Emerging evidence highlights the role of thyroid hormones in cancer, although findings are controversial. Research on thyroid-related traits in lung carcinogenesis is limited. Using UK Biobank data, we performed bidirectional Mendelian randomization (MR) to assess causal associations between lung cancer risk and thyroid dysfunction (hypothyroidism and hyperthyroidism) or functional traits (free thyroxine [FT4] and normal-range thyroid-stimulating hormone [TSH]). Furthermore, in the smoking-behavior-stratified MR analysis, we evaluated the mediating effect of thyroid-related phenotypes on the association between smoking behaviors and lung cancer. We demonstrated significant associations between lung cancer risk and hypothyroidism (hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 1.03-1.26, P = 0.009) and hyperthyroidism (HR = 1.55, 95% CI = 1.29-1.87, P = 1.90 × 10⁻⁶) in the UKB. Moreover, the MR analysis indicated a causal effect of thyroid dysfunction on lung cancer risk (OR_{inverse variance weighted [IVW]} = 1.09, 95% CI = 1.05-1.13, P = 3.12 × 10⁻⁶ for hypothyroidism; OR_IVW = 1.08, 95% CI = 1.04-1.12, P = 8.14 × 10⁻⁵ for hyperthyroidism). We found that FT4 levels were protective against lung cancer risk (OR_IVW = 0.93, 95% CI = 0.87-0.99, P = 0.030). Additionally, the stratified MR analysis demonstrated distinct causal effects of thyroid dysfunction on lung cancer risk among smokers. Hyperthyroidism mediated the effect of smoking behaviors, especially the age of smoking initiation (17.66% mediated), on lung cancer risk. Thus, thyroid dysfunction phenotypes play causal roles in lung cancer development exclusively among smokers and act as mediators in the causal pathway from smoking to lung cancer.

In the present study, we aimed to investigate whether anlotinib reverses osimertinib resistance by inhibiting the formation of epithelial-mesenchymal transition (EMT) and angiogenesis. In a clinical case, anlotinib reversed osimertinib resistance in non-small cell lung cancer (NSCLC). Therefore, we performed immunohistochemical analyses on tumor tissues from three NSCLC patients with osimertinib resistance to analyze alterations in the expression levels of EMT markers and vascular endothelial growth factor A (VEGFA) before and after the development of osimertinib resistance. The results revealed the downregulation of E-cadherin, coupled with the upregulation of vimentin and VEGFA in tumor tissues of patients exhibiting osimertinib resistance, compared with those in tissues from patients before receiving osimertinib. Subsequently, we established osimertinib-resistant (Osi-R) cell lines and found that the Osi-R cells acquired EMT features. Next, we analyzed the synergistic effects of the combination therapy to verify whether anlotinib could reverse osimertinib resistance by inhibiting EMT. The expression levels of VEGFA and tube formation were analyzed in the combination group in vitro. Finally, we determined the reversal of osimertinib resistance by the combination of osimertinib and anlotinib in vivo using 20 nude mice. The combined treatment of osimertinib and anlotinib effectively prevented the metastasis of Osi-R cells, inhibited tumor growth, exerted antitumor activity, and ultimately reversed osimertinib resistance in mice. The co-administration of osimertinib and anlotinib demonstrated synergistic efficacy in inhibiting EMT and angiogenesis in three NSCLC patients, ultimately reversing osimertinib resistance.

The present study assessed the efficacy and safety of thoracic radiotherapy (TRT) following first-line chemotherapy or chemoimmunotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC), focusing on the influence of different TRT timing strategies (consolidative vs. salvage) on survival rates. We retrospectively analyzed a total of 54 patients with ES-SCLC treated between January 2019 and July 2022. Patients receiving consolidative TRT (cTRT) within three months after completion of first-line treatment were compared with those receiving salvage TRT (sTRT) after disease progression. The primary endpoints were overall survival (OS), progression-free survival (PFS), locoregional-free survival (LRFS), and distant metastasis-free survival (DMFS); the secondary endpoint included safety. The cTRT group (n = 41) showed significantly longer median OS (26.6 vs. 14.8 months, P = 0.048), PFS (12.9 vs. 3.5 months, P < 0.0001), and DMFS (10.7 vs. 3.4 months, P = 0.0044) than the sTRT group (n = 13). Multivariate analysis revealed that cTRT was an independent, favorable prognostic factor. No significant differences in OS or LRFS were observed between high-dose (≥ 50 Gy) and low-dose (< 50 Gy) TRT. Hematologic and respiratory toxicities were the most frequently reported adverse events, with acceptable tolerability. In conclusion, cTRT after chemoimmunotherapy significantly improves survival outcomes for ES-SCLC patients, and low-dose TRT may be a suitable option.

