Differential expression of M3 muscarinic receptors in progressive colon neoplasia and metastasis
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Kunrong Cheng1,2, Aaron C. Shang2, Cinthia B. Drachenberg3, Min Zhan1,4, Jean-Pierre Raufman1,2,5
1Veterans Affairs Maryland Healthcare System, Baltimore VA Medical Center, Baltimore, MD, USA
2Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA
3Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA
4Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA
5Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
Jean-Pierre Raufman, email: [email protected]
Keywords: colon neoplasia, metastases, muscarinic receptors, matrix metalloproteinase-1, receptor expression
Received: November 30, 2016 Accepted: February 07, 2017 Published: February 18, 2017
M3 muscarinic receptor (M3R) activation promotes colon cancer cell proliferation, migration, and invasion in vitro. Although over-expression of CHRM3, the gene encoding M3R, is reported in primary colon cancers, expression of M3R itself has not been studied in colon neoplasia. We compared M3R expression in normal colon to colon adenomas, and primary and metastatic colon cancers. Compared to adjacent normal colon, CHRM3 expression was increased up to 128-fold in 10 of 18 consecutive surgical cancer specimens (56%) and associated with metastatic spread (P < 0.05). To analyze M3R protein expression we interrogated 29 consecutive paraffin-embedded colon adenocarcinomas and adjacent normal colon using a specific anti-M3R antibody and immunoperoxidase staining. This revealed weak M3R expression in normal colonocytes, primarily on basolateral surfaces. In contrast, in 25 of 29 cancer tissues (86%) we observed both cytoplasmic and plasma membrane over-expression of M3R; compared to normal epithelium, mean M3R staining intensity was increased more than two-fold in colon cancer (P < 0.001). M3R staining was also increased in 22 colon adenomas compared to adjacent normal colon (P < 0.001). In contrast, M3R staining intensity was not increased in lymph node or liver metastases. These findings suggest M3R expression plays an important role in early progression and invasion of colon neoplasia but is less important once tumors have spread.
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