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MUC1-C drives stemness in progression of colitis to colorectal cancer
Wei Li, … , Song Liu, Donald Kufe
Wei Li, … , Song Liu, Donald Kufe
Published May 19, 2020
Citation Information: JCI Insight. 2020;5(12):e137112. https://doi.org/10.1172/jci.insight.137112.
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Research Article Oncology Therapeutics

MUC1-C drives stemness in progression of colitis to colorectal cancer

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Abstract

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.

Authors

Wei Li, Ning Zhang, Caining Jin, Mark D. Long, Hasan Rajabi, Yota Yasumizu, Atsushi Fushimi, Nami Yamashita, Masayuki Hagiwara, Rongbin Zheng, Jin Wang, Ling Kui, Harpal Singh, Surender Kharbanda, Qiang Hu, Song Liu, Donald Kufe

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Figure 1

Targeting MUC1-C attenuates inflammation in MUC1+/– IL-10–/– mice.

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Targeting MUC1-C attenuates inflammation in MUC1+/– IL-10–/– mice.
(A) I...
(A) Images of descending colonic mucosa from a MUC1+/– mouse stained with H&E (upper) and for MUC1-C by IHC (lower). Red scale bars: 200 μm. Black scale bars: 50 μm. (B) Schema for GO-203 treatment of MUC1+/– IL-10–/– mice. GO-203 nanoparticles (GO-203/NPs) were administered i.p. twice a week for 3 weeks. (C) Body weight increase for untreated (shown in red) and GO-203–treated (shown in blue) MUC1+/– IL-10–/– mice. The results are expressed as the percentage increase (mean ± SEM) of baseline weight on day 1. Body weights on day 56 were compared using Student’s t test. The asterisk denotes a significant difference (P < 0.05). (D) Pie charts representing the percentage of control untreated (left) and GO-203–treated (right) MUC1+/– IL-10–/– mice with inflammation, dysplasia, and adenocarcinoma as determined by microscopic analysis and scoring of H&E staining (Supplemental Table 1). (E) Epithelial damage score of H&E-stained colons from control and GO-203–treated MUC1+/– IL-10–/– mice as determined by microscopic analysis (Supplemental Table 2). (F) Images of colons with colitis, dysplasia, and adenocarcinoma from control MUC1+/– IL-10–/– mice stained with H&E (upper panels) and for MUC1-C by IHC (lower panels). Red scale bars: 200 μm. Black scale bars: 50 μm. (G) Images of colons with colitis from control and GO-203–treated MUC1+/– IL-10–/– mice stained with H&E (upper panels) and for MUC1-C (lower panels). Red scale bars: 200 μm. Black scale bars: 50 μm.

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