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MicroRNA-766-3p-mediated downregulation of HNF4G inhibits proliferation in colorectal cancer cells through the PI3K/AKT pathway

Cancer Gene Therapy volume 29, pages 803–813 (2022)Cite this article

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Abstract

Nuclear receptors (NRs) are a class of transcription factors that play a pivotal role in carcinogenesis, but their function in colorectal cancer (CRC) remains unclear. Here, we investigate the role NRs play in CRC pathogenesis. We found that hepatocyte nuclear factor 4 gamma (HNF4G; NR2A2), hepatocyte nuclear factor 4α (HNF4A; NR2A1), and retinoid-related orphan receptor γ (RORC; NR1F3) were significantly upregulated in CRC tissues analyzed by GEPIA bioinformatics tool. The expression of HNF4G was examined in CRC samples and cell lines by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry. Increased expression of HNF4G was strongly associated with high tumor-node-metastasis stage and poor prognosis. Moreover, overexpression of HNF4G significantly promoted the proliferation of CRC cells in vitro. Next, we found that HNF4G promoted CRC proliferation via the PI3K/AKT pathway through targeting of GNG12 and PTK2. In addition, HNF4G was verified as a direct target of microRNA-766-3p (miR-766-3p). miR-766-3p inhibited the proliferation of CRC cells by targeting HNF4G in vitro and in vivo. Collectively, our study indicates that miR-766-3p reduces the proliferation of CRC cells by targeting HNF4G expression and thus inhibits the PI3K/AKT pathway. Therefore, development of therapies which target the miR-766-3p/HNF4G axis may aid in the treatment of CRC.

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Fig. 1: HNF4G is highly expressed in CRC patient tissues with node metastasis and high TNM stage.
Fig. 2: HNF4G increases CRC cell proliferation.
Fig. 3: HNF4G directly interacts with GNG12, PTK2, and activates the PI3K/AKT pathway in CRC cells.
Fig. 4: HNF4G is directly targeted by miR-766-3p in CRC cells.
Fig. 5: HNF4G reverses the repressive effects of miR-766-3p on the proliferation of CRC cells.
Fig. 6: Schematic diagram outlining the mechanism by which miR-766-3p regulated CRC progression.

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All data generated or analyzed during this study are included in this published article.

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Funding

This study has been funded by the Natural Science Foundation of Guangxi Province (Grant number: 2018GXNSFAA294013).

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Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Colorectal Cancer Clinical Medical Research Center of Guangxi, Nanning, China

    Xin-Xin He, Shan-Shan Luo, Hai-Quan Qin & Xian-Wei Mo

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Contributions

X-XH and X-WM conceived and designed the study. X-XH, H-QQ, and S-SL performed the experiments. X-XH, S-SL, and X-WM analyzed the data and drafted the manuscript. H-QQ revised the manuscript. All the authors read and approved the final manuscript.

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Correspondence to Xian-Wei Mo.

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The protocol has been approved by the Ethics Committee of Guangxi Medical University Cancer Hospital and Ethics Committee of Xiangya Hospital, Central South University. Written informed consent was obtained from all the participants in this study.

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He, XX., Luo, SS., Qin, HQ. et al. MicroRNA-766-3p-mediated downregulation of HNF4G inhibits proliferation in colorectal cancer cells through the PI3K/AKT pathway. Cancer Gene Ther 29, 803–813 (2022). https://doi.org/10.1038/s41417-021-00362-0

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