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

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Abstract

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.

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Funding

This work was supported by Clinical Research Fund project of Zhejiang Medical Association [Grant no. 2019ZYC-A107]. Beijing medical and health foundation [Grant no. B20318EN]. Zhejiang Soft Science Research Program [Grant no. 2021C25G2250721]. The Project of Zhejiang Province Traditional Chinese Medicine Science and Technology Plan (Grant no. 2024ZL949).

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  1. Luoluo Wang, Shuping Zhou and Xinhua Zhou have equally contributed to this work.

Authors and Affiliations

  1. Department of Abdominal Minimally Invasive Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, No.1111, Jiangnan Road, Yinzhou District, Ningbo, 315040, Zhejiang, China

    Luoluo Wang, Yi Ruan, Xiang Wu, Xueming Zhang, Dongjian Ying, Yeting Lu, Yuan Tian, Gong Cheng, Jing Zhang, Kaiji Lv & Xinhua Zhou

  2. Medical School of Ningbo University, Ningbo, 315040, Zhejiang, China

    Xiang Wu

  3. College of Computer Science and Artificial Intelligence Wenzhou University, Wenzhou, 325000, Zhejiang, China

    Yi Li

  4. Ningbo College of Health Sciences, No.51, Xuefu Road, Yinzhou District, Ningbo, 315040, Zhejiang, China

    Shuping Zhou

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12033_2024_1091_MOESM1_ESM.tif

Supplementary file1 (TIF 2168 KB) A and B Knockdown efficiency of circR3HCC1L in PAAD cells infected with lentivirus carrying sh-circR3HCC1L was determined by RT-qPCR, with sh-NC as a control (n = 3 biological replicates). C–F The transfection efficiencies of miR-873-5p mimic (C and D) and inhibitor (E and F) were estimated by RT-qPCR, with miR-NC or anti-NC as a control (n = 3 biological replicates). G RT-qPCR analyzed miR-873-5p in PAAD cells with respect to the hTERT-HPNE cell line (n = 3 biological replicates). H and I Protein levels of PKM2 in PAAD cells (normalized to the hTERT-HPNE cell line) (n = 3 biological replicates) and samples (normalized to paired non-tumor samples) (n = 4) were detected by western blotting. J and K Overexpression efficiency of the oe-PKM2 plasmid was evaluated using western blotting (normalized to vector) (n = 3 biological replicates). **P < 0.01 and ***P < 0.001

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Wang, L., Zhou, S., Ruan, Y. et al. Hypoxia-Challenged Pancreatic Adenocarcinoma Cell-Derived Exosomal circR3HCC1L Drives Tumor Growth Via Upregulating PKM2 Through Sequestering miR-873-5p. Mol Biotechnol (2024). https://doi.org/10.1007/s12033-024-01091-z

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