Colorectal cancer is a common cancer and a leading cause of cancer‐related death worldwide. The liver is a dominant metastatic site for patients with colorectal cancer. Molecular mechanisms that allow colorectal cancer cells to form liver metastases are largely unknown. Activation of epithelial–mesenchymal transition is the key step for metastasis of cancer cells. We recently reported that dual‐specificity tyrosine‐regulated kinase 2 (DYRK2) controls epithelial–mesenchymal transition in breast cancer and ovarian serous adenocarcinoma. The aim of this study is to clarify whether DYRK2 regulates liver metastases of colorectal cancer. We show that the ability of cell invasion and migration was abrogated in DYRK2‐overexpressing cells. In an in vivo xenograft model, liver metastatic lesions were markedly diminished by ectopic expression of DYRK2. Furthermore, we found that patients whose liver metastases expressed low DYRK2 levels had significantly worse overall and disease‐free survival. Given the findings that DYRK2 regulates cancer cell metastasis, we concluded that the expression status of DYRK2 could be a predictive marker for liver metastases of colorectal cancer.

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Dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) is a protein kinase that functions as a novel tumor suppressor. Previous studies have reported that DYRK2 expression is decreased in colorectal cancer compared with adjacent non-tumor tissues. However, the regulatory mechanisms by which the expression of DYRK2 is diminished remain unknown. The aim of the present study was to determine the regulatory mechanisms of DYRK2 expression. The present study identified the promoter regions of the DYRK2 gene and demonstrated that they contained CpG islands in human cancer cells. In addition, the DYRK2 promoter region exhibited a higher level of methylation in colorectal cancer tissues compared with healthy tissues from clinical samples. DYRK2 expression was increased at the mRNA and protein level in colorectal cancer cell lines by treatment with 5-Azacytidine, a demethylating agent. The results further demonstrated that knockdown of DNA methyltransferase (DNMT) 1 elevated DYRK2 expression in colorectal cancer cell lines. A colitis-related mouse carcinogenesis model also exhibited a lower DYRK2 level in colorectal cancer tissues compared with adjacent non-tumor tissues. In this model, nuclear staining of DNMT1 was detected in colorectal cancer cells, whereas a cytoplastic distribution pattern of DNMT1 staining was exhibited in healthy tissue. Overall, these findings suggested that DYRK2 expression was downregulated via transcriptional regulation by DNMT1 to elevate the proliferation of colorectal cancer cells.

Colorectal cancer is one of the most common gastrointestinal tumors with good outcomes; however, with distant metastasis, the outcomes are poor. Novel treatment methods are urgently needed. Our in vitro studies indicate that dual‐specificity tyrosine‐regulated kinase 2 (DYRK2) functions as a tumor suppressor in colorectal cancer by regulating cell survival, proliferation, and apoptosis induction. In addition, DYRK2 expression is decreased in tumor tissues compared to nontumor tissues in colorectal cancer, indicating a correlation with clinical prognosis. In this context, we devised a novel therapeutic strategy to overexpress DYRK2 in tumors by adenovirus‐mediated gene transfer. The present study shows that overexpression of DYRK2 in colon cancer cell lines by adenovirus inhibits cell proliferation and induces apoptosis in vitro. Furthermore, in mouse subcutaneous xenograft and liver metastasis models, enforced expression of DYRK2 by direct or intravenous injection of adenovirus to the tumor significantly inhibits tumor growth. Taken together, these findings show that adenovirus‐based overexpression of DYRK2 could be a novel gene therapy for liver metastasis of colorectal cancer.

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