PhD graduate who studied microRNAs, now part of an AI startup that's democratising science: Sparrho!
Follow the latest science behind how microRNAs and smoking lead to lung cancer risk
In 10 seconds? Since their discovery in the 1990s, microRNAs have been found to be involved in a wide range of biological processes in human cells, including the development of many cancers.
Abstract: Lung cancer is a leading clinical condition for the high rates of mortality throughout the world. For a long time, it was considered that the risk of lung cancer is associated with smoking. With the advent of new technologies that allowed better diagnostic approaches, knowledge on the genetic basis of lung cancer in never smokers is expanding. In an epidemiological and biological stand point, lung cancer in never smokers is now recognized as a distinct disease entity. In this review, we provide a comprehensive view of the factors that contribute to lung cancer in never smokers. Epidemiological and non-genetic factors such as pollution, occupational exposure, socioeconomic status, infections and medical history determine the risk of lung cancer in never smokers. With regard to genetic factors, chromosomal aberrations, gene polymorphisms, mutations and epigenetic changes in a variety of genes involved in drug metabolism, inflammation, DNA repair and cell proliferation exert a significant effect on the risk of lung cancer in never smokers. Interestingly, it is now believed that the risk of lung cancer is higher in women and the role of female hormones in lung cancer is gaining momentum. The fact that lung cancer is a disease of the smokers is slowly waning and a rethink on the risk factors that cause this disease is very much important. Recent advances using epigenetic screening suggests that lung cancer in never smokers is a distinct disease entity. Epidemiological and clinical studies that screen for lung cancer should opt for a biological rather than a clinical selection. Diagnostic and treatment strategies should be carefully planned for lung cancer patients without a history of smoking because of the differences in the genetics, epigenetics, pathobiology and treatment outcomes in these set of patients.
Pub.: 08 Jun '16, Pinned: 06 Apr '17
Abstract: Although genome-wide association studies (GWAS) have identified many genetic variants that are strongly associated with lung cancer, these variants have low penetrance and serve as poor predictors of lung cancer in individuals. We sought to increase the predictive value of germline variants by considering their cumulative effects in the context of biologic pathways.For individuals in the Environment and Genetics in Lung Cancer Etiology study (1,815 cases/1,971 controls), we computed pathway-level susceptibility effects as the sum of relevant single-nucleotide polymorphism (SNP) variant alleles weighted by their log-additive effects from a separate lung cancer GWAS meta-analysis (7,766 cases/37,482 controls). Logistic regression models based on age, sex, smoking, genetic variants, and principal components of pathway effects and pathway-smoking interactions were trained and optimized in cross-validation, and further tested on an independent dataset (556 cases/830 controls). We assessed prediction performance using area under the receiver operating characteristic curve (AUC).Compared to typical binomial prediction models which have epidemiologic predictors (AUC = 0.607) in addition to top GWAS variants (AUC = 0.617), our pathway-based smoking-interactive multinomial model significantly improved prediction performance in external validation (AUC = 0.656, P < 0.0001).Our biologically informed approach demonstrated a larger increase in AUC over non-genetic counterpart models relative to previous approaches that incorporate variants.This model is the first of its kind to evaluate lung cancer prediction using subtype-stratified genetic effects organized into pathways and interacted with smoking. We propose pathway-exposure interactions as a potentially powerful new contributor to risk inference.
