Abstract
BackgroundTumor protein D52 (TPD52) reportedly plays an important role in the proliferation and metastasis of various cancer cells, including oral squamous cell carcinoma (OSCC) cells, and is expressed strongly at the center of the tumor, where the microenvironment is hypoxic. Thus, the present study investigated the roles of TPD52 in the survival and death of OSCC cells under hypoxia, and the relationship with hypoxia-inducible factor (HIF). We examined the expression of TPD52 in OSCC cells under hypoxic conditions and analyzed the effects of HIF on the modulation of TPD52 expression. Finally, the combinational effects of TPD52 knockdown and HIF inhibition were investigated both in vitro and in vivo.ResultsThe mRNA and protein levels of TPD52 increased in OSCC cells under hypoxia. However, the increase was independent of HIF transcription. Importantly, the observation was due to upregulation of mRNA stability by binding of mRNA to T-cell intercellular antigen (TIA) 1 and TIA-related protein (TIAR). Simultaneous knockdown of TPD52 and inhibition of HIF significantly reduced cell viability. In addition, the in vivo tumor-xenograft experiments showed that TPD52 acts as an autophagy inhibitor caused by a decrease in p62.ConclusionsThis study showed that the expression of TPD52 increases in OSCC cells under hypoxia in a HIF-independent manner and plays an important role in the proliferation and survival of the cells in concordance with HIF, suggesting that novel cancer therapeutics might be led by TPD52 suppression.
Highlights
Tumor protein D52 (TPD52) reportedly plays an important role in the proliferation and metastasis of various cancer cells, including oral squamous cell carcinoma (OSCC) cells, and is expressed strongly at the center of the tumor, where the microenvironment is hypoxic
TPD52 mRNA was increased by hypoxia in all OSCC cells (SAS, HSC3, and HSC4) in a time-dependent manner, while TPD53 and 54 mRNAs were barely increased (Fig. 1a)
We used SAS cells as a representative of OSCC cells in the following experiments. These results suggest that TPD52 may play an important role in OSCC cells, not in normal keratinocytes, under hypoxia, compared to TPD53 and 54
Summary
Tumor protein D52 (TPD52) reportedly plays an important role in the proliferation and metastasis of various cancer cells, including oral squamous cell carcinoma (OSCC) cells, and is expressed strongly at the center of the tumor, where the microenvironment is hypoxic. TPD52 was identified more than 25 years ago [7] and revealed through overexpression of its coding gene in breast and lung cancer [7, 8] Other family members, such as TPD53 ( known as TPD52L1), TPD54 (TPD52L2), and TPD55 (TPD52L3), have been reported to be highly expressed in ovary [9,10,11], testis [12, 14], colon [15, 16], and prostate cancer [2, 15], as well as in brain tumors [16], lymphoma [17], and leukemias [17, 18].
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