Death-Associated Protein Kinase 1 Inhibits Progression of Thyroid Cancer by Regulating Stem Cell Markers.

Mi-Hyeon You,Min Ji Jeon,Dong Eun Song,Woo Kyung Lee,Meihua Jin,Won Gu Kim,Won Bae Kim,Sheue-Yann Cheng,Tae Yong Kim

doi:10.3390/cells10112994

Abstract

The activation of metastatic reprogramming is vital for cancer metastasis, but little is known about its mechanism. This study investigated the potential role of death-associated protein kinase 1 (DAPK1) in thyroid cancer progression. We generated knockdown (KD) DAPK1 using siRNA or shRNA in 8505C and KTC-1 cell lines, which we transiently or stably overexpressed in MDA-T32 and BCPAP cell lines. DAPK1 KD in 8505C and KTC-1 cells significantly increased cell proliferation and colony formation compared with controls. We observed significant inhibition of cancer cell invasion in cells overexpressing DAPK1, but the opposite effect in KD cells. Tumorsphere formation significantly increased after inhibition of DAPK1 expression in 8505C cells and was significantly suppressed in DAPK1-overexpressing MDA-T32 and BCPAP cells. DAPK1 overexpression inhibited mRNA and protein levels of stem markers (OCT4, Sox2, KLF4, and Nanog). Furthermore, the expression of these markers increased after KD of DAPK1 in 8505C cells. Mechanistic studies suggest that DAPK1 may modulate the expression of stem cell markers through the inhibition of β-catenin pathways. These findings were consistent with the public data and our thyroid tissue analysis, which showed higher DAPK1 expression was associated with advanced-stage papillary thyroid cancer with a higher stemness index and lower disease-free survival.

Highlights

Metastasis is a multi-step process that causes cancer cells to migrate from their primary site and progress into secondary tumors in other organs [1]
We first explored the clinical importance of the death-associated protein kinase 1 (DAPK1) gene in human thyroid cancer by conducting a comprehensive analysis with a transcriptome and its matched clinicopathological data in the The Cancer Genome Atlas (TCGA)-THCA data
The low DAPK1 tumor group consistently displayed more aggressive features, including more advanced TNM stage, (Figure 1d) and lower disease-free survival (DFS) (Figure 1e). These findings suggest that DAPK1 is a tumor suppressor in thyroid cancer and its low expression is associated with tumor progression

Summary

Introduction

Metastasis is a multi-step process that causes cancer cells to migrate from their primary site and progress into secondary tumors in other organs [1]. Cancer stem cells (CSCs) are a small subset of tumor cells with self-renewal and differentiation characteristics. DAPK1 plays an important role in apoptosis, autophagy, the immune response, ischemic injury of the brain, and neurodegenerative disease [8,9]. It has been identified as a tumor suppressor, and several studies have shown that DAPK1 regulates cell adhesion, DNA repair, cell cycle checkpoint control, and nuclear receptors during cancer progression [10–14]. One study reported that downregulation of DAPK1 promoted stem cell expression through modulating Ca2+ channel activation [13]. Other studies have demonstrated that downregulation of DAPK1 promotes CSCs by activating ZEB1 in colon and prostate cell lines [16,17]. Its role in thyroid cancer has not yet been determined

Methods

Results

Conclusion