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Sec62 promotes pro-angiogenesis of hepatocellular carcinoma cells under hypoxia

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Abstract

This study aimed to investigate the underlying molecular pathogenic mechanism of Sec62 in hepatocellular carcinoma (HCC). Microarray analysis was conducted to profile the global gene expression in the HCC cell line Huh7 cells transfected with Sec62high vs. NC and Sec62low vs. NC. Ingenuity pathway analysis and gene set enrichment analysis were used to perform Sec62-related signaling pathway analysis from screened differentially expressed genes (DEGs). A protein-protein interaction network was constructed. Experimental validation of the expression of key DEGs was conducted. Hypoxia-induced tube formation was undertaken to investigate the role of Sec62 in angiogenesis. A total of 74 intersected DEGs were identified from Huh7 cells with Sec62high vs. NC and Sec62low vs. NC. Among them, 65 DEGs were correlated with the expression of Sec62. The P53 signaling pathway was found to be enriched in Huh7 cells with Sec62high vs. NC, while the acute phase response signaling pathway was enriched in Huh7 cells with Sec62low vs. NC. DEGs, such as serine protease inhibitor E (SERPINE) and tumor necrosis factor receptor superfamily, member 11B (TNFRSF11B), were not only identified as the lead genes of these enriched pathways, but were also found to be closely related to Sec62. Moreover, knockdown of Sec62 decreased the expression of SERPINE1 (plasminogen activator inhibitor type 1 (PAI-1)) and TNFRSF11B, whereas overexpression of Sec62 had the opposite effects. In addition, knockdown of Sec62 inhibited hypoxia-induced tube formation via PAI-1. Sec62 promoted pro-angiogenesis of HCC under hypoxia by regulating PAI-1, and it may be a crucial angiogenic switch in HCC.

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Data availability

The datasets used during the present study are available from the corresponding author upon reasonable request.

Abbreviations

hepatocellular carcinoma:

HCC

ingenuity pathway analysis:

IPA

gene set enrichment analysis:

GSEA

differentially expressed genes:

DEGs

protein-protein interaction:

PPI

serine protease inhibitor E:

SERPINE

tumor necrosis factor receptor superfamily member 11B:

TNFRSF11B

unfolded protein response:

UPR

endoplasmic reticulum:

ER

fold-change:

FC

polymerase chain reaction:

PCR

quantitative PCR:

qPCR

negative control:

NC

standardized enrichment score:

NES

plasminogen activator inhibitor type 1:

PAI-1

glyceraldehyde-3-phosphate dehydrogenase:

GAPDH

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Acknowledgements

The present study was supported by the National Natural Scientific Foundation of China (grant no. 81473487 and 82074138 to JD, no.81803929 to Zifei Yin).

Authors’ Contributions

J.D. conceived and designed the study. Microarray analysis and acquisition of data, including qPCR, tube formation and western blot analyses were performed by H.Z. and Y.M. Cells culture, transfection and tube formation were performed by Z.Z. Analysis and interpretation of data, including statistical analysis, biostatistics, computational analysis was performed by Y.M. and J.D. J.D. and H.Z. wrote, reviewed and/or revised the manuscript. All authors read and approved the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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  1. These authors contributed equally: Yongbin Meng, Hetong Zhao

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  1. Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China

    Yongbin Meng, Hetong Zhao, Zhihao Zhao, Zifei Yin, Zhe Chen & Juan Du

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  1. Yongbin Meng
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Meng, Y., Zhao, H., Zhao, Z. et al. Sec62 promotes pro-angiogenesis of hepatocellular carcinoma cells under hypoxia. Cell Biochem Biophys 79, 747–755 (2021). https://doi.org/10.1007/s12013-021-01008-6

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