TY - JOUR
T1 - MUC1-C drives stemness in progression of colitis to colorectal cancer
AU - Li, Wei
AU - Zhang, Ning
AU - Jin, Caining
AU - Long, Mark D.
AU - Rajabi, Hasan
AU - Yasumizu, Yota
AU - Fushimi, Atsushi
AU - Yamashita, Nami
AU - Hagiwara, Masayuki
AU - Zheng, Rongbin
AU - Wang, Jin
AU - Kui, Ling
AU - Singh, Harpal
AU - Kharbanda, Surender
AU - Hu, Qiang
AU - Liu, Song
AU - Kufe, Donald
N1 - Funding Information:
The importance of chronic inflammation in promoting tumorigenesis is supported by the association between colitis and the development of colorectal cancer (CRC) (12). Prolonged inflammation and repetitive cycles of injury/repair in the intestinal mucosa have been linked to the expansion of intestinal stem cells (ISCs) in colitis and CSCs in CRC (13, 14). ISCs marked by expression of leucine-rich repeat–containing G protein–coupled receptor 5 (mouse Lgr5/human LGR5) are cycling populations located at the crypt base (15). Bmi1+ ISCs detectable above the crypt base represent a distinct quiescent pool with the capacity to regenerate Lgr5+ cells in response to damage (16, 17). Populations of Lgr5+ or Bmi1+ ISCs can give rise to colon cancer in mice (15, 16, 18). Human LGR5+ and BMI1+ ISCs have also been linked to CSCs in CRC (19–21). However, the regulation of LGR5 and BMI1 has not been fully investigated in CRC CSCs. Involvement of the oncogenic MUC1-C protein in the link between inflammation and cancer is unknown. The present work identifies a functional role for MUC1-C in inflammation-associated intestinal carcinogenesis by demonstrating the importance of this oncoprotein in driving (a) Lgr5+ ISCs in mouse models of colitis and (b) LGR5+ CSCs in colon cancer. Our results show that MUC1-C links the expansion of ISCs in colitis to the function of CSCs in CRC by promoting LGR5, BMI1, and core pluripotency factor expression. Of potential clinical significance, these findings indicate that MUC1-C is a druggable target for suppressing progression of colitis and CRC.
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/6/18
Y1 - 2020/6/18
N2 - Colitis is associated with the development of colorectal cancer (CRC) by largely undefined mechanisms that are critical for understanding the link between inflammation and cancer. Intestinal stem cells (ISCs) marked by leucine-rich repeat–containing G protein–coupled receptor 5 (LGR5) expression are of importance in both the inflammatory response to colitis and progression to colitis-associated colon cancer (CACC). Here, we report in human mucin 1–transgenic (MUC1-transgenic) mouse models of CACC, targeting the MUC1-C oncogenic protein suppresses the (a) Lgr5+ ISC population, (b) induction of Myc and core pluripotency stem cell factors, and (c) severity and progression of colitis to dysplasia and cancer. By extension to human colon cancer cells, we demonstrate that MUC1-C drives MYC, forms a complex with MYC on the LGR5 promoter, and activates LGR5 expression. We also show in CRC cells that MUC1-C induces cancer stem cell (CSC) markers (BMI1, ALDH1, FOXA1, LIN28B) and the OCT4, SOX2, and NANOG pluripotency factors. Consistent with conferring the CSC state, targeting MUC1-C suppresses the capacity of CRC cells to promote wound healing, invasion, self-renewal, and tumorigenicity. In analysis of human tissues, MUC1 expression associates with activation of inflammatory pathways, development of colitis, and aggressiveness of CRCs. These results collectively indicate that MUC1-C is of importance for integrating stemness and pluripotency in colitis and CRC. Of clinical relevance, the findings further indicate that MUC1-C represents a potentially previously unrecognized target that is druggable for treating progression of colitis and CRC.
AB - Colitis is associated with the development of colorectal cancer (CRC) by largely undefined mechanisms that are critical for understanding the link between inflammation and cancer. Intestinal stem cells (ISCs) marked by leucine-rich repeat–containing G protein–coupled receptor 5 (LGR5) expression are of importance in both the inflammatory response to colitis and progression to colitis-associated colon cancer (CACC). Here, we report in human mucin 1–transgenic (MUC1-transgenic) mouse models of CACC, targeting the MUC1-C oncogenic protein suppresses the (a) Lgr5+ ISC population, (b) induction of Myc and core pluripotency stem cell factors, and (c) severity and progression of colitis to dysplasia and cancer. By extension to human colon cancer cells, we demonstrate that MUC1-C drives MYC, forms a complex with MYC on the LGR5 promoter, and activates LGR5 expression. We also show in CRC cells that MUC1-C induces cancer stem cell (CSC) markers (BMI1, ALDH1, FOXA1, LIN28B) and the OCT4, SOX2, and NANOG pluripotency factors. Consistent with conferring the CSC state, targeting MUC1-C suppresses the capacity of CRC cells to promote wound healing, invasion, self-renewal, and tumorigenicity. In analysis of human tissues, MUC1 expression associates with activation of inflammatory pathways, development of colitis, and aggressiveness of CRCs. These results collectively indicate that MUC1-C is of importance for integrating stemness and pluripotency in colitis and CRC. Of clinical relevance, the findings further indicate that MUC1-C represents a potentially previously unrecognized target that is druggable for treating progression of colitis and CRC.
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UR - http://www.scopus.com/inward/citedby.url?scp=85086746667&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.137112
DO - 10.1172/jci.insight.137112
M3 - Article
C2 - 32427590
AN - SCOPUS:85086746667
VL - 5
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 12
M1 - 137112
ER -
