ABSTRACT
Previous studies have indicated that transmembrane protein 16A (TMEM16A) plays a crucial role in the pathogenesis and progression of various tumors by influencing multiple signaling pathways. However, the role of TMEM16A in regulating autophagy via the mammalian target of rapamycin (mTOR) pathway and its impact on the development of hypopharyngeal squamous cell carcinoma (HSCC) remain unclear. Immunohistochemistry and western blotting were used to assess the expression of TMEM16A in HSCC tissues and metastatic lymph nodes. Manipulation of TMEM16A expression levels was achieved in the FaDu cell line through overexpression or knockdown, followed by assessment of its biological effects using cell colony formation, wound healing, transwell and invasion assays. Additionally, apoptosis and autophagy-related proteins, as well as autophagosome formation, were evaluated through western blotting, transmission electron microscopy and immunofluorescence following TMEM16A knockdown or overexpression in FaDu cells. Our study revealed significantly elevated levels of TMEM16A in both HSCC tissues and metastatic lymph nodes compared with normal tissues. In vitro experiments demonstrated that silencing TMEM16A led to a notable suppression of HSCC cell proliferation, invasion and migration. Furthermore, TMEM16A silencing effectively inhibited tumor growth in xenografted mice. Subsequent investigations indicated that knockdown of TMEM16A in HSCC cells could suppress mTOR activation, thereby triggering autophagic cell death by upregulating sequestosome-1 (SQSTM1/P62) and microtubule-associated protein light chain 3 II (LC3II). This study highlights the crucial role of TMEM16A in modulating autophagy in HSCC, suggesting its potential as a therapeutic target for the treatment of this malignancy.
Subject(s)
Anoctamin-1 , Autophagy , Cell Movement , Cell Proliferation , Hypopharyngeal Neoplasms , Neoplasm Invasiveness , Neoplasm Proteins , Signal Transduction , TOR Serine-Threonine Kinases , Humans , TOR Serine-Threonine Kinases/metabolism , Hypopharyngeal Neoplasms/pathology , Hypopharyngeal Neoplasms/genetics , Hypopharyngeal Neoplasms/metabolism , Animals , Mice , Anoctamin-1/metabolism , Anoctamin-1/genetics , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Cell Line, Tumor , Male , Apoptosis , Gene Expression Regulation, Neoplastic , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/metabolism , Squamous Cell Carcinoma of Head and Neck/genetics , Female , Mice, Nude , Xenograft Model Antitumor Assays , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/geneticsABSTRACT
BACKGROUND: Lung adenocarcinoma (LUAD) is a common type of lung cancer with a high risk of metastasis, but the exact molecular mechanisms of metastasis are not yet understood. METHODS: This study acquired single-cell transcriptomics profiling of 11 distal normal lung tissues, 11 primary LUAD tissues, and 4 metastatic LUAD tissues from the GSE131907 dataset. The lung multicellular ecosystems were characterized at a single-cell resolution, and the potential mechanisms underlying angiogenesis and metastasis of LUAD were explored. RESULTS: We constructed a global single-cell landscape of 93,610 cells from primary and metastatic LUAD and found that IGF2BP2 was specifically expressed both in a LUAD cell subpopulation (termed as LUAD_IGF2BP2), and an endothelial cell subpopulation (termed as En_IGF2BP2). The LUAD_IGF2BP2 subpopulation progressively formed and dominated the ecology of metastatic LUAD during metastatic evolution. IGF2BP2 was preferentially secreted by exosomes in the LUAD_IGF2BP2 subpopulation, which was absorbed by the En_IGF2BP2 subpopulation in the tumor microenvironment. Subsequently, IGF2BP2 improved the RNA stability of FLT4 through m6A modification, thereby activating the PI3K-Akt signaling pathway, and eventually promoting angiogenesis and metastasis. Analysis of clinical data showed that IGF2BP2 was linked with poor overall survival and relapse-free survival for LUAD patients. CONCLUSIONS: Overall, these findings provide a novel insight into the multicellular ecosystems of primary and metastatic LUAD, and demonstrate that a specific LUAD_IGF2BP2 subpopulation is a key orchestrator promoting angiogenesis and metastasis, with implications for the gene regulatory mechanisms of LUAD metastatic evolution, representing themselves as potential antiangiogenic targets.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Humans , Methylation , Ecosystem , Endothelial Cells , Phosphatidylinositol 3-Kinases , Neoplasm Recurrence, Local , Adenocarcinoma of Lung/genetics , Lung Neoplasms/genetics , Tumor Microenvironment , RNA-Binding Proteins/geneticsABSTRACT
The human microbiota is symbiotic with the host and can create a variety of metabolites. Under normal conditions, microbial metabolites can regulate host immune function and eliminate abnormal cells in a timely manner. However, when metabolite production is abnormal, the host immune system might be unable to identify and get rid of tumor cells at the early stage of carcinogenesis, which results in tumor development. The mechanisms by which intestinal microbial metabolites, including short-chain fatty acids (SCFAs), microbial tryptophan catabolites (MTCs), polyamines (PAs), hydrogen sulfide, and secondary bile acids, are involved in tumorigenesis and development by regulating immune responses are summarized in this review. SCFAs and MTCs can prevent cancer by altering the expression of enzymes and epigenetic modifications in both immune cells and intestinal epithelial cells. MTCs can also stimulate immune cell receptors to inhibit the growth and metastasis of the host cancer. SCFAs, MTCs, bacterial hydrogen sulfide and secondary bile acids can control mucosal immunity to influence the occurrence and growth of tumors. Additionally, SCFAs, MTCs, PAs and bacterial hydrogen sulfide can also affect the anti-tumor immune response in tumor therapy by regulating the function of immune cells. Microbial metabolites have a good application prospect in the clinical diagnosis and treatment of tumors, and our review provides a good basis for related research.
