Effects of Supplemental Vitamin D and Calcium Alone or in Combination on Expression of Claudin-1 in the Normal Colorectal Mucosa of Colorectal Adenoma Patients. Open Access

Abstract

Abstract

Background: Dysfunction of the tight junction proteins (TJs) is considered to be one of the initial events in colorectal carcinogenesis. Evidence from animal, cell culture, and human studies strongly support calcium and vitamin D as being promising chemopreventive agents against colorectal neoplasms. Therefore, the aim of our study was to test whether calcium and/or vitamin D has an effect on claudin-1 (CLDN1) expression in the normal colorectal mucosa.

Methods: We tested calcium (1200 mg daily) and/or vitamin D3 (1000 IU daily) effects on the expression of CLDN1 in the normal-appearing colorectal mucosa of 105 sporadic colorectal adenoma patients, nested within a large randomized, double-blind, placebo controlled, partial 2 x 2 factorial chemopreventive clinical trial. We assessed CLDN1 expression at baseline and 1-yr follow up using standardized, automated immunohistochemistry and quantitative image analysis.

Results: Following 1-yr of treatment, in the calcium only group CLDN1 expression was increased by 14% (p=0.171) in the full length of the crypts compared to placebo. There was no change in expression of CLDN1 in the vitamin D only group and minimal non-significant increase in the combination group compared to placebo. Treatment effects of calcium were suggestively stronger among women (54%, p=0.01) compared to men, among individuals with positive family history of CRC (4-fold, p=0.02) compared to those without family history of CRC, and among individuals who had baseline serum 25(OH)D levels below median (29%, p=0.04) compared to those who had at or above median level of serum 25(OH)D. Baseline CLDN1 expression was 34% higher (p=0.02) in obese compared to normal weight, 18% higher (p=0.06) in regular aspirin users compared to aspirin non-users, and 26% lower (p=0.09) in participants with family history of CRC compared to those without family history of CRC.

Conclusion: Calcium may modify the expression of CLDN1 in the normal-appearing colorectal epithelium in humans. This finding further supports calcium as a chemopreventive agent against colorectal neoplasms.

Table of Contents

Table of Contents

Background 1
Vitamin D and Colorectal Neoplasms Risk 2
Calcium and Colorectal Neoplasms risk 4
Gut Barrier, Tight Junction Proteins, and Colorectal Neoplasms Risk 6
Materials and Methods 9
Participant Population 9
Clinical Trial Protocol 10
Adjunct Biomarker Study 11
Immunohistochemistry Protocol 12
Statistical Analysis 13
Results 15
Discussion 18
References 24
Tables 28
Figure 38
Appendix 39

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, Epidemiology
Keyword	Claudin-1 Colorectal adenoma Tight junction proteins Colorectal cancer
Committee Chair / Thesis Advisor	Fedirko, Veronika, Emory University
Partnering Agencies	Does not apply (no collaborating organization)

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