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Targeting the estrogen receptor alpha (ERα)-mediated circ-SMG1.72/miR-141-3p/Gelsolin signaling to better suppress the HCC cell invasion

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Abstract

Early studies indicated that estrogen receptor α (ERα) might impact the progression of hepatocellular carcinoma (HCC). However, the detailed mechanisms, especially its linkage to the gelsolin (GSN)-mediated cell invasion, remain unclear. Here we found that ERα could decrease HCC cell invasion via suppressing the circular RNA-SMG1.72 (circRNA-SMG1.72) expression via transcriptional regulation through directly binding to the 5′ promoter region of its host gene SMG1, We showed that ERα-suppressed circ-SMG1.72 could sponge and inhibit the expression of the microRNA (miRNA, miR), miR-141-3p, which could then result in increasing the GSN messenger RNA translation via reduced miR binding to its 3′ untranslated region (3′UTR). The preclinical study using an in vivo mouse model with orthotopic xenografts of HCC cells confirmed the in vitro data, and the human HCC clinical sample survey and tissue staining also confirmed the linkage of ERα/miR-141-3p/GSN signaling to the HCC progression. Together, our findings suggest that ERα can suppress HCC cell invasion via altering the ERα/circRNA-SMG1.72/miR-141-3p/GSN signaling, and targeting this newly identified signaling with small molecules may help in the development of novel therapies to better suppress the HCC progression.

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Fig. 1: HCC patients with higher ERα expression have higher survival rate.
Fig. 2: ERα may suppress HCC cell invasion via altering GSN expression.
Fig. 3: ERα may decrease GSN expression via altering the circRNA-SMG1.72 expression.
Fig. 4: The circRNA-SMG1.72 may regulate GSN expression via altering the miR-141-3p expression.
Fig. 5: ERα may transcriptionally regulate the circRNA-SMG1.72, and circRNA-SMG1.72 may act as a “sponge” to control miR-141-3p activity that may directly target the 3′UTR of GSN-mRNA to suppress its protein expression.
Fig. 6: Human clinical data analysis to correlate the ERα-miR141-3p-GSN axis to the HCC progression.
Fig. 7: Preclinical study using the in vivo mouse model to test the role of ERα and miR141-3p in liver cancer cell invasion.

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Acknowledgements

This work was supported by George Whipple Professorship Endowment, National Natural Science Foundation of China (81903004) and The 12th Five-year Key Discipline Construction in Hunan Province (Biomedical Engineering). We thank Karen Wolf for help preparing the manuscript.

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  1. These authors contributed equally: Yao Xiao, Guodong Liu

Authors and Affiliations

  1. Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China

    Yao Xiao, Guodong Liu & Liansheng Gong

  2. George Whipple Lab for Cancer Research, Departments of Urology, Pathology, Radiation Oncology and The Wilmot Cancer Center Institute, University of Rochester Medical Center, Rochester, New York 14642, USA

    Yao Xiao, Guodong Liu, Yin Sun, Yuan Gao, Xiwu Ouyang, Chawnshang Chang & Shuyuan Yeh

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  1. Yao Xiao
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Xiao, Y., Liu, G., Sun, Y. et al. Targeting the estrogen receptor alpha (ERα)-mediated circ-SMG1.72/miR-141-3p/Gelsolin signaling to better suppress the HCC cell invasion. Oncogene 39, 2493–2508 (2020). https://doi.org/10.1038/s41388-019-1150-6

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