Thirdhand smoke exposure promotes gastric tumor development in mouse and human.

The pollution of indoor environments and the consequent health risks associated with thirdhand smoke (THS) are increasingly recognized in recent years. However, the carcinogenic potential of THS and its underlying mechanisms have yet to be thoroughly explored. In this study, we examined the effects of short-term THS exposure on the development of gastric cancer (GC) in vitro and in vivo. In a mouse model of spontaneous GC, CC036, we observed a significant increase in gastric tumor incidence and a decrease in tumor-free survival upon THS exposure as compared to control. RNA sequencing of primary gastric epithelial cells derived from CC036 mice showed that THS exposure increased expression of genes related to the extracellular matrix and cytoskeletal protein structure. We then identified a THS exposure-induced 91-gene expression signature in CC036 and a homologous 84-gene signature in human GC patients that predicted the prognosis, with secreted phosphoprotein 1 (SPP1) and tribbles pseudokinase 3 (TRIB3) emerging as potential targets through which THS may promote gastric carcinogenesis. We also treated human GC cell lines in vitro with media containing various concentrations of THS, which, in some exposure dose range, significantly increased their proliferation, invasion, and migration. We showed that THS exposure could activate the epithelial-mesenchymal transition (EMT) pathway at the transcript and protein level. We conclude that short-term exposure to THS is associated with an increased risk of GC and that activation of the EMT program could be one potential mechanism. Increased understanding of the cancer risk associated with THS exposure will help identify new preventive and therapeutic strategies for tobacco-related disease as well as provide scientific evidence and rationale for policy decisions related to THS pollution control to protect vulnerable subpopulations such as children.

Multi-target tyrosine kinase inhibitor nanoparticle delivery systems for cancer therapy.

Multi-target Tyrosine Kinase Inhibitors (MTKIs) have drawn substantial attention in tumor therapy. MTKIs could inhibit tumor cell proliferation and induce apoptosis by blocking the activity of tyrosine kinase. However, the toxicity and drug resistance of MTKIs severely restrict their further clinical application. The nano pharmaceutical technology based on MTKIs has attracted ever-increasing attention in recent years. Researchers deliver MTKIs through various types of nanocarriers to overcome drug resistance and improve considerably therapeutic efficiency. This review intends to summarize comprehensive applications of MTKIs nanoparticles in malignant tumor treatment. Firstly, the mechanism and toxicity were introduced. Secondly, various nanocarriers for MTKIs delivery were outlined. Thirdly, the combination treatment schemes and drug resistance reversal strategies were emphasized to improve the outcomes of cancer therapy. Finally, conclusions and perspectives were summarized to guide future research.

Molecular Characteristics, Clinical Significance, and Cancer Immune Interactions of Angiogenesis-Associated Genes in Gastric Cancer.

Background: Immunotherapy has evolved as a critical option to treat diverse cancers. The active response to immunotherapy relies on the unique interaction between cancer and the tumor microenvironment (TME). Angiogenesis is one of the hallmarks of cancer. However, the association between angiogenesis and clinical outcome, immune cell infiltration, and immunotherapy remains unknown in gastric cancer (GC). Methods: We systematically assessed 36 angiogenesis-associated genes (AAGs) and comprehensively identified the correlation between angiogenesis and transcriptional patterns, prognosis, and immune cell infiltration. The AAG_score was applied to quantify the angiogenesis subtypes of each patient. We then evaluated their values in prognostic prediction and therapeutic responses in GC. Results: We discussed the mutations of AAGs in GC specimens from genetic levels and identified their expression patterns from TCGA and GEO cohorts. We determined two different molecular subtypes and observed that AAG mutations were related to patients' clinicopathological characteristics, prognosis, and infiltrating TME. Next, an AAG_score for predicting overall survival (OS) was established and its reliable predictive ability in GC patients was confirmed. Furthermore, we created a highly reliable nomogram to facilitate the clinical viability of the AAG_score. A low AAG_score, characterized by elevated microsatellite instability-high, mutation burden, and immune activation, demonstrated a superior OS. Additionally, the AAG_score was remarkedly correlated with the cancer stem cell index and drug susceptibility. Conclusion: Collectively, we identified a prognostic AAG signature for GC patients. This signature may contribute to clarifying the characteristics of TME and enable the exploration of more potent immunotherapy strategies.

