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Effects of vitamin D and calcium on expression of MSH2 and transforming growth factors in normal‐appearing colorectal mucosa of sporadic colorectal adenoma patients: A randomized clinical trial
Author(s) -
Kwan Albert K.,
Um Caroline Y.,
Rutherford Robin E.,
Seabrook March E.,
Barry Elizabeth L.,
Fedirko Veronika,
Baron John A.,
Bostick Roberd M.
Publication year - 2019
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22945
Subject(s) - colorectal adenoma , autocrine signalling , medicine , vitamin d and neurology , biology , paracrine signalling , vitamin , adenoma , msh2 , endocrinology , colorectal cancer , intestinal mucosa , gastroenterology , cancer , dna mismatch repair , receptor
Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFβ 1 (growth inhibitor) is common during colorectal carcinogenesis. To estimate vitamin D and calcium effects on these biomarkers in the normal‐appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a pilot, randomized, double‐blinded, placebo‐controlled, modified 2 × 2 factorial chemoprevention clinical trial ( N = 104) of supplemental vitamin D 3 (1000 IU daily) and calcium (1200 mg daily), alone and in combination, versus placebo over 1 year. The expression of the three biomarkers and Ki‐67/mib‐1 in colorectal crypts in biopsies of normal‐appearing rectal mucosa were detected using automated immunohistochemistry and quantified using image analysis. In the vitamin D 3 and vitamin D 3 plus calcium groups, relative to their reference groups, in the upper 40% (differentiation zone) of crypts, it was estimated that, respectively, the MSH2/mib‐1 ratio increased by 47% ( P = 0.14) and 62% ( P = 0.08), TGFβ 1 expression increased by 41% ( P = 0.25) and 78% ( P = 0.14), and the TGFα/TGFβ 1 ratio decreased by 25% ( P = 0.31) and 44% ( P = 0.13). Although not statistically significant, these results support further research into (i) whether supplemental vitamin D 3 , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFβ 1 expression, and decrease autocrine/paracrine growth promotion relative to growth inhibition in the colorectal epithelium, all hypothesized to reduce risk for colorectal carcinogenesis; and (ii) the expression of MSH2 relative to mib‐1, TGFβ 1 alone, and TGFα relative to TGFβ 1 in the normal‐appearing rectal mucosa as potential modifiable, pre‐neoplastic markers of risk for colorectal neoplasms.