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Taurodeoxycholic acid-YAP1 upregulates OTX1 in promoting gallbladder cancer malignancy through IFITM3-dependent AKT activation

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Abstract

Orthodenticle homeobox (OTX1) is reported to be involved in numerous cancers, but the expression level and molecular function of OTX1 in gallbladder cancer (GBC) remain unknown. Here, we found the elevated level of OTX1 associated with poor prognosis in human gallbladder cancer. In vitro and in vivo studies of human gallbladder cancer cell lines demonstrated that overexpression of OTX1 promoted cell proliferation, whereas the downregulation inhibited it. Additionally, we found a tight correlation between the serum level of taurodeoxycholic acid (TDCA) and OTX1 expression. TDCA-induced activation of YAP1 by phosphorylation inhibition contributed to the transcriptional activation of OTX1. Mechanistically, we identified that OTX1 activated AKT signaling pathway by transactivating the expression of IFITM3 and thus promoted the proliferation of GBC cells. Taken together, our results showed that TDCA-YAP1-dependent expression of OTX1 regulated IFITM3 and affected GBC proliferation via the AKT signaling pathway. Our experiments also suggested that OTX1 is a novel therapeutic target for GBC.

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Fig. 1: Highly expressed OTX1 identified in GBC samples.
Fig. 2: Elevated OTX1 correlated with the poor prognosis of GBC patients.
Fig. 3: OTX1 promoted the proliferation of GBC cells in vitro and in vivo.
Fig. 4: Taurodeoxycholic acid (TDCA) induced YAP1 activation in elevating OTX1 expression in GBC.
Fig. 5: TDCA induced YAP1-OTX1 signaling in promoting GBC progression.
Fig. 6: High expression levels of OTX1 influenced the genes related to interferon responses.
Fig. 7: OTX1 regulated AKT signaling pathway via directly transactivating IFITM3.
Fig. 8: IFITM3 knockdown attenuated the tumor-promoting role of OTX1 on the proliferation of GBC cells in vitro and in vivo.

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Data availability

The primary RNA-Seq data generated for this study will be available in a public, open-access repository with an accession number at the time of publication. The public datasets analyzed during the current study are available in the repositories listed below: The Cancer Genome Atlas: TCGA-LUSC; TCGA-LUAD; TCGA-COAD; TCGA-UCEC; TCGA-STAD; TCGA-BRCA; TCGA-PRAD; TCGA-BLCA; TCGA-LIHC; TCGA-CHOL; TCGA-ESCA; TCGA-PAAD; TCGA-KIRP; TCGA-KIRC; TCGA-THCA; TCGA-KICH; TCGA-HNSC; TCGA-ACC; TCGA-LGG; TCGA-MESO; TCGA-SARC. Gene Expression Omnibus: GSE62335; GSE76633; GSE100363; GSE139682.

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Acknowledgements

We are grateful to our laboratory members and professors for their insightful comments. This work was supported by the National Natural Science Foundation of China (Grant number: 82072668).

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Author notes

  1. These authors contributed equally: Ruifeng Yang, Linhua Yang, Manmei Long, Fengyao Wu.

Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China

    Ruifeng Yang, Ran Xia, Junjie Lv, Yiyin Zhang, Yu Lei, Yang Jiao, Chenchen Zhao & Wei Wei

  2. Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Linhua Yang & Hui Wang

  3. Department of Pathology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China

    Manmei Long

  4. Department of Molecular Diagnostics & Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China

    Fengyao Wu

  5. Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Yongheng Shi

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Contributions

WW, HW, and CCZ conceived the project. RFY, LHY, MML, and FYW designed the experiments. RFY, LHY, MML, and FYW performed most of the experiments. YHS, RX, and JJL assisted with the animal experiments and data collection. YYZ, YL, and YJ provided technical suggestions. RFY and FYW wrote the first version of the manuscript. WW and HW revised the manuscript. All authors read and approved the manuscript.

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Correspondence to Chenchen Zhao, Hui Wang or Wei Wei.

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Yang, R., Yang, L., Long, M. et al. Taurodeoxycholic acid-YAP1 upregulates OTX1 in promoting gallbladder cancer malignancy through IFITM3-dependent AKT activation. Oncogene 42, 1466–1477 (2023). https://doi.org/10.1038/s41388-023-02660-3

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