Upregulation of MUC4 in Cervical Squamous Cell Carcinoma: Pathologic Significance

Abstract

SummaryMUC4 is a transmembrane glycoprotein more highly expressed in cervical dysplasia than benign cervical epithelium. We sought to determine whether MUC4 expression differs between benign and malignant cervical tissue. Fifty-eight patients with benign, dysplastic, or malignant cervical pathology were identified retrospectively, and representative sections were stained with a mouse monoclonal anti-MUC4 antibody. Semiquantitative analysis was performed on benign, dysplastic, and malignant regions by scoring staining intensity (0: negative, 1: weak, 2: moderate, and 3: strong) and distribution (focal <10%, multifocal = 10%-60%, diffuse ≥60%). In samples with benign glycogenated squamous epithelium, only the parabasal cells had MUC4 staining, and 48.5% had an intensity of 2 or 3. All samples with immature squamous metaplasia were positive through the entire epithelial thickness. Cervical intraepithelial neoplasia (CIN) 1 samples had variable staining with an intensity similar to glycogenated squamous epithelium but distribution similar to squamous metaplasia. All CIN 3 (n = 21) and invasive squamous cell carcinomas (n = 17) had increased MUC4 staining intensity (P<0.001 and P<0.001) and increased diffuse staining (P<0.001 and P<0.001) compared with the limited staining in glycogenated squamous epithelium. In contrast, no differences in staining were observed between benign endocervical glands, adenocarcinoma in situ, and invasive adenocarcinoma. These expression patterns suggest that MUC4 is a lineage marker in benign cervical tissue that may have aberrant expression in squamous dysplasia and carcinoma. Further studies may elucidate the role of MUC4 in the development of squamous cell cervical cancer. Recently, it has been noted that MUC4, a membrane-bound mucin, is upregulated in several different malignancies including pancreatic, ovarian, and breast cancer (6-10). Our recent studies have shown that ErbB2 (also known as HER2/neu) signaling is regulated by MUC4 in pancreatic tumor cells (11). In addition, rat Muc4/sialomucin complex serves as a ligand for rat p185/neu, a homolog of ErbB2 (12). Activation of this receptor can lead to an increase in signaling molecules that stimulate cell proliferation and the dissociation of cell-cell adhesions, promoting metastatic potential (13,14). Variable ErbB2 expression in some types of cervical cancer has been examined in attempts to correlate expression with prognosis (15-20). KeywordsPrior studies have provided evidence that MUC4 is upregulated in squamous cervical dysplasia (21). In addition, a study of only glandular lesions of the cervix found MUC4 expression in benign endocervical glands and 38% of adenocarcinoma in situ (AIS) and 75% of adenocarcinoma (AC) (22). No studies have evaluated the expression of MUC4 in squamous cell carcinoma (SCC) of the cervix. Thus, we sought to evaluate MUC4 expression in benign and malignant cervical epithelia. Differential expression could suggest a role for MUC4 in the signaling pathways involved in cervical cancer and lead to fur...

Aberrant upregulation of MUC4 mucin expression in cutaneous condyloma acuminatum and squamous cell carcinoma suggests a potential role in the diagnosis and therapy of skin diseases

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“…We have previously developed and characterised a monoclonal antibody (clone 8G7) raised against the TR region of MUC4 4. Employing this antibody, we and others have demonstrated an aberrant overexpression of MUC4 in cholangiocarcinoma,5 6 and pancreatic,7 8 cervical,9 gastric,10 ovarian,11 12 lung13 and prostate cancer 14. However, the status of MUC4 expression in cutaneous pathologies remains unknown.…”

MiR-211 inhibits invasion and epithelial-to-mesenchymal transition (EMT) of cervical cancer cells via targeting MUC4

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Genetically engineered mucin mouse models for inflammation and cancer

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