Bone metastasis is the primary cause of mortality in breast cancer (BC) patients. The present study elucidates the functional role of the differentiated embryonic chondrocyte-expressed gene 1 (DEC1) in promoting BC-related bone metastasis. Analysis of patient-derived samples and public databases revealed a significant upregulation of DEC1 and CXCR4 in breast tumors compared with adjacent normal tissues, with elevated levels correlating with increased metastatic potential, suggesting their synergistic involvement in BC progression. Intracardiac injection experiments demonstrated that Dec1-WT 4T1 cells induced more severe osteolysis and larger metastatic lesions than Dec1-KD 4T1 cells. In MDA-MB-231 cells, DEC1 overexpression (OE) upregulated CXCR4 and proliferation/migration-related genes, whereas DEC1 knockdown reversed these effects. Notably, AMD3100, a specific CXCR4 antagonist, partially reversed the DEC1-OE-induced upregulation of CXCR4 and associated pro-metastatic genes. Mechanistically, DEC1 bound to the CXCR4 promoter region (−230 to −326) and activated its transcription, corroborated by ChIP-seq data. Furthermore, pharmacological inhibition of AKT (LY294002) or JAK2 (AZD1480), but not ERK (PD98059), attenuated DEC1-mediated CXCR4 upregulation, although all three inhibitors mitigated DEC1-driven migration-related gene expression. Additionally, DEC1 enhanced CXCL12 secretion from mesenchymal stromal cells and osteoblasts, amplifying the CXCR4/CXCL12 axis within the bone microenvironment. Collectively, our findings demonstrate that DEC1 promotes BC bone metastasis by directly transactivating CXCR4 expression, providing a molecular basis for targeting DEC1 to prevent and treat BC bone metastasis.

Gastric cancer (GC) is a prevalent and devastating disease with a poor prognosis. The lack of biomarkers for early detection and effective targeted therapeutics for GC patients represents two major challenges. Through isobaric tags for relative and absolute quantitation (iTRAQ) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) phosphoproteomic analysis of 14 GC and gastric epithelial cell lines, we discovered the discoidin domain receptor tyrosine kinase 1 (DDR1) as a top potential drug target out of 40 tyrosine kinases detected along with over 1000 phosphoproteins profiled. The DDR1 protein and mRNA levels were upregulated in GC cells concurrent with DDR1 gene amplification. Immunohistochemistry staining of more than 200 clinical samples revealed that DDR1 was overexpressed in approximately 41% and 48% of the intestinal and diffuse types of GC cases, respectively, compared with only 3.5% in normal tissues. Higher DDR1 expression was associated with poor prognosis. In cellular models, DDR1 overexpression led to accelerated proliferation, invasion, and malignant transformation, putatively via inhibition of the Hippo pathway and consequent activation of YAP-TEAD target gene expression. Notably, DDR1-overexpressing GC cells exhibited high vulnerability to selective DDR1 inhibitors. The present study provides preclinical support for the application of DDR1-selective inhibitors in DDR1-overexpressing GC.

Hepatocellular carcinoma (HCC) remains the third leading cause of cancer-related deaths worldwide; however, its therapeutic options are limited. Understanding the molecular mechanisms of HCC could provide insight into new therapies. Emerging studies indicate the important role of long-noncoding RNAs (lncRNAs) in the pathogenesis of HCC. The expression of the well-studied lncRNA taurine upregulated gene 1 (TUG1) is upregulated in HCC tissues, but its transcriptomic effects in HCC cells remain unexplored. We established TUG1-knockdown and control HCC cells for RNA-seq experiments. KEGG analysis revealed glycolysis as the top enriched pathway upon TUG1 silencing. Accordingly, TUG1-depleted HCC cells showed impairments in glucose uptake, ATP synthesis, and lactate production. Clinical HCC tissue data revealed positive gene expression correlations between TUG1 and several glycolysis-related genes. To identify a molecular function of TUG1 in glycolysis, we explored the competing endogenous model and used bioinformatic tools to find the five microRNAs (miRNAs) that had the most binding sites for TUG1. Among these miRNAs, miR-122-5p exhibited an inverse correlation in gene expression with most TUG1-regulated glycolysis genes, including PKM, ALDOA, ENO2, and PFKM. Dual-luciferase assays demonstrated the direct interaction between TUG1 and miR-122-5p and between miR-122-5p and the 3ʹ untranslated regions of both PKM and ALDOA. We further showed that inhibition of miR-122-5p alleviated the suppression of glycolysis induced by TUG1 depletion. Together, our RNA-seq analysis of TUG1-depleted HCC cells, combined with clinical data, reveals a critical role of TUG1 in regulating glycolysis and provides new insight into its oncogenic function in HCC.

The effect of prenatal exposure to ambient particulate matter (PM) on birth weight varies considerably across studies, and the findings remain inconclusive. In this study, we conducted a meta-analysis to assess the associations between exposure to PM_2.5 and PM₁₀ and birth weight. A total of 74 studies were identified through searches in Web of Science, PubMed, Embase, and Ovid Medline, as well as manual searches, up to October 2024. We found that for each 10 μg/m³ increase in PM_2.5, the risk of low birth weight (LBW) increased significantly during the entire pregnancy (odds ratio [OR] = 2.41, 95% confidence interval [CI]: 1.99-2.91) and in all trimesters. Similarly, for every 10 μg/m³ increase in PM₁₀ concentration, the risk of LBW increased significantly during the entire pregnancy (OR = 1.46, 95% CI: 1.16-1.84). Subgroup analysis by maternal age for PM_2.5 showed that mothers aged 30 and above had a significantly higher risk of LBW (OR = 3.69, 95% CI: 2.81-4.84), compared with those under 30. In conclusion, maternal exposure to PM_2.5 and PM₁₀ is associated with an increased risk of LBW across all trimesters. Additionally, mothers aged 30 and above are at a higher risk of LBW, compared with younger mothers. Further research is needed to clarify the biological mechanisms by which PM pollution may contribute to LBW.