Molecular implications of MUC5AC-CD44 axis in colorectal cancer progression and chemoresistance
Open Access
- 25 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Molecular Cancer
- Vol. 19 (1), 1-14
- https://doi.org/10.1186/s12943-020-01156-y
Abstract
Background Differential expression of mucins has been associated with several cancers including colorectal cancer (CRC). In normal physiological conditions, secretory mucin MUC5AC is not expressed in the colonic mucosa, whereas its aberrant expression is observed during development of colon cancer and its precursor lesions. To date, the molecular mechanism of MUC5AC in CRC progression and drug resistance remains obscure. Methods MUC5AC expression was determined in colon tissue microarray by immunohistochemistry. A RNA interference and CRISPR/Cas9-mediated system was used to knockdown/knockout the MUC5AC in CRC cell lines to delineate its role in CRC tumorigenesis using in vitro functional assays and in vivo (sub-cutaneous and colon orthotopic) mouse models. Finally, CRC cell lines and xenograft models were used to identify the mechanism of action of MUC5AC. Results Overexpression of MUC5AC is observed in CRC patient tissues and cell lines. MUC5AC expression resulted in enhanced cell invasion and migration, and decreased apoptosis of CRC cells. MUC5AC interacted with CD44 physically, which was accompanied by the activation of Src signaling. Further, the presence of MUC5AC resulted in enhanced tumorigenesis and appearance of metastatic lesions in orthotopic mouse model. Additionally, up-regulation of MUC5AC resulted in resistance to 5-fluorouracil (5-FU) and oxaliplatin, and its knockout increased sensitivity to these drugs. Finally, we observed that up-regulation of MUC5AC conferred resistance to 5-FU through down-regulation of p53 and its target gene p21 and up-regulation of beta-catenin and its target genes CD44 and Lgr5. Conclusion Our findings suggest that differential expression of secretory mucin MUC5AC results in enhanced tumorigenesis and also confers chemoresistance via CD44/beta-catenin/p53/p21 signaling.Funding Information
- National Cancer Institute (CA210637, CA206444, CA183459, CA200466, CA127297, CA217798)
This publication has 45 references indexed in Scilit:
- Epigenetic and genetic features of 24 colon cancer cell linesOncogenesis, 2013
- MUC4 stabilizes HER2 expression and maintains the cancer stem cell population in ovarian cancer cellsJournal of Ovarian Research, 2011
- Loss of E-cadherin and MUC2 Expressions Correlated with Poor Survival in Patients with Stages II and III Colorectal CarcinomaAnnals of Surgical Oncology, 2010
- MUC4 down-regulation reverses chemoresistance of pancreatic cancer stem/progenitor cells and their progeniesCancer Letters, 2010
- RNA interference suppression of mucin 5AC (MUC5AC) reduces the adhesive and invasive capacity of human pancreatic cancer cellsJournal of Experimental & Clinical Cancer Research, 2010
- MUC4 activates HER2 signalling and enhances the motility of human ovarian cancer cellsBritish Journal of Cancer, 2008
- MUC4 Mucin Interacts with and Stabilizes the HER2 Oncoprotein in Human Pancreatic Cancer CellsCancer Research, 2008
- Hypersensitivity of Tumor Cell Lines with Microsatellite Instability to DNA Double Strand Break Producing Chemotherapeutic Agent BleomycinCancer Research, 2004
- Down-Regulation of β-Catenin by Activated p53Molecular and Cellular Biology, 2001
- Immunohistochemical study of the expression of MUC5AC and MUC6 in breast carcinomas and adjacent breast tissuesJournal of Clinical Pathology, 2001