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Exosome-derived SNHG16 sponging miR-4500 activates HUVEC angiogenesis by targeting GALNT1 via PI3K/Akt/mTOR pathway in hepatocellular carcinoma

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Abstract

Accumulating evidence suggests cancer-derived exosomes play an important role in promoting angiogenesis. Long noncoding RNA small nucleolar RNA host gene 16 (SNHG16) is known to aggravate hepatocellular carcinoma (HCC) progression. However, the function of exosomal SNHG16 in HCC angiogenesis remains unclear. In this study, the expression of SNHG16 was significantly upregulated in HCC tissues and cell lines. The proliferative, migratory, and angiogenic abilities of HUVECs were enhanced after exposure to exosomes derived from HCC cells by transmitting SNHG16. In addition, SNHG16 was validated to promote the biological function of HUVECs directly. Exosomal SNHG16 increased GALNT1 expression to promote angiogenesis via sponging miR-4500. SNHG16/miR-4500/GALNT1 axis played an important role in exosome-mediated angiogenesis and tumor growth in vitro and vivo. Furthermore, SNHG16 activated PI3K/Akt/mTOR pathway via competing endogenous miR-4500 and GALNT1. Meanwhile, the expression of plasma exosomal SNHG16 upregulated in the plasma of HCC patients. These data elucidated the essential role of exosomal SNHG16 in communication between HCC cells and endothelial cells. Exosomal SNHG16 could be utilized as a therapeutic target for anti-angiogenesis in HCC progression.

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Data availability

All data generated or analyzed during this study are included in this article and are available from the corresponding author upon reasonable request.

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Acknowledgements

Thank you for the editors and reviewers for their helpful comments on this paper.

Funding

This work was supported by grants from the National Natural Science Foundation of China (81772277) and the distinguished professor of Liaoning Province.

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Author notes

  1. Shuangda Li and Yu Qi contributed equally to this work.

Authors and Affiliations

  1. College of Laboratory Medicine, Dalian Medical University, 9 Lvshunnan Road **duan, Dalian, 116044, Liaoning Province, China

    Shuangda Li, Yu Qi, Yiran Huang, Yanru Guo, Tong Huang & Li Jia

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  1. Shuangda Li
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  2. Yu Qi
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  3. Yiran Huang
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  4. Yanru Guo
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Contributions

Shuangda Li and Yu Qi performed in vitro and in vivo experiments and wrote the manuscript. Yiran Huang and Tong Huang conducted cell culture and transfection in this study. Shuangda Li and Yanru Guo collected the clinical samples and supported the analysis of data. Li Jia conceived and supervised this research. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Li Jia.

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Key points

• SNHG16 was upregulated in HCC tissues, HCC cells, and HCC exosomes.

• Exosomal SNHG16 promoted HUVEC angiogenesis in vitro and in vivo.

• SNHG16 acted as a ceRNA by sponging miR-4500 and regulated GALNT1 expression.

• Exomal SNHG16 activated PI3K/Akt/mTOR pathway in HUVECs.

Supplementary information

Fig. S1

Exosomal SNHG16 was upregulated in the plasma of HCC patients. a Exosomes were isolated from the plasma of HCC patients (n=10) and plasma samples undergoing physical examination during the same period (n= 10), the images produced by transmission electron microscopy were shown. b Relative SNHG16 expression in plasma exosomes was detected by qRT-PCR. *p< 0.05. (PNG 777 kb)

High Resolution Image (TIF 2038 kb)

Fig. S2

SNHG16 facilitates the G2/M transition in HUVECs. a the G2/M transition in treated HUVECs was deteced by cycle cell analysis. b The corresponding quantitative analyses were shown. Each experiment was repeated three times. *p< 0.05. (PNG 1683 kb)

High Resolution Image (TIF 520 kb)

Fig. S3

PI3K/AKT/mTOR inhibitors could inhibit HUVEs proliferation when exo-SNHG16-Huh-7 is added. a, b The ability of HUVECs proliferation was tested by using colony formation assay and CCK-8 assay. Each experiment was repeated three times. *p< 0.05. (PNG 949 kb)

High Resolution Image (TIF 1023 kb)

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Li, S., Qi, Y., Huang, Y. et al. Exosome-derived SNHG16 sponging miR-4500 activates HUVEC angiogenesis by targeting GALNT1 via PI3K/Akt/mTOR pathway in hepatocellular carcinoma. J Physiol Biochem 77, 667–682 (2021). https://doi.org/10.1007/s13105-021-00833-w

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