Maspin is a deoxycholate-inducible, anti-apoptotic stress-response protein differentially expressed during colon carcinogenesis

Abstract

Increased maspin expression in the colon is related to colon cancer risk and patient survival. Maspin is induced by the hydrophobic bile acid, deoxycholate (DOC), which is an endogenous carcinogen and inducer of oxidative stress and DNA damage in the colon. Persistent exposure of colon epithelial cells, in vitro, to high physiologic levels of DOC results in increased constitutive levels of maspin protein expression associated with the development of apoptosis resistance. When an apoptosis-resistant colon epithelial cell line (HCT-116RC) developed in the authors’ laboratory was treated with a maspin-specific siRNA probe, there was a statistically significant increase in apoptosis compared to treatment with an siRNA control probe. These results indicate, for the first time, that maspin is an anti-apoptotic protein in the colon. Immunohistochemical evaluation of maspin expression in human colonic epithelial cells during sporadic colon carcinogenesis (131 human tissues evaluated) indicated a statistically significant increase in maspin protein expression beginning at the polyp stage of carcinogenesis. There was no statistically significant difference in maspin expression between hyperplastic/adenomatous polyps and colonic adenocarcinomas. The absence of “field defects” in the non-neoplastic colonic mucosa of patients with colonic neoplasia indicates that maspin may drive the growth of tumors, in part, through its anti-apoptotic function.

Maspin is a marker for early recurrence in primary stage III and IV colorectal cancer

“…Experimental studies show that high Maspin expression is correlated with increased apoptosis resistance in CRC cells (Payne et al , 2011). Furthermore, it has been shown that circulating tumour cells in peripheral blood of CRC patients express high levels of Maspin (Findeisen et al , 2008).…”

Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer

“…Both deficiency of CcOI and increased Maspin protein expression appear to cause apoptosis resistance, as reviewed for CcOI by Bernstein et al [ 12 ], and shown for Maspin by Payne et al [ 61 ]. Immunohistochemical evaluations were made for deficiency of cytochrome coxidase subunit I (CcOI) [ 12 ] or increased expression of Maspin [ 61 ] in colonic epithelium.…”

“…Both deficiency of CcOI and increased Maspin protein expression appear to cause apoptosis resistance, as reviewed for CcOI by Bernstein et al [ 12 ], and shown for Maspin by Payne et al [ 61 ]. Immunohistochemical evaluations were made for deficiency of cytochrome coxidase subunit I (CcOI) [ 12 ] or increased expression of Maspin [ 61 ] in colonic epithelium. These evaluations were made in tissues from biopsies of patients with no history of colonic neoplasia, from tissue samples taken from resections 1-10 cm distant from colon cancers, tissues at the margins of cancers and tissue samples within cancers (and for Maspin, also within adenomas).…”

“…Strongly increased maspin protein expression was only seen in polyps or in colon cancers, but not in tissues surrounding cancers [ 61 ]. Thus, increased maspin expression is likely among the last changes in formation of a colon cancer.…”

Secondary bile acids effects in colon pathology. Experimental mice study

“…Progression to colon cancer proceeds by means of numerous changes in the colonic mucosa, progressing from normal tissue to "field defects" in the non-neoplastic flat mucosa, to hyperplastic polyps, to adenomatous polyps (adenomas), and, ultimately, to colon cancer 18 .…”