research

Impaired neutralisation of SARS-CoV-2 delta variant in vaccinated patients with B cell chronic lymphocytic leukaemia

Research

Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial

Correspondence

Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients
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