Irreversible Gene Expression Changes From Smoking

Reading time: 6 – 10 minutes

Recent research published in the online open journal BMC Genomics shows that smoking leads to changes in gene expression, some of which are reversible and some of which are permanent. Genes that are irreversibly changed may help to explain why former smokers, even after 10 years of not smoking, are still more susceptible to lung cancer than those who have never smoked.

smoking.jpgLung tissue samples were collected from 24 current and former smokers, as well as samples from those who had never smoked, and used to identify changes in gene expression. Researchers found that some gene expression changes were reversible, including genes associated with mucus secretion, nucleic acid metabolism and xenobiotic metabolism. Genes related to oxidative stress were considered part of the nucleic acid metabolism/xenobiotic metabolism.


A xenobiotic is a chemical found in an organism that is not normally produced or expected to be present in that organism. For example, antibiotics are considered to be xenobiotics in humans because the human body does not produce them and they would not be expected to be present in the body. Other xenobiotics include chemical carcinogens, insecticides, petroleum products and other environmental pollutants. In the body, xenobiotic metabolism is responsible for the removal of xenobiotics. Xenobiotics are metabolized in a two-phase process that typically occurs in the liver. Phase I reactions involve the addition or unmasking of a functional polar group (meaning that one end of the molecule is more positively charged while the other is more negatively charged) on the xenobiotic. In the second phase, glutathione, glucuronic acid or sulphuric acid is conjugated (meaning the union of a substance with a normal constituent of the body) to the xenobiotic and facilitates excretion. The cytochrome P450 enzymes, a superfamily of more than 160 known proteins, catalyze many reactions involved in drug metabolism and are important Phase 1 enzymes.

Gene Expression Changes

Genes associated with airway mucosal response were found to be strongly involved with airway epithelium repair and regeneration. Many of the genes involved in airway repair and regeneration have varying degrees of reversibility. Following smoking cessation, reversible gene expression changes included Trefoil factor 3 (gene symbol TFF3), a structural component of mucus that is elevated in inflammatory response, Ectonucleoside triphosphate diphosphohydrolase 8 (gene symbol ENTPD8), an enzyme involved in nucleic acid metabolism that may play a role in the chemical formation of DNA adducts and Calcium binding tyrosine-(Y) phosphorylation regulated (gene symbol CABYR), a newly discovered bronchial protein that may be involved in ciliary function associated with muco-ciliary clearance response within the lungs.

Gene expression changes that were partially reversible included Mucin 5 (gene symbol MUC5AC), a mucin gene and extracellular matrix structural constituent.

Gene expression changes that were irreversible consisted of functionally diverse genes but included a small number related to the cell cycle and DNA repair. The expression of P21/Cdc42/Rac1-activated kinase 1 (gene symbol PAK1), a protein that regulates cell motility and morphology, and Cyclins D1 (gene symbol CCND1) and G2 (gene symbol CCNG2), proteins that function as regulatory subunits for cell cycle progression, all appeared to be irreversibly lower in both current and former smokers relative to those who had never smoked. Additionally, APEX nuclease (multifunctional DNA repair enzyme) 1 (gene symbol APEX1), High-mobility group box 1 (gene symbol HMGB1), REV1-like (gene symbol REV1) and Tumor suppressor candidate 4 (gene symbol TUSC4) are DNA repair genes that were found to be irreversibly under-expressed in both current and former smokers.

Although CABYR gene expression was found to be reversible, one of its few known interactions occurs with another gene called Glycogen synthase kinase 3 beta (gene symbol GSK3B). Although GSK3B was not identified in the primary analysis, it too is irreversibly reduced in current and former smokers. GSK3B has been shown to negatively interact with Cyclooxygenase 2 (gene symbol COX2), an enzyme responsible for inflammation and pain [1]. The authors suggest that its reduced expression may account for the exaggerated inflammatory response despite smoking cessation and may contribute to the development of lung cancer [2].

According to the first author [3] of the study:

Those genes and functions which do not revert to normal levels upon smoking cessation may provide insight into why former smokers still maintain a risk of developing lung cancer.

Indeed, until recently, many smoking cessation timelines showed that, after 10 years of not smoking, the risk of cancer was that of people who had never previously smoked. However, statistics show an increased risk of lung cancer, even after a decade of not smoking. Age at cessation has a major impact on subsequent lung cancer risk. Although the risk of lung cancer is higher for former smokers than for those who have never smoked, lower lung cancer death is observed for people that quit earlier in life [4].

Your best bet? Don’t start smoking in the first place. If you do smoke, now is the time to quit.


  1. Thiel et al. Expression of cyclooxygenase-2 is regulated by glycogen synthase kinase-3beta in gastric cancer cells. J Biol Chem. 2006 Feb 24;281(8):4564-9. Epub 2005 Dec 21.
    View abstract
  2. Chari et al. Effect of active smoking on the human bronchial epithelium transcriptome. BMC Genomics. 2007 Aug 29;8(1):297 [Epub ahead of print]
    View abstract
  3. Smoking Turns On Genes — Permanently. Science Daily. 2007 Aug 30.
  4. Halpern et al. Patterns of absolute risk of lung cancer mortality in former smokers. J Natl Cancer Inst. 1993 Mar 17;85(6):457-64.
    View abstract
About the Author

Walter Jessen, Ph.D. is a Data Scientist, Digital Biologist, and Knowledge Engineer. His primary focus is to build and support expert systems, including AI (artificial intelligence) and user-generated platforms, and to identify and develop methods to capture, organize, integrate, and make accessible company knowledge. His research interests include disease biology modeling and biomarker identification. He is also a Principal at Highlight Health Media, which publishes Highlight HEALTH, and lead writer at Highlight HEALTH.