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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 8

Upregulation of MUC1 expression in patients with UC and CRC.

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Upregulation of MUC1 expression in patients with UC and CRC.
(A) The GSE...
(A) The GSE75214 data set containing expression profiles from control normal colon (n = 11), UC colon inactive (n = 23), and UC colon active (n = 74) samples was analyzed for MUC1 (left) and MYC (right) expression. The results are presented as violin plots. The dot in the center is the mean. Differences between groups were determined by the Wilcoxon rank sum test. (B) MUC1hi versus MUC1lo differential expression from UC samples (GSE75214) was assessed for functional enrichment with gene set enrichment analysis (GSEA) against the hallmark and canonical pathways. Enrichment plots for select gene signatures are shown. (C) The TCGA-COAD data set was analyzed for MUC1 expression in microsatellite stable (MSS) tumors (n = 175), microsatellite instability-low (MSI-L) tumors (n = 48), and microsatellite instability-high (MSI-H) tumors (n = 48) as compared with that in normal colon tissue (n = 41). (D) MUC1hi versus MUC1lo differential expression from CRC samples was assessed for functional enrichment with GSEA against hallmark and canonical pathways. Enrichment plots for select gene signatures are shown. (E) CRC samples (n = 638) (UCSC Xena data hub) were compared with normal colonic mucosa (n = 51) (upper). Multiple probe set IDs for the indicated genes were averaged for each patient sample after normalization to obtain a representative expression value. The center line indicates the median value, bounds of the box denote 25th (lower) and 75th (upper) percentiles, and whiskers indicate minimum (lower) and maximum (upper) values. Student’s t test was used to compare groups. Kaplan-Meier curves for relapse-free survival of patient groups with CRCs expressing the indicated genes (lower). Blue lines show low signatures groups; red lines, high signatures groups. P = 0.020, 0.045, and 0.043 for MUC1 + MYC, MUC1 + MYC + LGR5, and MUC1 + MYC + LGR5 + BMI1, respectively (log-rank test). For both high and low for MUC1 + MYC, MUC1 + MYC + LGR5, and MUC1 + MYC + LGR5 + BMI1, n = 91. TPM, transcripts per kilobase million; FPKM, fragments per kilobase million.

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