Role of Oncogenic K-Ras in Cancer Stem Cell Activation by Aberrant Wnt/β-Catenin Signaling

• Published in: JNCI : Journal of the National Cancer Institute 2014-02, Vol.106 (2), p.djt373-djt373
• Main Authors: MOON, Byoung-San, JEONG, Woo-Jeong, JIEUN PARK, TAE IL KIM, DO SIK MIN, CHOI, Kang-Yell
• Format: Article
• Language: English
• Subjects: AC133 Antigen; Adenomatous Polyposis Coli - metabolism; Adenomatous Polyposis Coli Protein; Adult; Aged; Animals; Antigens, CD - metabolism; beta Catenin - metabolism; Biological and medical sciences; Cell Adhesion Molecules, Neuronal - metabolism; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Female; Fetal Proteins - metabolism; Gene Expression Regulation, Neoplastic; Genes, ras; Glycoproteins - metabolism; Heterografts; Humans; Hyaluronan Receptors - metabolism; Male; Medical sciences; Mice; Middle Aged; Mutation; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Peptides - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Republic of Korea; Signal Transduction; Tumors; Wnt Proteins - metabolism
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/djt373

Adenomatous polyposis coli (APC) loss-of-function mutations and K-Ras gain-of-function mutations are common abnormalities that occur during the initiation and intermediate adenoma stages of colorectal tumorigenesis, respectively. However, little is known about the role these mutations play in cancer stem cells (CSCs) associated with colorectal cancer (CRC) tumorigenesis. We analyzed tissue from CRC patients (n = 49) to determine whether K-Ras mutations contributed to CSC activation during colorectal tumorigenesis. DLD-1-K-Ras-WT and DLD-1-K-Ras-MT cells were cultured and evaluated for their ability to differentiate, form spheroids in vitro, and form tumors in vivo. Interaction between APC and K-Ras mutations in colorectal tumorigenesis was evaluated using APC (Min/+)/K-Ras (LA2) mice and DLD-1-K-Ras-WT and DLD-1-K-Ras-MT cell xenografts. (n = 4) Group differences were determined by Student t test. All statistical tests were two-sided. The sphere-forming capability of DLD-1-K-Ras-MT cells was statistically significantly higher than that of DLD-1-K-Ras-WT cells (DLD-1-K-Ras-MT mean = 86.661 pixel, 95% confidence interval [CI] = 81.701 to 91.621 pixel; DLD-1-K-Ras-WT mean = 42.367 pixel, 95% CI = 36.467 to 48.267 pixel; P = .003). Moreover, both the size and weight of tumors from DLD-1-K-Ras-MT xenografts were markedly increased compared with tumors from DLD-1-K-Ras-WT cells. Expression of the CSC markers CD44, CD133, and CD166 was induced in intestinal tumors from APC (Min/+)/K-Ras (LA2)mice, but not K-Ras (LA2) mice, indicating that APC mutation is required for CSC activation by oncogenic K-Ras mutation. K-Ras mutation activates CSCs, contributing to colorectal tumorigenesis and metastasis in CRC cells harboring APC mutations. Initial activation of β-catenin by APC loss and further enhancement through K-Ras mutation induces CD44, CD133, and CD166 expression.