Epigenetic effects and molecular mechanisms of tumorigenesis induced by cigarette smoke: an overview

Abstract

Cigarette smoking is one of the major causes of carcinogenesis. Direct genotoxicity induced by cigarette smoke leads to initiation of carcinogenesis. Nongenotoxic (epigenetic) effects of cigarette smoke also act as modulators altering cellular functions. These two effects underlie the mechanisms of tumor promotion and progression. While there is no lack of general reviews on the genotoxic and carcinogenic potentials of cigarette smoke in lung carcinogenesis, updated review on the epigenetic effects and molecular mechanisms of cigarette smoke and carcinogenesis, not limited to lung, is lacking. We are presenting a comprehensive review of recent investigations on cigarette smoke, with special attentions to nicotine, NNK, and PAHs. The current understanding on their molecular mechanisms include (1) receptors, (2) cell cycle regulators, (3) signaling pathways, (4) apoptosis mediators, (5) angiogenic factors, and (6) invasive and metastasis mediators. This review highlighted the complexity biological responses to cigarette smoke components and their involvements in tumorigenesis.

Figure 1

Diagrammatic models summarizing simplified molecular mechanisms of genotoxic and non-genotoxic modes of action in carcinogenesis by cigarette smoke. (a) Nitrosamines and PAHs are carcinogens, inducing genotoxic effects leading to cancer initiation. (b) Non-genotoxic (epigenic) effects of cigarette smoke components (nicotine, nitrosamines, and PAHs) in cancer promotion and progression. Activation of nAChR, β-AR, or AhR, followed by neurotransmitters release, activation of signaling pathways (PKA, 5-LOX, Stat3 and PPARβ/δ), and increased the expression of transcriptional factors (JUN, FOS, MYC, and CREB) regulate cancer promotion by cigarette smoke. PKC, PI3K/AKT, ERK, and COX-2 signaling pathways downstream of receptors play important roles in both promotion and progression stages. p38, Src, VEGF, and NO releasing involve in enhancement of cancer progression by cigarette smoke.