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Methylation Mediated Downregulation of TOB1-AS1 and TOB1 Correlates with Malignant Progression and Poor Prognosis of Esophageal Squamous Cell Carcinoma

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Abstract

Background

TOB1, a member of the transducer of erbB-2 /B-cell translocation gene family, was detected to be down-regulated in ESCC by RNA sequencing. TOB1-AS1, a head-to-head antisense lncRNA with TOB1, was down-regulated in several cancers. However, the roles of them in esophageal squamous cell carcinoma (ESCC) remained unclarified.

Aims

To investigate the roles and functions of TOB1-AS1 and TOB1 in ESCC tumorigenesis.

Materials and Methods

The expression levels, methylation status, biological function and mechanisms of TOB1-AS1 and TOB1 in ESCC were, respectively, detected.

Results

Frequent down-regulation of TOB1-AS1 and TOB1 was verified in esophageal cancer cells and ESCC tissues, and there was a positive correlation between them in ESCC tissues. The CpG sites hypermethylation within proximal promoter of TOB1-AS1 and TOB1 could lead to transcriptional inhibition of both genes. Furthermore, expression and proximal promoter methylation status of TOB1-AS1 or TOB1 may be associated with ESCC patients’ prognosis. TOB1-AS1 and TOB1 may function as tumor suppressors by inhibiting growth, migration, and invasion of esophageal cancer cells. Up-regulation of TOB1-AS1 increased expression level of TOB1, and TOB1-AS1 could work as a ceRNA to modulate ATF3 expression via competitively binding with miR-103a-2-5p. Meanwhile, ATF3, as a transcription factor, could regulate transcription of TOB1; down-regulation of TOB1-AS1 in ESCC led to decreased expression of ATF3 through ceRNA mechanism, and further influenced the transcription of TOB1.

Conclusion

TOB1-AS1 and TOB1 may act as tumor suppressors and may serve as potential targets for antitumor therapy in ESCC.

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Acknowledgments

This study was supported by Grants from the National Natural Science Foundation of China (No. 81772612), Natural Science Foundation of Hebei Province (No. H2020206363).

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Author notes

  1. Zhiming Dong and Guoqiang Zhang contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Pathology, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China

    Zhiming Dong, Juntao Lu, Yanli Guo, Jia Liang, Supeng Shen & Wei Guo

  2. The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

    Guoqiang Zhang

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  1. Zhiming Dong
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Supplementary Information

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10620_2022_7664_MOESM1_ESM.tif

Supplementary figure 1. Influence of knocking down TOB1-AS1 and TOB1 on proliferation, migration, and invasion ability of KYSE170 cells. A. Knock-down efficiency of TOB1-AS1 siRNAs transfection in KYSE170 cells. B. Influence of siRNA-TOB1-AS1-1 transfection on KYSE170 cells viability. C. Influence of siRNA-TOB1-AS1-1 transfection on KYSE170 cells migration ability. D. Influence of siRNA-TOB1-AS1-1 transfection on KYSE170 cells invasion ability. E. Knock-down efficiency of TOB1 siRNAs transfection in KYSE170 cells. F. Influence of siRNA-TOB1-1 transfection on KYSE170 cells viability. G. Influence of siRNA-TOB1-1 transfection on KYSE170 cells migration ability. H. Influence of siRNA-TOB1-1 transfection on KYSE170 cells invasion ability. * P < 0.05. (TIF 140 kb)

10620_2022_7664_MOESM2_ESM.tif

Supplementary figure 2. The expression levels of miR-103a-2-5p in databases. A. The expression level of miR-103a-2-5p in different kinds of tumor types in ONCOMIR database. B. The expression level of miR-103a-2-5p in different kinds of tumor types in YM500v2 database. (TIF 250 kb)

Supplementary file3 (DOCX 24 kb)

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Dong, Z., Zhang, G., Lu, J. et al. Methylation Mediated Downregulation of TOB1-AS1 and TOB1 Correlates with Malignant Progression and Poor Prognosis of Esophageal Squamous Cell Carcinoma. Dig Dis Sci 68, 1316–1331 (2023). https://doi.org/10.1007/s10620-022-07664-9

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