Molecular implications of MUC5AC-CD44 axis in colorectal cancer progression and chemoresistance

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

doi:10.1186/s12943-020-01156-y

Ramesh Pothuraju, Shiv Ram Krishn + Show 10 more

Open Access

https://doi.org/10.1186/s12943-020-01156-y

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Journal: Molecular Cancer	Publication Date: Feb 25, 2020
Citations: 91	License type: open-access

Affiliation: University of Nebraska Medical Center

Abstract

BackgroundDifferential 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.MethodsMUC5AC 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.ResultsOverexpression 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.ConclusionOur findings suggest that differential expression of secretory mucin MUC5AC results in enhanced tumorigenesis and also confers chemoresistance via CD44/β-catenin/p53/p21 signaling.

Highlights

Differential expression of mucins has been associated with several cancers including colorectal cancer (CRC)
MUC5AC expression is up-regulated in human colon cancer tissues and cell lines Our aim was to study whether MUC5AC had a role in colon cancer progression
We examined MUC5AC expression in colon TMA, which showed a higher expression of secretory mucin MUC5AC protein in both adenocarcinoma (n = 34, p < 0.01) and metastatic adenocarcinoma (n = 20, p < 0.01) patient tissues (Fig. 1b)

Summary

Introduction

Differential expression of mucins has been associated with several cancers including colorectal cancer (CRC). 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. Loss of MUC2 expression in colon adenocarcinoma has been strongly associated with poor prognosis in stage II and III CRC patients [5]. Expression of secretory mucin MUC5AC is restricted to stomach, lungs, ear, conjunctiva, nasopharynx, and gallbladder. MUC5AC expression is absent in normal colon, its expression increases across benign and malignant conditions [8]. Krishn et al (2016) observed the down-regulation of MUC2 and MUC4, and overexpression of MUC1 and MUC5AC in colonic polyps, adenomas and CRC [3]. To date the molecular mechanism of MUC5AC in CRC progression and drug resistance remains obscure

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