The cause of lung cancer in persons who have never smoked remains uncertain. Yet, vitamin D may reduce lung cancer mortality due to its ability to inhibit cell proliferation and promote cell differentiation and apoptosis. Normal respiratory epithelial cells have high levels of the vitamin D receptor and of the enzyme involved in forming active vitamin D; however, these are dysregulated in malignant lung tissues.
Vitamin A (retinol) is involved in vitamin D-regulated gene transcription but excess dietary levels can interrupt this process. Thus, Ting-Yuan David Cheng and Marian Neuhouser of the Public Health Sciences Division recently set out to investigate the association between serum 25-hydroxyvitamin D, the accepted biomarker of vitamin D status, and death from lung cancer, while taking into account smoking status, circulating levels of vitamin A, and vitamin A/β-carotene supplement use.
In a nationally representative sample of 16,693 men and women from the Third National Health and Nutrition Examination Survey, the authors observed an inverse association between serum vitamin D and lung cancer mortality among non-smokers, despite no overall association between serum vitamin D and lung cancer mortality. Serum vitamin D ≥44 nmol/L vs. <44 nmol/L was associated with a 47-69% reduced risk of lung cancer mortality [former/never smokers: Hazard Ratio (HR) 0.53, 95% Confidence Interval (CI) 0.31-0.91; distant-former (quit ≥20 years)/never smokers: HR 0.31, 95% CI 0.13-0.77]. Additionally, vitamin A appeared to diminish the inverse association between vitamin D and lung cancer mortality, such that the beneficial effect of serum vitamin D ≥44 nmol/L was not seen among individuals with excess circulating vitamin A (serum retinyl esters ≥7.0 µg/dL or ratio of retinyl esters to retinol ≥0.08) or among vitamin A/β-carotene supplement users, although statistical tests to confirm effect modification by vitamin A were not conclusive.
In this study, the difference between non-smokers with high versus low serum vitamin D translated into a lower lung cancer mortality rate by 581 per 10,000. Yet, 29% of this nationally-representative sample had excess circulating vitamin A. Thus, if the observed antagonistic actions of excess vitamin A and vitamin A/β-carotene supplement use reflect the true underlying etiology, the associations between elevated vitamin D levels and reduced lung cancer mortality may have been even greater in those with normal levels of vitamin A.
Further research to determine the exact level of vitamin A intake that reduces the anti-carcinogenic actions of vitamin D are needed and will be important for understanding the true nature of the associations between vitamin D and lung cancer development and progression.
Cheng TY, Neuhouser ML. (2012). Serum 25-hyroxyvitamin D, vitamin A, and lung cancer mortality in the US population: a potential nutrient-nutrient interaction. Cancer Causes Control. 23:1557-1565.
Basic Sciences Division
Human Biology Division
Maggie Burhans, Ph.D.
Public Health Sciences Division
Vaccine and Infectious Disease Division
Clinical Research Division
Julian Simon, Ph.D.
Clinical Research Division
and Human Biology Division
Arnold Digital Library