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IFITM3 knockdown reduces the expression of CCND1 and CDK4 and suppresses the growth of oral squamous cell carcinoma cells

Abstract

Purpose

Oral squamous cell carcinoma (OSCC) is a challenging disease to treat. Up to 50% of OSCC patients with advanced disease develop recurrences. Elucidation of key molecular mechanisms underlying OSCC development may provide opportunities to target specific genes and, thus, to improve patient survival. In this study, we examined the expression and functional role of interferon transmembrane protein 3 (IFITM3) in OSCC development.

Methods

The expression of IFITM3 in OSCC and normal oral mucosal tissues was assessed by qRT-PCR and immunohistochemistry. The role of IFITM3 in driving OSCC cell proliferation and survival was examined using siRNA-mediated gene knockdown, and the role of IFITM3 in driving cell cycle regulators was examined using Western blotting.

Results

We found that IFITM3 is overexpressed in more than 79% of primary OSCCs. We also found that IFITM3 knockdown led to impaired OSCC cell growth through inhibition of cell proliferation, induction of cell cycle arrest, senescence and apoptosis. In addition, we found that IFITM3 knockdown led to reduced expressions of CCND1 and CDK4 and reduced RB phosphorylation, leading to inhibition of OSCC cell growth. This information may be instrumental for the design of novel targeted therapeutic strategies.

Conclusions

From our data we conclude that IFITM3 is overexpressed in OSCC and may regulate the CCND1-CDK4/6-pRB axis to mediate OSCC cell growth.

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Acknowledgments

We would like to thank all consented patients who participated in this study. This study was funded by Ministry of Science, Technology and Innovation (MOSTI 06-00-00-0000), University of Malaya (UM.C/625/1/HIR/MOHE/DENT-03) and sponsors of Cancer Research Malaysia. Cancer Research Malaysia is a non-profit research organization. We are committed to an understanding of cancer prevention, diagnosis and treatment through a fundamental research program.

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Correspondence to Sok Ching Cheong.

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Supplementary fig. 1
figure6

mRNA expression of IFITM family members in head and neck cancer in TCGA database (PNG 2550 kb)

Supplementary fig. 2
figure7

(a) Endogenous expression of IFITM3 in oral cancer cell lines. (b&c) Specific IFITM3 knockdown by si18 determined by qRT-PCR analysis (PNG 529 kb)

Supplementary fig. 3
figure8

Microscopic view of cells after transfection with si18. Morphological changes and floating cells are apparent after IFITM3 knockdown compared to that in NT siRNA cells. (b) Microscopic view of soft agar assay comparing IFITM3 knockdown cells with NT siRNA cells (PNG 1537 kb)

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Supplementary Table 1

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Gan, C.P., Sam, K.K., Yee, P.S. et al. IFITM3 knockdown reduces the expression of CCND1 and CDK4 and suppresses the growth of oral squamous cell carcinoma cells. Cell Oncol. 42, 477–490 (2019). https://doi.org/10.1007/s13402-019-00437-z

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Keywords

  • Oral squamous cell carcinoma
  • IFITM3
  • Proliferation
  • CCND1
  • CDK4