Lin Peng

Chronic cadmium exposure is linked to esophageal squamous cell carcinoma (ESCC) progression, treatment resistance, and poor prognosis, but its molecular mechanisms remain unclear. Based on whole-transcriptome sequencing (RNA-seq) on chronic cadmium-treated (CCT) and untreated human EC109 ESCC cells, we performed lncRNA-mRNA co-expression and protein-protein interaction (PPI) network analyses to screen the hub genes related to cadmium exposure. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses depicted that these genes were mainly enriched in nucleocytoplasmic transport, ferroptosis, Huntington disease, and cellular senescence. Based on the lncRNA-miRNA-mRNA potential interaction, three lncRNAs (AC107068.1, TTN-AS1, MAPKAPK5-AS1) and ten mRNAs (IPO5, NUDCD1, OSTM1, CCNB1, FANCD2, TFRC, POLR2B, HTT, NUP43, NBN) were selected for competitive endogenous RNA (ceRNA) network construction. Connectivity map (CMap) analysis for the target mRNAs showed that JAK3-inhibitor-I was the most promising therapeutic drug for cadmium-induced ESCC progression. The prognostic value and abnormal expression of the candidate mRNAs were then validated in TCGA cohorts, cadmium-treated cancer cells and 41 ESCC specimens. Moreover, migration and invasion assays were performed to assess the effects of the identified gene on cell malignant phenotypes. As a result, IPO5 was identified as the pivotal gene and MAPKAPK5-AS1-hsa-miR-379-5p-IPO5 was deemed as a potential ceRNA regulatory mechanism for cadmium carcinogenesis in ESCC. Using TIMER and EPIC algorithms, IPO5 was correlated with increased infiltration of CD4⁺ T cells and macrophages, while negatively associated with CD8⁺ T cells and NK cells in ESCC tissues. Collectively, our study provides valuable information in understanding the molecular mechanisms involved in cadmium-induced ESCC progression and treatment resistance. Furthermore, we predict potential agents for cadmium carcinogenicity prevention and treatment.

Introduction: Existing epidemiological and experimental evidence have unveiled individual PBDE congeners facilitate the initiation of breast cancer. However, the comprehensive molecular mechanisms by which PBDE mixtures contribute to breast cancer pathogenesis remains poorly understood. This study aims to identify the PBDE congeners that preferentially accumulate in female adipose tissues and to intricate their interactions and key targets and molecular pathways implicated in breast cancer tumorigenesis.Materials and methods: Adipose tissue specimens were collected from 183 patients with breast cancer and 145 women with benign breast disease or non breast-related diseases. Adipose PBDEs concentrations were determined by gas chromatograph-mass spectrometer. The ChEMBL, STITCH, GeneCards, OMIM, TCGA-BRCA databases, as well as a protein-protein interaction (PPI) network, were utilized to identify the primary targets of PBDEs and their interactions. Molecular docking was performed using Autodock Vina to validate the binding affinities between chemicals and targets. Functional enrichment analysis was then performed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Machine learning strategies were applied to refine core genes involved in pathogenesis of breast cancer.Results: BDE-47, BDE-138, BDE-153, BDE-183 and BDE-209 were recognized as the major PBDE congeners accumulated in adipose tissues. The top 20 candidate target genes were enriched for response to chemical stress, gland development, protein ligase binding, lipid and atherosclerosis and chemical carcinogenesis. The intersected genes and pathways between breast cancer and chemical carcinogenesis revealed significant associations with pathways in the PD-1/PD-L1 checkpoint and the HIF-1 signaling pathway. Machine learning strategies nominated CASP3, ESR1, MMP9, PARP1, and PPARG as crucial genes involved in breast cancer pathogenesis, exhibiting high-affinity binding to the major PBDE congeners.Conclusion: This integrative network study uncovers a mechanistic framwork linking adipose-accumulated PBDE mixtures to breast cancer pathogenesis. These findings provide insights for preventive and therapeutic interventions against PBDE-associated breast cancer.