Subject(s)
Hydrogen Sulfide , Neoplasms , Humans , Carcinogenesis , Cell Transformation, Neoplastic , Immunity, Mucosal , Bile Acids and SaltsABSTRACT
Head and neck squamous cell carcinoma (HNSCC), the most common head and neck malignant tumor, with only monotherapy, is characterized by poor prognosis, and low 5-year survival rate. Due to the lack of therapeutic targets, the targeted drugs for HNSCC are rare. Therefore, exploring the regulation mechanism of HNSCC and identifying effective therapeutic targets will be beneficial to its treatment of. Circular RNA (CircRNA) is a class of RNA molecules with a circular structure, which is widely expressed in human body. CircRNAs regulate gene expression by exerting the function as a miRNA sponge, thereby mediating the occurrence and development of HNSCC cell proliferation, apoptosis, migration, invasion, and other processes. In addition, circRNAs are also involved in the regulation of tumor sensitivity to chemical drugs and other biological functions. In this review, we systematically listed the functions of circRNAs and explored the regulatory mechanisms of circRNAs in HNSCC from the aspects of tumor growth, cell death, angiogenesis, tumor invasion and metastasis, tumor stem cell regulation, tumor drug resistance, immune escape, and tumor microenvironment. It will assist us in discovering new diagnostic markers and therapeutic targets, while encourage new ideas for the diagnosis and treatment of HNSCC.
ABSTRACT
Objective: We aim to establish and validate computed tomography (CT)-based radiomics model for predicting TP53 status in patients with laryngeal squamous cell carcinoma (LSCC). Methods: We divided all patients into a training set 1 (n=66) and a testing set 1 (n=30) to establish and validate radiomics model to predict TP53. Radiomics features were selected by analysis of variance (ANOVA) and the least absolute shrinkage and selection operator (Lasso) regression analysis. Five radiomics models were established by using K-Nearest Neighbor, logistics regressive, linear-support vector machine (SVM), gaussian-SVM, and polynomial-SVM in training set 1. We also divided all patients into a training set 2 and a testing set 2 according to different CT equipment to establish and evaluate the stability of the radiomics models. Results: After ANOVA and subsequent Lasso regression analysis, 22 radiomics features were selected to build the radiomics model in training set 1. The radiomics model based on linear-SVM has the best predictive performance of the five models, and the area under the receiver operating characteristic curve in training set 1 and testing set 1 were 0.831(95% confidence interval [CI] 0.692-0.970) and 0.797(95% CI 0.632-0.957) respectively. The specificity, sensitivity, and accuracy were 0.971(95% CI 0.834-0.999), 0.714(95% CI 0.535-0.848), and 0.843(95% CI 0.657-0.928) in training set 1 and 0.750(95% CI 0.500-0.938), 0.786(95% CI 0.571-1.000), and 0.667(95% CI 0.467-0.720) in testing set 1, respectively. In addition, the radiomics model also achieved stable prediction results even in different CT equipment. Decision curve analysis showed that the radiomics model for predicting TP53 status could benefit LSCC patients. Conclusion: We developed and validated a relatively optimal radiomics model for TP53 status prediction by trying five different machine learning methods in patients with LSCC. It shown great potential of radiomics features for predicting TP53 status preoperatively and guiding clinical treatment.
ABSTRACT
OBJECTIVE: To explore the role of DNA methyltransferase 1 (DNMT1) in development and progression of hypopharyngeal squamous carcinoma. DESIGN: A total of 32 hypopharyngeal squamous carcinoma biopsy samples and 20 normal tissue specimens were collected. Immunohistochemical staining, quantitative real-time polymerase chain reaction, and Western blot were performed for expression analysis. The mRNA and protein expression in the specimens and subcellular localization were analyzed. hypopharyngeal squamous carcinoma cells (FaDu) were used for small interfering RNA of DNMT1, and proliferation, cell cycle, and apoptosis were determined in the transfected cells. Furthermore, metastatic ability and methylation status of O6-methylguanine-DNAmethyl-transferase (MGMT) promoter was assessed. RESULTS: Our results showed that DNMT1 was overexpressed, while MGMT was down expressed in hypopharyngeal squamous carcinoma. DNMT1 overexpression and MGMT down expression were significantly associated with poorly differentiated tumors, lymph node metastasis, and clinical stage. DNMT1 and MGMT were majorly distributed in the nucleus. Furthermore, knockdown of DNMT1 inhibited proliferation and metastasis, induced apoptosis and G1 phase arrest in FaDu cells, and upregulated MGMT expression to reverse methylation status of MGMT promoter. CONCLUSIONS: This study for the first time demonstrated the clinical value and the role of DNMT1 and MGMT in the biological function of hypopharyngeal squamous carcinoma. This work suggested that DNMT1 might serve as a potential therapeutic target for patients with hypopharyngeal squamous carcinoma.