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Ubiquitous mitochondrial creatine kinase downregulated in oral squamous cell carcinoma

T Onda1, K Uzawa, Y Endo

  • 1Department of Oral and Maxillo-Facial Surgery, Tokyo Dental College, 1-2-2 Masago, Mihama-ku Chiba 261-8502, Japan.

British Journal of Cancer
|February 16, 2006
PubMed

Insights

Downregulation of ubiquitous mitochondrial creatine kinase (CKMT1) is linked to oral squamous cell carcinoma (OSCC) development. Epigenetic changes, specifically hypermethylation, inactivate CKMT1, potentially blocking apoptosis in oral cancer.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Oral squamous cell carcinoma (OSCC) is a significant global health concern.
  • Identifying molecular markers for OSCC development is crucial for early detection and targeted therapies.
  • The role of mitochondrial creatine kinase (CKMT1) in oral carcinogenesis is not well understood.

Purpose of the Study:

  • To identify proteins associated with OSCC development.
  • To investigate the role of ubiquitous mitochondrial creatine kinase (CKMT1) in oral carcinogenesis.
  • To explore the regulatory mechanisms, including epigenetic alterations, of CKMT1 expression in OSCC.

Main Methods:

  • Two-dimensional electrophoresis (2-DE) and mass spectrometry to compare protein expression between OSCC cell lines and normal oral keratinocytes (NOKs).
  • Quantitative real-time RT-PCR and Western blotting to assess CKMT1 mRNA and protein levels.
  • Analysis of CKMT1 gene sequencing, CpG island methylation, and functional studies involving gene transfection and demethylation.
  • Immunohistochemistry and quantitative real-time RT-PCR on clinical samples to correlate CKMT1 expression with tumor differentiation.

Main Results:

  • Ubiquitous mitochondrial creatine kinase (CKMT1) was found to be downregulated in all examined OSCC cell lines compared to NOKs.
  • No significant coding region variations were found, but frequent hypermethylation of the CKMT1 CpG island region was observed, which was reversible upon demethylation.
  • Transfection of CKMT1 into OSCC cell lines induced apoptosis but did not affect invasiveness.
  • CKMT1 downregulation was detected in a significant proportion of clinical OSCC samples and correlated significantly with poor tumor differentiation (P<0.0001).

Conclusions:

  • Ubiquitous mitochondrial creatine kinase (CKMT1) is frequently inactivated during oral carcinogenesis.
  • Epigenetic mechanisms, particularly hypermethylation, play a key role in the loss of CKMT1 expression in OSCC.
  • The inactivation of CKMT1 may contribute to the blockage of apoptosis, promoting oral cancer development.

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