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IFIT1 and IFIT3 promote oral squamous cell carcinoma metastasis and contribute to the anti-tumor effect of gefitinib via enhancing p-EGFR recycling

Oncogene volume 38, pages 3232–3247 (2019)Cite this article

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Abstract

IFIT1 and IFIT3 are abundant products of interferon-stimulating genes. While the importance of IFIT1 and IFIT3 in the prognosis of cancer has been reported, the molecular basis of IFIT1 and IFIT3 in cancer progression remains unexplored. In the present study, we investigated the modes of action and the clinical significance of IFIT1 and IFIT3 in oral squamous cell carcinoma (OSCC). Ectopic expression of IFIT1 or IFIT3 induced OSCC cell invasion by promoting the epithelial-mesenchymal transition, whereas IFIT1 or IFIT3 knockdown exhibited opposite effects. Overexpression of IFIT1 or IFIT3 promoted tumor growth, regional and distant metastasis in xenograft and orthotopic nude mice models. Most importantly, IFIT1 or IFIT3 overexpression increased the levels of p-EGFRY1068 and p-AKTS473 in OSCC cells and also enhanced tumor inhibitory effect of gefitinib. By immunoprecipitation and LC-MS/MS analysis, we found that IFIT1 and IFIT3 interacted with ANXA2 that enhanced p-EGFRY1068 endosomal recycling. Depletion of ANXA2 using siRNA therefore abolished p-EGFRY1068 and p-AKTS473 expression in IFIT1- or IFIT3-overexpressed cells. Furthermore, a significant positive association of increased IFIT1 and IFIT3 expression with advanced T-stage, lymph node metastasis, perineural invasion, lymphovascular invasion, extranodal extension, and poor overall survival rate was confirmed in OSCC patients. We also found a statistically positive correlation of p-EGFRY1068 expression with IFIT1 and IFIT3 in OSCC tumors and poor clinical outcome in patients. Collectively, we demonstrated a novel role of IFIT1 and IFIT3 in driving OSCC progression and metastasis by interacting with ANXA2 and hence enhancing p-EGFR recycling and its downstream signaling.

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Acknowledgements

We are thankful to Dr. Fann Cathy S.-J, and Ms. Jenny Chang, Institute of Biomedical Sciences, for their help in clinical data analysis. We are grateful for the excellent technical services provided by Dr. Fu-An Li, Proteomic Core Laboratories, Taiwan Mouse Clinic, and Pathology Core laboratories, and Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

Funding

This work was supported by grants from the Ministry of Science and Technology (NSC 101-2321-B-001-044, NSC 102-2321-B-001-032, MOST 103-2321-B-001-019, and MOST 104-2320-B-001-008), Taiwan (T.C. Lee).

Author contributions

VKP and TCL designed the research. VKP performed cellular, molecular, and biochemical experiments. VKP and HBP performed animal experiments. VKP, AHY and HBP performed immunohistochemical assays. VKP, MMW, HBP, KWC and CJL analyzed the data. CJL provided the patient’s information and tumor samples. VKP wrote the manuscript. VKP, HBP and TCL revised the manuscript. CJL and TCL supervised the study. All authors read and approved the manuscript.

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Authors and Affiliations

  1. Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University, and Academia Sinica, Taipei, Taiwan

    Vijaya Kumar Pidugu & Te-Chang Lee

  2. Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan

    Vijaya Kumar Pidugu, Ai-Hsin Yen, Hima Bindu Pidugu & Te-Chang Lee

  3. Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan

    Meei-Maan Wu

  4. Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, 11221, Taiwan

    Kuo-Wei Chang

  5. Department of Oral and Maxillofacial Surgery, Mackay Memorial Hospital, Taipei, 10449, Taiwan

    Chung-Ji Liu

  6. Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan

    Te-Chang Lee

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Pidugu, V.K., Wu, MM., Yen, AH. et al. IFIT1 and IFIT3 promote oral squamous cell carcinoma metastasis and contribute to the anti-tumor effect of gefitinib via enhancing p-EGFR recycling. Oncogene 38, 3232–3247 (2019). https://doi.org/10.1038/s41388-018-0662-9

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