Effects of Vitamin D and Calcium on MSH2, TGF-α, and TGF-β Expression in Normal-Appearing Colorectal Mucosa of Sporadic Colorectal Adenoma Patients: A Randomized Clinical Trial Open Access

Abstract

Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGF-α (growth promoter) and TGF-β1 (growth inhibitor) is common during colorectal carcinogenesis. To estimate the effects of vitamin D and calcium on these biomarkers in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a randomized, double-blinded, placebo-controlled, modified 2×2 factorial chemoprevention clinical trial (N=104) of supplemental vitamin D3 (1,000 IU daily) and calcium (1,200 mg daily), alone and in combination, versus placebo. 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 D3 and vitamin D3 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), TGF-β1 expression increased by 41% (p=0.25) and 78% (p=0.14), and the TGF-α/TGF-β1 ratio decreased by 25% (p=0.31) and 44% (p=0.13). Although not statistically significant, these results (i) suggest that supplemental vitamin D3, alone or in combination with calcium may increase DNA mismatch repair relative to proliferation, increase TGF-β1 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) provide further support for the expression of MSH2 relative to MIB-1, TGF-β1 alone, and TGF-α relative to TGF-β1 in the normal-appearing rectal mucosa as modifiable, pre-neoplastic markers of risk for colorectal neoplasms.

Table of Contents

TABLE OF CONTENTS

Chapter 1: Introduction Page 1
Background and Significance……......…………………………….……………...2
References………………………………………………………………………..20

Chapter 2: Manuscript 34
Effects of Vitamin D and Calcium on MSH2, TGF-α, and TGF-β Expression in Normal-Appearing Colorectal Mucosa of Sporadic Colorectal Adenoma Patients: A Randomized Clinical Trial……………………………………….....35
References………………………………………………………………………..58
Tables and Figures…………………………...…………………………………..65
Supplementary Materials………………………………………………………...73

Chapter 3: Conclusions and Future Directions 80

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Degree	MPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Oncology Health Sciences, Epidemiology
Keyword	clinical trial TGF-β colorectal neoplasms TGF-α biological markers calcium MSH2 vitamin D
Committee Chair / Thesis Advisor	Bostick, Roberd M, Emory University
Partnering Agencies	Emory University schools, faculty or affiliated programs University, college or educational institution (other than Emory) Hospital or other health care provider

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