RESUMO
Background: Lung squamous cell carcinoma (LSCC) is a major subtype of lung cancer with poor prognosis and low survival rate. Compared with lung adenocarcinoma, yet no FDA-approved targeted-therapy has been found for lung squamous cell carcinoma. Methods: To identify potential drug targets for LSCC, Summary-data-based Mendelian randomization (SMR) analysis was used to examine the potential association between 4,543 druggable genes and LSCC, followed by colocalization analysis and HEIDI tests to confirm the robustness of the result. Phenome-wide association study (PheWAS) explored potential side effects of candidate drug targets. Enrichment analysis and protein-protein interaction networks revealed the function and significance of therapeutic targets. Single-cell expression analysis was used to examine cell types with enrichment expression of druggable genes in LSCC tissue. Drug prediction included screening potential drug candidates and evaluating their interactions with targets through molecular docking. Results: This research has identified ten significant drug targets for LSCC through a comprehensive SMR analysis. These targets included (COPA, PKD2L1, CCR1, C2, CYP21A2, and NCSTN as risk factors, and CCNA2, C4A, APOM, and LPAR2 as protective factors). PheWAS demonstrated that C2, CCNA2, LPAR2, and NCSTN exhibited associations with other phenotypes at the genetic level. Then, we found four potentially effective drugs with the Dsigdb database. Subsequently, molecular docking indicated that favorable binding interactions between drug candidates and potential target molecules. In the druggability evaluation, five out of ten drug target genes have been used in drug development (APOM, C4A, CCNA2, COPA, and PKD2L1). Six out of ten druggable genes showed significant expression in LSCC tissues (COPA, PKD2L1, CCR1, C2, NCSTN, LPAR2). Besides, Single-cell expression analysis revealed that C2 and CCNA2 were primarily enriched in macrophages, while COPA and NCSTN were enriched in both macrophages and epithelial cells. Conclusion: Our research revealed ten potential druggable genes for LSCC treatment, which might help to advance the precise and efficient therapeutic approaches of LSCC.
RESUMO
Background: This study was designed to evaluate the effects of body mass index (BMI) and weight change on the risk of developing cancer overall and cancer at different sites. Methods: We searched PubMed and other databases up to July 2023 using the keywords related to 'risk', 'cancer', 'weight', 'overweight', and 'obesity'. We identified eligible studies, and the inclusion criteria encompassed cohort studies in English that focused on cancer diagnosis and included BMI or weight change as an exposure factor. Multiple authors performed data extraction and quality assessment, and statistical analyses were carried out using RevMan and R software. We used random- or fixed-effects models to calculate the pooled relative risk (RR) or hazard ratio along with 95% confidence intervals (CIs). We used the Newcastle-Ottawa Scale to assess study quality. Results: Analysis included 66 cohort studies. Compared to underweight or normal weight, overweight or obesity was associated with an increased risk of endometrial cancer, kidney cancer, and liver cancer but a decreased risk of prostate cancer and lung cancer. Being underweight was associated with an increased risk of gastric cancer and lung cancer but not that of postmenopausal breast cancer or female reproductive cancer. In addition, weight loss of more than five kg was protective against overall cancer risk. Conclusions: Overweight and obesity increase the risk of most cancers, and weight loss of >5 kg reduces overall cancer risk. These findings provide insights for cancer prevention and help to elucidate the mechanisms underlying cancer development. Registration: Reviewregistry1786.