Role of oncogenic K-Ras in cancer stem cell activation by aberrant wnt/β-catenin signaling

Byoung San Moon, Woo Jeong Jeong, Jieun Park, Tae Il Kim, Do Sik Min, Kang-Yell Choi

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Background: 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. Methods: 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 APCMin/+/K-RasLA2 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. Results: The sphere-forming capability of DLD-1-K-Ras-MT cells was statistically significantly higher than that of DLD-1-KRas-WT cells (DLD-1-K-Ras-MT mean = 86.661 pixel, 95% confidence interval [CI] = 81.701 to 91.621 pixel; DLD-1-KRas-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 APCMin/+/K-RasLA2mice, but not K-RasLA2mice, indicating that APC mutation is required for CSC activation by oncogenic K-Ras mutation. Conclusions: 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.

Original languageEnglish
JournalJournal of the National Cancer Institute
Volume106
Issue number2
DOIs
Publication statusPublished - 2014 Feb 1

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Catenins
Neoplastic Stem Cells
Mutation
Adenomatous Polyposis Coli
Carcinogenesis
Colorectal Neoplasms
Heterografts
Confidence Intervals
Neoplasms
Tumor Burden
Adenoma
Cultured Cells
Students
Neoplasm Metastasis

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Moon, Byoung San ; Jeong, Woo Jeong ; Park, Jieun ; Kim, Tae Il ; Min, Do Sik ; Choi, Kang-Yell. / Role of oncogenic K-Ras in cancer stem cell activation by aberrant wnt/β-catenin signaling. In: Journal of the National Cancer Institute. 2014 ; Vol. 106, No. 2.
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abstract = "Background: 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. Methods: 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 APCMin/+/K-RasLA2 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. Results: The sphere-forming capability of DLD-1-K-Ras-MT cells was statistically significantly higher than that of DLD-1-KRas-WT cells (DLD-1-K-Ras-MT mean = 86.661 pixel, 95{\%} confidence interval [CI] = 81.701 to 91.621 pixel; DLD-1-KRas-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 APCMin/+/K-RasLA2mice, but not K-RasLA2mice, indicating that APC mutation is required for CSC activation by oncogenic K-Ras mutation. Conclusions: 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.",
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Role of oncogenic K-Ras in cancer stem cell activation by aberrant wnt/β-catenin signaling. / Moon, Byoung San; Jeong, Woo Jeong; Park, Jieun; Kim, Tae Il; Min, Do Sik; Choi, Kang-Yell.

In: Journal of the National Cancer Institute, Vol. 106, No. 2, 01.02.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Role of oncogenic K-Ras in cancer stem cell activation by aberrant wnt/β-catenin signaling

AU - Moon, Byoung San

AU - Jeong, Woo Jeong

AU - Park, Jieun

AU - Kim, Tae Il

AU - Min, Do Sik

AU - Choi, Kang-Yell

PY - 2014/2/1

Y1 - 2014/2/1

N2 - Background: 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. Methods: 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 APCMin/+/K-RasLA2 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. Results: The sphere-forming capability of DLD-1-K-Ras-MT cells was statistically significantly higher than that of DLD-1-KRas-WT cells (DLD-1-K-Ras-MT mean = 86.661 pixel, 95% confidence interval [CI] = 81.701 to 91.621 pixel; DLD-1-KRas-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 APCMin/+/K-RasLA2mice, but not K-RasLA2mice, indicating that APC mutation is required for CSC activation by oncogenic K-Ras mutation. Conclusions: 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.

AB - Background: 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. Methods: 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 APCMin/+/K-RasLA2 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. Results: The sphere-forming capability of DLD-1-K-Ras-MT cells was statistically significantly higher than that of DLD-1-KRas-WT cells (DLD-1-K-Ras-MT mean = 86.661 pixel, 95% confidence interval [CI] = 81.701 to 91.621 pixel; DLD-1-KRas-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 APCMin/+/K-RasLA2mice, but not K-RasLA2mice, indicating that APC mutation is required for CSC activation by oncogenic K-Ras mutation. Conclusions: 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.

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