DigitalCommons@UNMC

Title

Molecular Implications of MUC5AC-CD44 Axis in Colorectal Cancer Progression and Chemoresistance

Authors

Ramesh Pothuraju, University of Nebraska Medical CenterFollow
Satyanarayana Rachagani, University of Nebraska Medical CenterFollow
Shiv Ram Krishn, University of Nebraska Medical Center
Sanjib Chaudhary, University of Nebraska Medical CenterFollow
Rama Krishna Nimmakayala, University of Nebraska Medical CenterFollow
Jawed A. Siddiqui, University of Nebraska Medical CenterFollow
Koelina Ganguly, University of Nebraska Medical CenterFollow
Imayavaramban Lakshmanan, University of Nebraska Medical CenterFollow
Jesse L. Cox, University of Nebraska Medical CenterFollow
Kavita Mallya, University of Nebraska Medical CenterFollow
Sukhwinder Kaur, University of Nebraska Medical CenterFollow
Surinder K. Batra, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

Molecular Cancer

Publication Date

2020

Volume

19

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 β-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/β-catenin/p53/p21 signaling.

ISSN

1476-4598

DOI Link

10.1186/s12943-020-01156-y

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Pothuraju, Ramesh; Rachagani, Satyanarayana; Krishn, Shiv Ram; Chaudhary, Sanjib; Nimmakayala, Rama Krishna; Siddiqui, Jawed A.; Ganguly, Koelina; Lakshmanan, Imayavaramban; Cox, Jesse L.; Mallya, Kavita; Kaur, Sukhwinder; and Batra, Surinder K., "Molecular Implications of MUC5AC-CD44 Axis in Colorectal Cancer Progression and Chemoresistance" (2020). Journal Articles: Biochemistry & Molecular Biology. 128.
https://digitalcommons.unmc.edu/com_bio_articles/128