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Hsa_circ_0000437 promotes pathogenesis of gastric cancer and lymph node metastasis

Oncogene volume 41, pages 4724–4735 (2022)Cite this article

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Abstract

Cellular communication between gastric cancer (GC) cells with different metastatic potentials and microenvironments and resultant cancer progression is not fully understood. Circular RNAs (circRNAs) and exosomal circRNAs are known to play extremely important regulatory roles in GC occurrence and progression. Here, we revealed significant differences in coronin-like actin-binding protein 1C (CORO1C) derived circRNA hsa_circ_0000437 between GC and para-cancer tissues. Hsa_circ_0000437 regulated GC cell proliferation, invasion, migration and apoptosis by targeting Ser/Arg-rich splicing factor 3 (SRSF3) and inhibiting programmed cell death 4 (PDCD4). The ectopic expression of hsa_circ_0000437 dramatically promoted tumor growth in nude mice in vivo. Furthermore, both gain-of-function and loss-of-function experiments demonstrated that hsa_circ_0000437 promoted human lymphatic endothelial cells (HLECs) invasion, migration, and tube formation in vitro and also promoted lymphangiogenesis and lymph node metastasis (LNM) in popliteal LNM model in vivo, when it was enriched in GC-secreted exosomes and transferred into HLECs. Mechanistically, exosomal hsa_circ_0000437 induced LNM via HSPA2-ERK signaling pathway independent of VEGF-C. Clinical data showed that exosomal hsa_circ_0000437 was enriched in the serum of GC patients, which was associated with LNM. In summary, these findings highlight the potential role of hsa_circ_0000437 as an outcome biomarker in GC patients with LNM, which may provide a novel target for GC therapy.

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Fig. 1: Hsa_circ_0000437 is upregulated in gastric cancer.
Fig. 2: Hsa_circ_0000437 plays an oncogene role in vitro and in vivo.
Fig. 3: Hsa_circ_0000437 directly targets SRSF3.
Fig. 4: Hsa_circ_0000437 targets SRSF3 inhibiting PDCD4 to regulate gastric cancer cell function.
Fig. 5: GC-secreted exosomal hsa_circ_0000437 can be transferred to LECs.
Fig. 6: Gastric cancer-secreted exosomal hsa_circ_0000437 promotes lymphangiogenesis in vitro and in vivo.
Fig. 7: Exosomal hsa_circ_0000437 induces lymphangiogenesis via ERK signaling pathway independent of VEGF-C.
Fig. 8: Exosomal hsa_circ_0000437 is associated with lymph node metastasis in gastric cancer patients.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81871720, 82072363), Nantong Science and Technology Project (MS12021002). The project of Nantong Commission of Health (MB2021061).

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Authors and Affiliations

  1. Laboratory Medicine Center, Affiliated Hospital of Nantong University, #20 Xisi Road, Nantong, 226001, Jiangsu, P. R. China

    Xianjuan Shen, Shan Kong, Shuo Ma, Lei Shen, Ming zheng, Shiyi Qin & Shaoqing Ju

  2. Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, #20 Xisi Road, Nantong, 226001, Jiangsu, P. R. China

    Xianjuan Shen & Jing Qi

  3. Department of Clinical Laboratory, Nantong Maternal and Child Health Care Hospital, Affiliated to Nantong University, Nantong, 226018, Jiangsu, P. R. China

    Qiuhong Wang

  4. Department of general surgery, Affiliated Hospital of Nantong University, #20 Xisi Road, Nantong, 226001, Jiangsu, P. R. China

    Xiaopeng Cui

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Contributions

XS and SK designed the project. XS and SM performed the experiments. LS collected the GC samples and clinical information. JQ and QW processed the data. XS and SJ wrote the manuscript. All the authors read and approved the final manuscript.

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Correspondence to Xiaopeng Cui or Shaoqing Ju.

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Shen, X., Kong, S., Ma, S. et al. Hsa_circ_0000437 promotes pathogenesis of gastric cancer and lymph node metastasis. Oncogene 41, 4724–4735 (2022). https://doi.org/10.1038/s41388-022-02449-w

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