MUC1-C drives stemness in progression of colitis to colorectal cancer
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
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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Research Article Oncology Therapeutics

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

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 9

Proposed model for involvement of MUC1-C in progression of intestinal inflammation and carcinogenesis.

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Proposed model for involvement of MUC1-C in progression of intestinal in...
MUC1-C activates the TAK1/IKK/NF-κB inflammatory pathway in colitis and colon cancers (23). In turn, MUC1-C/NF-κB signaling induces changes in gene expression that include upregulation of (a) MUC1 itself in an autoinductive circuit (57) and (b) epigenetic modifiers, such as DNMTs and EZH2 (5). MUC1-C also activates the WNT/β-catenin/TCF4 pathway, induces MYC expression, and binds directly to MYC (11, 43–46). In this way, MUC1-C contributes to the regulation of MYC target genes involved in chromatin remodeling and dedifferentiation (11, 63). The present results link MUC1-C/MYC signaling to induction of LGR5 and BMI1 in support of a role in driving stemness in colitis and CRC. Stemness is associated with pluripotency, and, in this context, we show that MUC1-C/MYC signaling also drives OCT4, SOX2, and NANOG expression. Stemness and pluripotency are essential for wound healing and in the response to damage associated with colitis. The prolonged autoinduction of MUC1-C in settings of chronic inflammation with repetitive cycles of damage and repair could therefore drive NF-κB, MYC, and epigenetic modifications associated with stemness and pluripotency that become reprogrammed and promote carcinogenesis.