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CircSOD2 Contributes to Tumor Progression, Immune Evasion and Anti-PD-1 Resistance in Hepatocellular Carcinoma by Targeting miR-497-5p/ANXA11 Axis

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Abstract

Circular RNAs (circRNAs) can function as functional molecules in hepatocellular carcinoma (HCC). Herein, circRNA superoxide dismutase 2 (circSOD2) was researched in HCC progression and immune system. The real-time polymerase chain reaction (qRT-PCR) was used for quantification of circSOD2, microRNA-497-5p (miR-497-5p) and Annexin A11 (ANXA11). Cell assays were performed by 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) and colony formation assays for proliferation, flow cytometry for apoptosis and cell cycle, wound healing assay for migration and transwell assay for migration/invasion. ANXA11 and metastatic protein levels were measured by western blot. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to analyze target binding. CD8+ T cell immunity was assessed by Immunohistochemistry (IHC) assay, and the effect of circSOD2 on programmed cell death 1 (PD-1) immune checkpoint inhibitors (anti-PD-1) therapy was evaluated by mice xenograft assay. CircSOD2 was upregulated in HCC tissues and cells. Knockdown of circSOD2 resulted in HCC cell growth inhibition, apoptosis promotion, cell cycle arrest and metastasis suppression. Mechanically, circSOD2 promoted HCC development by acting as a miR-497-5p sponge and miR-497-5p played a tumor-inhibitory role in HCC cells by targeting ANXA11. Moreover, circSOD2 induced upregulation of ANXA11 expression by interacting with miR-497-5p. Also, the promoting effects of circSOD2 on immune evasion and anti-PD-1 resistance were related to miR-497-5p/ANXA11 axis. This study elucidated the pivotal function of circSOD2 in HCC progression and immunosuppression by mediating miR-497-6p/ANXA11 axis. CircSOD2/miR-497-5p/ANXA11 axis was a novel view of circRNA research in HCC.

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Data Availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

circRNAs:

Circular RNAs

HCC:

Hepatocellular carcinoma

circSOD2:

CircRNA superoxide dismutase 2

qRT-PCR:

Real-time polymerase chain reaction

miR-497-5p:

MicroRNA-497-5p

IHC:

Immunohistochemistry

PD-1:

Programmed cell death 1

ANXA11:

Annexin A11

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  1. Rong Ye and Xingyu Lu are co-first authors.

Authors and Affiliations

  1. Department of General Surgery 3, The First Affiliated Hospital of Gannan Medical University, No. 128 Jinling Road, Jingkai District, Ganzhou, 341000, China

    Rong Ye, Jianping Liu, Qing Duan, Junqi Xiao, Xunhong Duan, Zhibiao Yue & Fengen Liu

  2. Outpatient department, Ganzhou City Third People’s Hospital, Ganzhou, 341001, China

    Xingyu Lu

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Correspondence to Zhibiao Yue or Fengen Liu.

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The study was approved by the Ethics Committee of the First Affiliated Hospital of Gannan Medical College and was carried out according to the guidelines of Declaration of Helsinki.

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10528_2022_10273_MOESM1_ESM.tif

Supplementary file1 (TIF 1649 kb)—The target screening for circSOD2 and miR-497-5p. (A) Venn diagram analysis was used to select the mutual miRNAs for circSOD2 by circbank and starbase. (B) The levels of miR-148a-3p, miR-152-3p, miR-424-5p and miR-497-5p were detected by qRT-PCR after transfection with si-NC or si-circSOD2#1. (C) Venn diagram was used for selecting target genes for miR-497-5p from Targetscan, starbase, miRDB and GEPIA. (D) PHF19 and ANXA11 mRNA levels were examined using qRT-PCR after transfection of miR-NC or miR-497-5p. *P < 0.05.

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Ye, R., Lu, X., Liu, J. et al. CircSOD2 Contributes to Tumor Progression, Immune Evasion and Anti-PD-1 Resistance in Hepatocellular Carcinoma by Targeting miR-497-5p/ANXA11 Axis. Biochem Genet 61, 597–614 (2023). https://doi.org/10.1007/s10528-022-10273-w

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