Muc4’s Role in Colorectal Cancer | Aging-US
Channel: Aging (Aging-US)
Date: 17/03/2022

Aging (Aging-US) published this priority research paper as the cover for Volume 14, Issue 5, entitled, "Depletion of transmembrane mucin 4 (Muc4) alters intestinal homeostasis in a genetically engineered mouse model of colorectal cancer" by researchers from the Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE; Department of Medicine, Baylor College of Medicine, Houston, TX; Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA; VA San Diego Healthcare System, San Diego, CA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE.

DOI - https://doi.org/10.18632/aging.203935

Corresponding author - Surinder K. Batra - sbatra@unmc.edu

Abstract

Mucins are components of the mucus layer overlying the intestinal epithelial cells, which maintains physiological homeostasis. Altered mucin expression is associated with disease progression. Expression of MUC4 decreases in colorectal cancer (CRC); however, its functional role and implications in the intestinal pathology in CRC are not studied well. Therefore, we generated a genetically engineered Muc4 knockout (Muc4-/-) CRC mouse model by crossing with Muc4-/- and Apcflox/flox mice in the presence of colon-specific inducible Cre. We observed that deficiency of Muc4 results in an increased number of macroscopic tumors in the colon and rectal region and leads to poor survival. Further, the absence of Muc4 was associated with goblet cell dysfunction where the expression of intestinal homeostasis molecules (Muc2 and Fam3D) was downregulated. Next, we also observed that loss of Muc4 showed reduced thickness of mucus layer, leading to infiltration of bacteria, reduction in anti-microbial peptides, and upregulation of pro-inflammatory cytokines. Further, Apc gene mutation results in activation of the Wnt/β-catenin signaling pathway that corroborated with an increased nuclear accumulation of β-catenin and activation of its target genes: cyclin D1 and c-Myc in Muc4-/- mice was observed. We conclude that the presence of Muc4 is essential for intestinal homeostasis, reduces tumor burden, and improves overall survival.

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Keywords - aging, mucin, MUC4, intestinal homeostasis, colorectal cancer

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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