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

Vijaya Kumar Pidugu, Meei Maan Wu, Ai Hsin Yen, Hima Bindu Pidugu, Kuo Wei Chang, Chung Ji Liu, Te Chang Lee

Research output: Contribution to journalArticle

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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-EGFR Y1068 and p-AKT S473 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-EGFR Y1068 endosomal recycling. Depletion of ANXA2 using siRNA therefore abolished p-EGFR Y1068 and p-AKT S473 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-EGFR Y1068 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.

Original languageEnglish
Pages (from-to)3232-3247
Number of pages16
JournalOncogene
Volume38
Issue number17
DOIs
Publication statusPublished - Apr 25 2019

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Recycling
Squamous Cell Carcinoma
Neoplasm Metastasis
Neoplasms
Epithelial-Mesenchymal Transition
Immunoprecipitation
Heterografts
Nude Mice
Interferons
Small Interfering RNA
gefitinib
Survival Rate
Lymph Nodes
Growth
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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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. / Pidugu, Vijaya Kumar; Wu, Meei Maan; Yen, Ai Hsin; Pidugu, Hima Bindu; Chang, Kuo Wei; Liu, Chung Ji; Lee, Te Chang.

In: Oncogene, Vol. 38, No. 17, 25.04.2019, p. 3232-3247.

Research output: Contribution to journalArticle

Pidugu, Vijaya Kumar ; Wu, Meei Maan ; Yen, Ai Hsin ; Pidugu, Hima Bindu ; Chang, Kuo Wei ; Liu, Chung Ji ; Lee, Te Chang. / IFIT1 and IFIT3 promote oral squamous cell carcinoma metastasis and contribute to the anti-tumor effect of gefitinib via enhancing p-EGFR recycling. In: Oncogene. 2019 ; Vol. 38, No. 17. pp. 3232-3247.
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AU - Wu, Meei Maan

AU - Yen, Ai Hsin

AU - Pidugu, Hima Bindu

AU - Chang, Kuo Wei

AU - Liu, Chung Ji

AU - Lee, Te Chang

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