Abstract
The overexpression of human telomerase reverse transcriptase (hTERT) has been associated with the proliferation and migration of colorectal cancer (CRC) cells. We investigated the roles of KRT23 and hTERT in promoting CRC cell proliferation and migration. We verified the relationship between KRT23 and hTERT in CRC using streptavidin-agarose pulldown and chromatin immunoprecipitation (ChIP) assays. One hundred and fifty-four human CRC specimens were analyzed using immunohistochemistry. The roles of KRT23 and hTERT in cell growth and migration were studied using siRNA and lentiviruses in vivo and in vitro. Western blot and wound scratch analyses were used to determine the signaling pathway for KRT23-mediated activation of CRC growth and migration. Telomerase activity was measured by using the TeloTAGGG Telomerase PCR ELISA PLUS Kit. We identified KRT23 as a new hTERT promoter-binding protein. Patients with high KRT23 and hTERT expression had markedly shorter overall survival. Overexpression of KRT23 upregulated the expression of hTERT protein, hTERT promoter-driven luciferase and telomerase activity in CRC. Conversely, inhibition of KRT23 by a KRT23-specific siRNA repressed the endogenous hTERT protein, the expression of hTERT promoter-driven luciferase and telomerase activity. Overexpression of KRT23 also promoted CRC proliferation and migration. By contrast, KRT23 inhibition significantly inhibited tumor cell growth in vitro and in vivo. KRT23 promoted cancer stem cell properties and increased the expression of CD133 and CD44. These results demonstrate that KRT23 is an important cellular factor that promotes CRC growth by activating hTERT expression and that KRT23 is a potential novel therapeutic target for CRC.
Highlights
Colorectal cancer (CRC) is one of the most common malignancies and the third most common cause of cancerrelated mortality in the world.[1]
Research has demonstrated that colorectal adenocarcinoma exhibits high levels of telomerase activity[7,8] and human telomerase reverse transcriptase has been identified as a potential biomarker for CRC.[9]
We predicted that the candidate CRC-specific human telomerase reverse transcriptase (hTERT) promoter-binding protein was KRT23
Summary
Colorectal cancer (CRC) is one of the most common malignancies and the third most common cause of cancerrelated mortality in the world.[1]. CSCs have many characteristics that promote tumorigenesis, such as selfrenewal, differentiation, multidrug resistance and metastatic potential.[15,16,17,18,19,20] CD44 and CD133 are well known as stem cell biomarkers that are expressed in CRC.[21,22] Elevated CD133 expression is correlated with tumorigenesis, metastasis and poor prognosis.[22] CD133 is an important potential target of drug therapies because many colon cancer cell lines express CD133.23,24 CD44 can promote cell–cell adhesion and maintain cell–matrix interactions.[22] When CD44 expression is upregulated, the growth and antiapoptotic properties of tumor cells are increased.[24]. We studied the clinical association between KRT23 and hTERT in CRC tissue samples
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