Toxic elements exposure and imbalance in essential element homeostasis remain incomprehensive in esophageal squamous cell carcinoma (ESCC) carcinogenesis, especially in tumor progression. To reveal the toxic and essential elements inside body associated with ESCC occurrence, aggressive features and outcomes, whole blood concentrations of eight trace elements were quantified in 150 ESCC cases and 177 controls using inductively coupled plasma-mass spectrometry (ICP-MS). Concentrations of cadmium (Cd), lead (Pb), chromium (Cr), copper (Cu), arsenic (As), and selenium (Se) showed significant differences between the case and control subjects. The restricted cubic spline (RCS) analysis showed As, Zinc (Zn), and manganese (Mn) was linked with ESCC risk in a U-shaped pattern, whereas an inverted U-shaped curve for Cd (all P-non-linear < 0.05). Contrary to Se, the elements Pb, Cr and Cu were positively associated with ESCC risk. By Bayesian Kernel Machine Regression models, the mixtures of the eight trace elements were found to be significantly associated with ESCC risk and metastasis, with Cr, Mn, Cu, Zn, and Pb having a PIP of 1.000 for occurrence risk and Mn being the main contributor for metastatic risk (PIP = .6570). The weighted quantile sum (WQS) model consistently showed that Cu, Cr, Pb, and Cd ranked as the top four positive elements for ESCC risk. Multivariable logistic regression analysis indicated Pb and As were positively associated with tumor invasion (adjusted OR 3.024 [1.053–8.689]; OR 4.385 [1.271–15.126], respectively), whereas Se had the opposite trend (adjusted OR 0.261 [0.074–0.927). Patients with high Cr, Mn, or Pb showed worse overall survival (OS), and high Mn were linked to inferior progression-free survival (PFS) (all P < 0.05). Zn and Pb, and Mn and Cu were identified as independent prognostic factors for OS and PFS, respectively. This study suggests trace element disbalance in human body contributes to the risk of onset and progression of ESCC, especially in a high-incidence region. Further epidemiological and experimental studies were needed to clarify the probable pathogenic processes underpinning the potential link between trace element mixtures and ESCC.

Absence of effective prognostic biomarkers and therapeutic targets for reversing chemoresistance of endometrial carcinoma (EC) remains a huge challenge for clinicians. Mitophagy plays a crucial role in carcinogenesis and chemoresistance. FUN14 domain-containing protein 1 (FUNDC1) is a novel mitophagy receptor protein involved in tumorigenesis under hypoxic conditions. However, the implication of FUNDC1 in EC progression, chemoresistance in particular, remains unclear. Based on The Cancer Genome Atlas (TCGA) cohort, comprised of 403 EC patients, the association of FUNDC1 mRNA levels with hypoxia-inducible factor 1α (HIF-1α) expression, clinicopathologic features and prognosis in EC was analyzed, and subsequently verified utilizing immunohistochemistry of 288 EC specimens. Analysis of the cohort in TCGA showed that patients with higher FUNDC1 levels exhibited worse OS, with the shortest OS exhibited by patients with co-upregulated FUNDC1 and HIF-1α (P < 0.05). Analysis of the validation cohort indicated that OS and PFS rates of high-FUNDC1 patients were lower than that of low-FUNDC1 group (P < 0.05). Cases with co-downregulation of FUNDC1 and HIF-1α had higher OS and PFS rates than those with co-upregulation of these two proteins (88.8% vs. 71.2%, P = 0.002; 85.6% vs. 71.2%, P = 0.009). Higher FUNDC1 expression was observed in platinum-resistant patients. Multivariate Cox regression analysis revealed that FUNDC1 expression, FIGO stage, lymphatic invasion, depth of myometrial invasion, and ascites were independent risk factors for OS and PFS. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that FUNDC1 was closely related to spliceosome, neurodegeneration pathways of multiple diseases, and cell cycle signaling pathways. Significantly enriched RNA splicing and ncRNA processing were identified in Gene Ontology (GO) analysis. Gene set enrichment analysis (GSEA) indicated that abnormal expression of FUNDC1 was involved in endometrial cancer, NOD-like receptor signaling pathway and cytokine signaling in the immune system. In addition, immune cell infiltration analysis by Tumor Immune Estimation Resources (TIMER) database and the Xiantao academic tool demonstrated that FUNDC1 expression was strongly associated with the infiltration of Th2, NK, Th17, Tem, pDC, neutrophil, MDSC, CD4+ T, and γδ T cells. Knockdown of FUNDC1 using shRNA in HEC-1B and Ishikawa EC cells inhibited proliferation, migration and invasion, accompanied by enhanced chemotherapeutic susceptibility to carboplatin and paclitaxel. Accordingly, FUNDC1 could be a prospective prognostic biomarker and potential therapeutic target for EC.