High expression of S100A2 predicts poor prognosis in patients with endometrial carcinoma.

BACKGROUND: S100A2, a member of the S100 protein family, is abnormally expressed and plays a vital role in multiple cancers. However, little is known about the clinical significance of S100A2 in endometrial carcinoma. METHODS: Clinicopathological data were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Omnibus (GEO), and Clinical Proteomic Tumor Analysis Consortium (CPTAC). First, the expression and prognostic value of different S100 family members in endometrial carcinoma were evaluated. Subsequently, the Kaplan-Meier plotter and Cox regression analysis were used to assess the prognostic significance of S100A2, while the association between S100A2 expression and clinical characteristics in endometrial carcinoma was also analyzed using logistic regression. A receiver operating characteristic (ROC) curve and a nomogram were constructed. The putative underlying cellular mechanisms were explored using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and gene set enrichment analysis (GSEA). RESULTS: Our results revealed that S100A2 expression was significantly higher in endometrial carcinoma tissue than in non-cancerous tissue at both the mRNA and protein levels. Analysis of Kaplan-Meier plotter data revealed that patients with high S100A2 expression had shorter overall survival (OS) and disease specific survival (DSS) compared with those of patients with low S100A2 expression. Multivariate Cox analysis further confirmed that high S100A2 expression was an independent risk factor for OS in patients with endometrial carcinoma. Other clinicopathologic features found to be related to worse prognosis in endometrial carcinoma included age, clinical stage, histologic grade, and tumor invasion. Importantly, ROC analysis also confirmed that S100A2 has a high diagnostic value in endometrial carcinoma. KEGG enrichment analysis and GSEA revealed that the estrogen and IL-17 signaling pathways were significantly upregulated in the high S100A2 expression group, in which estrogen response, JAK-STAT3, K-Ras, and TNFα/NF-κB were differentially enriched. CONCLUSIONS: S100A2 plays an important role in endometrial carcinoma progression and may represent an independent diagnostic and prognostic biomarker for endometrial carcinoma.

Lobaplatin Induces Pyroptosis in Cervical Cancer Cells via the Caspase-3/GSDME Pathway.

BACKGROUND: Increasing evidence shows that GSDME is involved in tumor chemotherapy. Lobaplatin is an important chemotherapy drug for the treatment of cervical cancer. However, the exact mechanism of lobaplatin in the treatment of cervical cancer remains unclear. OBJECTIVE: In this study, whether GSDME is a new mechanism of lobaplatin in the treatment of cervical cancer has been explored. METHODS: Cell pyroptosis was measured by Cell Counting Kit-8 and flow cytometry analyses. Western blot analysis was used to check proteins expression. RESULTS: The cell viability was significantly decreased by lobaplatin treatment. Compared with the control group, the percentage of pyroptosis (PI and Annexin-V double-positive cells) increased after lobaplatin treatment. In addition, lobaplatin induced caspase-3 activation and GSDME cleavage. z-DEVD, a specific inhibitor of caspase-3, reduced lobaplatin-mediated GSDME cleavage and concurrently inhibited pyroptosis. More importantly, GSDME deficiency obviously reduced lobaplatin-induced pyroptosis. CONCLUSION: These data demonstrate that caspase-3/GSDME axis contributed to the lobaplatin-mediated pyroptosis in cervical cancer cells. This finding indicates that GSDME-mediated pyroptosis is a new mechanism for lobaplatin to kill tumor cells and suggests that the caspase-3/GSDME pathway offers new insights into cancer chemotherapy.

A novel human monoclonal Trop2-IgG antibody inhibits ovarian cancer growth in vitro and in vivo.

Trop2 is a tumor-related antigen closely related to the development of a variety of tumors and has been identified as a promising target for cancer immunotherapy. In this study, a Trop2-IgG antibody was constructed by a eukaryotic expression system based on our previously constructed Trop2-Fab antibody. SDS-PAGE, cell ELISA, affinity assays, fluorescence staining and FACS analyses were performed to characterize Trop2-IgG. Then, CCK-8, wound healing, Transwell and annexin V-PI assays were employed to evaluate the tumor inhibitory effects of Trop2-IgG on OC in vitro, while tumor-bearing mice were constructed to examine the tumor inhibitory effects of Trop2-IgG on OC in vivo. Trop2-IgG was successfully constructed by a eukaryotic expression system and maintained recognition characteristics to Trop2 antigen. In vitro, Trop2-IgG could inhibited tumor cell growth, migration, and invasion compared to those of control cells and induced tumor cell apoptosis. In vivo, Trop2-IgG exerted critical tumor inhibitory effects in OC xenografts. Our data suggest that the use of Trop2-IgG provides a potential therapeutic strategy for the immunotherapy of Trop2-expressing OC.

