| Title | De novo expression of CD44 variants in sporadic and hereditary gastric cancer |
| Publication Type | Journal Article |
| 2010 |
| Authors | Da Cunha, CB, Oliveira, C, Wen, X, Gomes, B, Sousa, S, Suriano, G, Grellier, M, Huntsman, DG, Carneiro, F, Granja, PL, Seruca, R |
| Journal | Laboratory InvestigationLab. Invest. |
| Volume | 90 |
| Issue | 11 |
| Pagination | 1604 - 1614 |
| Date Published | 2010/// |
| 00236837 (ISSN) |
| Alternative Splicing, Antigens, CD44, article, Cadherins, CD44, CD44v6, CD44v6 antigen, CD44v7 antigen, Cell Line, Tumor, clinical article, controlled study, E-cadherin, familial cancer, Gastric Mucosa, Germ-Line Mutation, HDGC, Hermes antigen, human, human tissue, Humans, immunohistochemistry, intestine metaplasia, messenger RNA, Neoplasm Metastasis, priority journal, protein expression, real time polymerase chain reaction, reverse transcription polymerase chain reaction, RNA splicing, RNA, Messenger, splicing, sporadic GC, stomach, stomach cancer, stomach mucosa, Stomach Neoplasms, stomach polyp, tumor marker, unclassified drug, uvomorulin |
| CD44 is the major ubiquitously expressed cell surface receptor for hyaluronate. The CD44 gene encodes several protein isoforms due to extensive alternative splicing and post-translational modifications. Some of these CD44 variable isoforms have been foreseen as key players in malignant transformation and their expression is highly restricted and highly specific, unlike the canonical CD44 standard isoform. In this study, we aimed at dissecting the mRNA splicing pattern of CD44 in normal stomach and gastric cancer (GC) cell lines (n9) using cloning and quantitative mRNA amplification assays. Moreover, we assessed the RNA levels and protein expression pattern of relevant splicing forms in distinct premalignant and malignant gastric lesions (sporadic (n43) and hereditary (n3) forms) using real-time RT-PCR and immunohistochemistry. We also explored the association of CD44 and E-cadherin expression by immunohistochemistry, as E-cadherin has a pivotal functional role in GC. We established the pattern of CD44 variant forms in normal stomach and gastric malignancy. We observed that although exon v6-containing isoforms were rarely expressed in normal gastric mucosa, they became increasingly expressed both in gastric premalignant (hyperplastic polyps, complete and incomplete intestinal metaplasia, low- and high-grade dysplasia) and malignant lesions (cell lines derived from GCs, primary sporadic GCs and hereditary diffuse GCs (HDGCs)). Moreover, we verified that whenever E-cadherin expression was absent, exon v6-containing CD44 isoforms were overexpressed. The lack of expression of CD44 isoforms containing exon v6 in the surface and foveolar epithelia of normal stomach and, its de novo expression in premalignant, as well as in sporadic and hereditary malignant lesions of the stomach, pinpoint CD44 v6-containg isoforms as potential biomarkers for early transformation of the gastric mucosa. Further, our results raise the hypothesis of using CD44v6 as a marker of early invasive intramucosal carcinoma in HDGC CDH1 mutation carriers that lack CDH1 expression in their tumors. © 2010 USCAP, Inc All rights reserved. |
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