Accurate risk stratification for patients with serous ovarian cancer (SOC) is pivotal for treatment decisions. In this study, we identified a lncRNA-based signature for predicting platinum resistance and prognosis stratification for SOC patients. We analyzed the RNA-sequencing data and the relevant clinical information of 295 SOC samples obtained from The Cancer Genome Atlas (TCGA) database and 180 normal ovarian tissues from the Genotype-Tissue Expression (GTEx) database. A total of 284 differentially expressed lncRNAs were screened out between platinum-sensitive and platinum-resistant groups by univariate Cox regression analysis. Then, a signature consisting of eight prognostic lncRNAs was used to construct a lncRNA score model by least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis. The ROC analysis showed that this signature had a good predictive performance for chemotherapy response in the training set (AUC = 0.8524) and the testing and whole sets with 0.8142 and 0.8393 of AUC, respectively. Dichotomized by the risk score of lncRNAs (lncScore), the high-risk patients showed significantly shorter progression-free survival (PFS) and overall survival (OS). Based on the final Cox model, a nomogram comprising the 8-lncRNA signature and 3 clinicopathological risk factors was then established for clinical application to predict the 1, 2, and 3-year PFS of SOC patients. The gene set enrichment analysis (GSEA) revealed that genes in the high-risk group were active in ATP synthesis, coupled electron transport, and mitochondrial respiratory chain complex assembly. Overall, our findings demonstrated the potential clinical significance of the 8-lncRNA-based classifier as a novel biomarker for outcome prediction and therapy decisions in SOC patients with platinum treatment.

DNA N6-methyladenosine (6mA) is a novel epigenetic signaling modification in humans and has been implicated in the progression and tumorigenesis of several cancers. However, the function and mechanism of 6mA in breast cancer (BC), the most common cancer among women, are unclear. Here, we found that decreases in N6AMT1 correlated with the extent of 6mA in clinical BC tissues and predicted a worse survival of BC patients. Functionally, knockdown of N6AMT1 markedly reduced 6mA in DNA and promoted colony formation and migration of BC cells, whereas overexpression of N6AMT1 had the opposite effect. Moreover, silencing of N6AMT1 reduced 6mA modification and enhanced the growth of BC cells in vitro and tumors in vivo. 6mA immunoprecipitation sequencing (6mA-IP-seq), RNA-seq, 6mA-IP-PCR, and bioinformatics analysis indicated that N6AMT1 was a functional methyltransferase for genomic 6mA DNA modifications and related to gene transcriptional activity. Critical negative regulators of the cell cycle, such as RB1, P21, REST, and TP53 were identified as targets of N6AMT1 in BC. These results suggest N6AMT1 enhances DNA 6mA levels to repress tumor progression via transcriptional regulation of cell cycle inhibitors.

Cadmium (Cd) exposure has been implicated in the etiology of esophageal squamous cell carcinoma (ESCC), albeit with inconsistent results from epidemiologic studies and without causal evidence. In this study, we explore the relationship of Cd exposure and the development, progression and therapeutic resistance of ESCC. A total of 150 ESCC patients and 177 matched controls from a coastal region with a high incidence of ESCC in China were included in the study. It was found that the median blood Cd level (BCL) was significantly higher in ESCC patients than that in the controls. Odds ratios for ESCC risk were 3.12 (95% CI 1.54-6.30) and 3.71 (95% CI 1.84-7.48) in the third and fourth quartiles of Cd distribution, respectively. Notably, BCL above 4.71 μg/L was strongly associated with shorter progression-free survival time compared to that below 1.60 μg/L (p < 0.001). The chronic Cd-treated ESCC cells (CCT-ESCC) CCT-EC109 and CCT-EC9706 exhibited increased cell proliferation and tumorigenesis, enhanced migration and invasion, and upregulated EMT biomarkers following 12 weeks of exposure to 5 μM cadmium chloride. Furthermore, Cd treatment attenuated the efficacy of 5-fluorouracil, cisplatin and irradiation treatment in CCT-ESCC cells both in vitro and in vivo. Moreover, we revealed that Cd stimulated the cancer cell stemness and Wnt/β-catenin signaling pathway in the CCT-ESCC cells. Additionally, 5-aza-2-deoxy-cytidine treatment resulted in suppression of the Wnt/β-catenin signaling pathway and rescue of the Cd-induced cell radioresistance. These results offer new insights into the role of environmental Cd exposure in the development, progression and chemoradioresistance of ESCC.