Antitumor activity of a newly developed monoclonal antibody against ROR1 in ovarian cancer cells.

Receptor-tyrosine-kinase-like Orphan Receptor 1 (ROR1) is a tyrosine-protein kinase transmembrane receptor and ROR1 overexpression is associated with a poor prognosis in various cancers, including ovarian cancer. Targeting of ROR1 has been evaluated as a novel cancer therapy strategy. This study developed a novel chimeric anti-ROR1 Fab antibody (named ROR1-cFab) and then assessed the antitumor activity of this antibody in ovarian cancer cells, an in vitro model of preclinical cancer therapy. A ROR1-cFab prokaryotic expression vector was constructed from positive fusion cells (splenocytes from mice with high ROR1 immune titers were fused with myeloma cells) after three rounds of sub-clone affinity screening. Then, a variety of assays were employed to assess the binding selectivity and specificity of ROR1-cFab to ROR1 protein. Furthermore, CCK8, flow cytometric apoptosis, wound healing, and Transwell migration assays were used to assess antitumor activity of this newly developed anti-ROR1 antibody in ovarian cancer cells. We demonstrated that ROR1-cFab could specifically bind to ROR1 protein and ROR1-positive ovarian cancer A2780 cells. Functional assays revealed that ROR1-cFab inhibited tumor cell proliferation and migration, as well as inducing apoptosis of ROR1-positive A2780 cells in a dose dependent manner. These effects were not observed in ROR1-negative lose386 cells. In conclusion, ROR1-cFab is a novel anti-ROR1 antibody with a high affinity to ROR1 protein and inhibitory effects on ROR1-positive cells. Future studies will determine whether the ROR1-cFab might be a promising candidate for treatment of ROR1-positive ovarian cancer.

ROR1 expression correlated with poor clinical outcome in human ovarian cancer.

The receptor-tyrosine-kinase-like orphan receptor 1 (ROR1) is a transmembrane protein belongs to receptor tyrosine kinase (RTK) family. This study aimed to examine the expression of ROR1 in human ovarian cancer and investigate the relationship between its expression and the prognosis of ovarian cancer patients. In this present study, one-step quantitative reverse transcription-polymerase chain reaction (15 ovarian cancer samples of high FIGO stage, 15 ovarian cancer samples of low FIGO stage and nine normal ovary tissue samples) and immunohistochemistry by tissue microarrays (100 ovarian cancer samples and 50 normal ovary samples) were performed to characterize expression of the ROR1 gene in ovarian cancer. Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of ovarian cancer. The results of qPCR and IHC analysis showed that the expression of ROR1 in ovarian cancer was significantly higher than that in normal ovary tissues (all p < 0.05). Survival analysis showed that ROR1 protein expression was one of the independent prognostic factors for disease-free survival and overall survival (both p < 0.05). The data suggest that ROR1 expression is correlated with malignant attributes of ovarian cancer and it may serve as a novel prognostic marker in ovarian cancer.

The inhibitory effect of a new scFv/tP protein as siRNA delivery system to target hWAPL in cervical carcinoma.

Targeted immunotherapy has become a popular research topic in cancer. The development and metastasis of cervical carcinoma are closely related to epidermal growth factor (EGF) and EGF-1 receptor (EGFR). We successfully constructed a single-chain human anti-EGFR antibody (scFv) and truncated protamine (tP) fusion protein (scFV/tP) expression vector using overlap extension PCR. Enzyme-linked immunosorbent assay and gel shift assay showed that the fusion protein retained the DNA and antigen-binding activity of the original antibody. Using the non-viral scFv/tP vector as a delivery tool, small interfering RNA (siRNA) of the human wings apart-like gene (hWAPL) was effectively transfected into cervical cancer HeLa cells. The hWAPL mRNA expression levels were reduced by 97.23% in contrast with control cells, and the proliferation capability declined by 66.71%, indicating significant inhibition. The present results provide a novel strategy for targeted gene therapy and siRNA therapy of EGFR-positive cervical cancers.