Hypoxia-Challenged Pancreatic Adenocarcinoma Cell-Derived Exosomal circR3HCC1L Drives Tumor Growth Via Upregulating PKM2 Through Sequestering miR-873-5p.

Publisher: Springer Country of Publication: Switzerland NLM ID: 9423533 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-0305 (Electronic) Linking ISSN: 10736085 NLM ISO Abbreviation: Mol Biotechnol Subsets: MEDLINE

Publication: [Cham] : Springer
Original Publication: Totowa, NJ : Humana Press, c1994-

Exosomes*/metabolism ; Exosomes*/genetics ; MicroRNAs*/genetics ; MicroRNAs*/metabolism ; RNA, Circular*/genetics ; RNA, Circular*/metabolism ; Pancreatic Neoplasms*/genetics ; Pancreatic Neoplasms*/pathology ; Pancreatic Neoplasms*/metabolism ; Thyroid Hormone-Binding Proteins* ; Cell Proliferation* ; Membrane Proteins*/metabolism ; Membrane Proteins*/genetics ; Thyroid Hormones*/metabolism ; Thyroid Hormones*/genetics ; Gene Expression Regulation, Neoplastic* ; Cell Movement*; Humans ; Animals ; Cell Line, Tumor ; Mice ; Adenocarcinoma/genetics ; Adenocarcinoma/metabolism ; Adenocarcinoma/pathology ; Up-Regulation ; Carrier Proteins/metabolism ; Carrier Proteins/genetics ; Mice, Nude ; Male ; Pyruvate Kinase/metabolism ; Pyruvate Kinase/genetics ; Female

Competing Interests: Declarations. Ethics Approval: Written informed consents were obtained from all participants and this study was permitted by the Ethics Committee of Ningbo Medical Center Lihuili Hospital.
Pancreatic adenocarcinoma (PAAD) is a fatal disease with poor survival. Increasing evidence show that hypoxia-induced exosomes are associated with cancer progression. Here, we aimed to investigate the function of hsa_circ_0007678 (circR3HCC1L) and hypoxic PAAD cell-derived exosomal circR3HCC1L in PAAD progression. Through the exoRBase 2.0 database, we screened for a circular RNA circR3HCC1L related to PAAD. Changes of circR3HCC1L in PAAD samples and cells were analyzed with real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation, migration, invasion were analyzed by colony formation, cell counting, and transwell assays. Measurements of glucose uptake and lactate production were done using corresponding kits. Several protein levels were detected by western blotting. The regulation mechanism of circR3HCC1L was verified by dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays. Exosomes were separated by differential ultracentrifugation. Animal experiments were used to verify the function of hypoxia-derived exosomal circR3HCC1L. CircR3HCC1L was upregulated in PAAD samples and hypoxic PAAD cells. Knockdown of circR3HCC1L decreased hypoxia-driven PAAD cell proliferation, migration, invasion, and glycolysis. Hypoxic PAAD cell-derived exosomes had higher levels of circR3HCC1L, hypoxic PAAD cell-derived exosomal circR3HCC1L promoted normoxic cancer cell malignant transformation and glycolysis in vitro and xenograft tumor growth in mouse models in vivo. Mechanistically, circR3HCC1L regulated pyruvate kinase M2 (PKM2) expression via sponging miR-873-5p. Also, PKM2 overexpression or miR-873-5p silencing offset circR3HCC1L knockdown-mediated effects on hypoxia-challenged PAAD cell malignant transformation and glycolysis. Hypoxic PAAD cell-derived exosomal circR3HCC1L facilitated PAAD progression through the miR-873-5p/PKM2 axis, highlighting the contribution of hypoxic PAAD cell-derived exosomal circR3HCC1L in PAAD.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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2019ZYC-A107 Clinical Research Fund project of Zhejiang Medical Association; B20318EN Beijing Medical and Health Foundation; 2021C25G2250721 Zhejiang Soft Science Research Program; 2024ZL949 The Project of Zhejiang Province Traditional Chinese Medicine Science and Technology Plan

Keywords: CircR3HCC1L; Exosomes; Hypoxia; PAAD; PKM2; miR-873-5p

0 (MicroRNAs)
0 (RNA, Circular)
0 (Thyroid Hormone-Binding Proteins)
0 (Membrane Proteins)
0 (Thyroid Hormones)
0 (Carrier Proteins)
EC 2.7.1.40 (Pyruvate Kinase)

Date Created: 20240325 Date Completed: 20250108 Latest Revision: 20250108

20250110

10.1007/s12033-024-01091-z

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