miR-137 Regulates the Tumorigenicity of Colon Cancer Stem Cells through the Inhibition of DCLK1

Abstract

miRNAs have important roles in regulating cancer stem cell (CSC) properties and are considered to be potential therapeutic targets. However, few studies have focused on miRNAs which are specifically related to colon CSCs. Here, a PCR-based miRNA profiling analysis of normal colon stem cells (NCSC) and colonÀ ) identified miRNAs which regulate colon CSC properties. Interestingly, miRNA-137 (miR-137) expression was downregulated in the colon CSCs compared with NCSCs, while doublecortin-like kinase 1 (DCLK1) mRNA was highly expressed in the colon CSCs but low in the NCSCs. In fact, DCLK1-positive cancer cells were widely distributed in clinically resected colon cancer specimens, while DCLK1-positve epithelial cells were rarely detected in normal colon tissues including the crypt bottoms. Luciferase assay and immunoblot analysis revealed that miR-137 regulated DCLK1 gene expression. Transduction of exogenous miR-137 suppressed the development of colon cancer organoids in vitro and the tumorigenicity of colon cancer cells in vivo without affecting the growth of normal intestinal organoids. Furthermore, the suppression of miR-137 enhanced the organoid development of normal colon cells. These data demonstrate that miR-137 has the capacity to suppress the tumorigenicity of colon CSCs and that maintained expression of miR-137 in NCSCs contributes to suppressing uncontrolled cell proliferation through the inhibition of DCLK1 expression.Implications: The miR-137/DCLK1 axis as an important regulator in NCSCs and colon CSCs; further understanding of this axis may foster the development of potential gene therapeutic strategies targeting colon CSCs.

Doublecortin-Like Kinase 1 (DCLK1) Regulates B Cell-Specific Moloney Murine Leukemia Virus Insertion Site 1 (Bmi-1) and is Associated with Metastasis and Prognosis in Pancreatic Cancer

“…Recent studies provide strong evidence that DCLK1 is involved in tumor progression and can be regarded as a CSC marker [11][12][13]17]. In this study, we found that DCLK1 was overexpressed in pancreatic cancer, correlating with metastasis and prognosis.…”

“…Accumulating evidence suggests that CSCs are responsible for cancer metastasis, recurrence and radio/chemo-resistance [36][37][38], and previous reports demonstrate that DCLK1 can mark CSCs in gastrointestinal and other cancers [12][13][14]. A recent study revealed that DCLK1 is essential for the invasive and metastatic properties of CSCs in human pancreatic cancer and that it might be a promising therapeutic target [11].…”

“…Moreover, a recent report showed that in preinvasive pancreatic cancer, DCLK1 distinguishes a morphologically distinct and functionally unique population of cancer-initiating cells with stem cell properties [10]. These and several other studies provide strong evidence that DCLK1 can be regarded as a CSC marker in pancreatic cancer [11], colon cancer [12,13], breast cancer [14] and clear renal cell carcinoma [15]. CSCs are now considered to be primarily responsible for tumor relapse and can potentially initiate metastatic growth [16].…”

“…4E). Previous studies demonstrated that DCLK1 marks CSC in pancreatic and colorectal cancer and regulates stemness [11,12]. We therefore examined the expression of pluripotency markers after cells were transfected with si-DCLK1.…”

Targeting cancer stem cells in cancer therapy

“…One study utilized PCR-based miRNA profiling analysis of normal colon stem cell (NCSCs) and colon CSCs (EpCAM+/CD44+/CD66a-) to identify miR-137 (miRNA-137), which serves to regulate colon CSC properties [16] . MiR-137 was downregulated in the colon CSCs compared to NCSCs.…”