Class A scavenger receptor deficiency exacerbates lung tumorigenesis by cultivating a procarcinogenic microenvironment in humans and mice.
Genetic alterations on 8p22 have been implicated in multiple cancers, including lung cancer. In this region, genetic variants of the class A scavenger receptor (SR-A) gene have been associated with prostate cancer risk and have been highlighted as a potential susceptibility gene of cancer.
To determine whether common polymorphisms in the SR-A gene are associated with human lung cancer risk and to clarify the role of SR-A in lung carcinogenesis.
The relationship of three potentially functional polymorphisms (T-365C, T+25C, and Ala275Pro) in the SR-A gene with lung cancer risk was evaluated in 1287 lung cancer case subjects and 1261 control subjects from the Chinese population. At the same time, SR-A null mice were used to investigate its role in lung cancer development.
MEASUREMENTS AND MAIN RESULTS
The T+25C polymorphism was independently associated with lung cancer risk and significantly correlated with decreased expression of SR-A. The decreased SR-A expression was also found in tumor tissues as compared with normal tissues. Depletion of SR-A boosted the growth and angiogenesis of implanted Lewis lung carcinoma in mice. The cancer-suppressing capability of SR-A was attributable to its expression in bone marrow-derived cells as evidenced by bone marrow transplantation. Further analysis revealed augmented expression of proangiogenic factors including matrix metalloproteinase-9 (MMP9) in SR-A-deficient mice, indicative of a more procarcinogenic microenvironment. Last, zoledronate, an MMP9 inhibitor, abrogated acceleration of tumor growth conferred by SR-A loss-of-function.
Evidence from the population study and mouse model strongly indicates that SR-A may function as a tumor modulator to inhibit lung cancer growth through affecting the tumor microenvironment.
Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
SourceAmerican journal of respiratory and critical care medicine 186:8 2012 Oct 15 pg 763-72
Asian Continental Ancestry Group
Carcinoma, Lewis Lung
Genetic Predisposition to Disease
Scavenger Receptors, Class A
Pub Type(s)Journal Article
Research Support, Non-U.S. Gov't