Pub.: 26 May '16, Pinned: 06 Apr '17
Abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease that is refractory to treatment and carries a high mortality rate. IPF is frequently associated with lung cancer. Identification of molecular targets involved in both diseases may elucidate novel molecular mechanisms contributing to their pathology. Recent studies of microRNA (miRNA) expression signatures showed that microRNA-29a (miR-29a) was downregulated in IPF and lung cancer. The aim of this study was to investigate the functional significance of miR-29a in lung cancer cells (A549 and EBC-1) and lung fibroblasts (MRC-5) and to identify molecular targets modulated by miR-29a in these cells. We confirmed the downregulation of miR-29a in clinical specimens of IPF and lung cancer. Restoration of miR-29a suppressed cancer cell aggressiveness and fibroblast migration. A combination of gene expression data and in silico analysis showed that a total of 24 genes were putative targets of miR-29a. Among them, lysyl oxidase-like 2 (LOXL2) and serpin peptidase inhibitor clade H, member 1 (SERPINH1) were direct targets of miR-29a by luciferase reporter assays. The functions of LOXL2 and SERPINH1 contribute significantly to collagen biosynthesis. Overexpression of LOXL2 and SERPINH1 was observed in clinical specimens of lung cancer and fibrotic lesions. Downregulation of miR-29a caused overexpression of LOXL2 and SERPINH1 in lung cancer and IPF, suggesting that these genes are involved in the pathogenesis of these two diseases.Journal of Human Genetics advance online publication, 4 August 2016; doi:10.1038/jhg.2016.99.
Pub.: 05 Aug '16, Pinned: 06 Apr '17
Abstract: Lung cancer is one of the most prevalent malignant tumors, and is one of the primary causes of cancer-associated deaths. In 2002, an estimated 1.18 million lung cancer-associated deaths were recorded, accounting for 18% of cancer-related deaths and 2% of total mortality. Despite the great progress that has been made in lung cancer therapies, the mechanisms underlying lung cancer formation and development remain largely unknown. Meanwhile, the microRNA miR-129 has been shown to be involved in the formation of many types of cancer. Therefore, this study aims to investigate whether miR129b could suppress proliferation of lung cancer cell lines. NSCLC tissue samples were collected from the Department of Respiratory Medicine between April 2013 and December 2015. Ten normal health individuals were recruited as controls. Lung cancer cell lines A549 and H1299 were used to examine the suppressive effects of miR129b. Quantitative real-time PCR was used to detect miR129b expression. The MTT assay was used to analyze cell proliferation. Results indicated that miR-129b is down-regulated in lung cancer cell lines and NSCLC tissues. Furthermore, overexpression of miR-129b inhibited proliferation of lung cancer cells. In conclusion, miR-129b suppresses lung cancer cell proliferation, and can be a potential therapeutic target for treatment of lung cancers.
Pub.: 05 Nov '16, Pinned: 06 Apr '17
Abstract: Cigarette smoking is the top environmental risk factor for lung cancer. Nicotine, the addictive component of cigarettes, induces lung cancer cell proliferation, invasion and migration via the activation of nicotinic acetylcholine receptors (nAChRs). Genome-wide association studies (GWAS) show that CHRNA5 gene encoding α5-nAChR is especially relevant to lung cancer. However, the mechanism of this subunit in lung cancer is not clear. In the present study, we demonstrate that the expression of α5-nAChR is correlated with phosphorylated STAT3 (pSTAT3) expression, the smoking history and lower survival of non-small cell lung cancer (NSCLC) samples. Nicotine increased the levels of α5-nAChR mRNA and protein in NSCLC cell lines and activated the JAK2/STAT3 signaling cascade. Nicotine-induced activation of JAK2/STAT3 signaling was inhibited by the silencing of α5-nAChR. Characterization of the CHRNA5 promoter revealed four STAT3-response elements. ChIP assays confirmed that the CHRNA5 promoter contains STAT3 binding sites. By silencing STAT3 expression, nicotine-induced upregulation of α5-nAChR was suppressed. Downregulation of α5-nAChR and/or STAT3 expression inhibited nicotine-induced lung cancer cell proliferation. These results suggest that there is a feedback loop between α5-nAChR and STAT3 that contributes to the nicotine-induced tumor cell proliferation, which indicates that α5-nAChR is an important therapeutic target involved in tobacco-associated lung carcinogenesis.
Pub.: 21 Mar '17, Pinned: 06 Apr '17