查看更多>>摘要：? 2021Exosomes are lipid bilayer extracellular vesicles with a size of 30–150 nm, which can be released by various types of cells including breast cancer cells. Exosomes are enriched with multiple nucleic acids, lipids, proteins and play critical biological roles by binding to recipient cells and transmitting various biological cargos. Studies have reported that tumor-derived exosomes are involved in cancer initiation and progression, such as promoting cancer invasion and metastasis, accelerating angiogenesis, contributing to epithelial-mesenchymal transition, and enhancing drug resistance in tumors. Recently the dysregulating of exosomes has been found in triple-negative breast cancer (TNBC), relating to the clinicopathological characteristics and prognosis of TNBC patients. Considering the poor prognosis and lack of adequate response to conventional therapy of TNBC, the discovery of certain exosomes as a new target for diagnosis and treatment of TNBC may be a good choice that provides new opportunities for the early diagnosis, clinical treatment of TNBC. Here, we first discuss the innovative prognostic and predictive effects of exosomes on TNBC, as well as the practical clinical problems. Secondly, we focus on the new therapeutic areas represented by exosomes, especially the impact of introducing exosomes in TNBC treatment in the future.
查看更多>>摘要：? 2021Acquired drug resistance represents a major obstacle to tyrosine kinase inhibitor (TKI)-induced differentiation therapy of radioiodine-refractory papillary thyroid cancer (RR-PTC); thus, there is an urgent need to elucidate the underlying mechanisms. Here, selumetinib-resistant PTC (PTCSR) cell lines, which were characterized by loss of sodium/iodide symporter expression, enhanced insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), and activated V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) signaling, were initially established using a dose escalation method. Upon knockdown of IGF2BP2 in PTCSR cells, ERBB2 signaling was inhibited, and the acquired drug resistance was partially reversed. Mechanistically, the luciferase activity assay showed that IGF2BP2 bound to the N6-methyladenosine-binding site in the coding sequence of ERBB2 mRNA, yielding an increased ERBB2 translation efficacy revealed by polysome profiling. Inhibition of ERBB2 and IGF2BP2 by lapatinib robustly rescued the PTCSR cells from acquired dedifferentiation. Our study demonstrated that IGF2BP2-dependent ERBB2 signaling activation contributes to acquired resistance to TKI, which may be a promising differentiation strategy for RR-PTC by targeting IGF2BP2.
查看更多>>摘要：? 2021 Elsevier B.V.Ferroptosis resistance is an important mechanism of tumor progression. Interleukin-6 (IL-6) is a representative inflammatory cytokine during chronic inflammation; however, our current understanding of its regulatory role of ferroptosis during carcinogenesis of head and neck squamous cell carcinoma is limited. Chromatin immunoprecipitation and functional observations were performed to investigate xCT-regulatory function of IL-6. We observed a gradual increase in lipid peroxide 4-hydroxynonenal and IL-6 levels during progression from normal oral mucosa to leukoplakia and HNSCC. Meanwhile, the expression of xCT, a key amino acid antiporter assisting ferroptosis resistance, was correlated with IL-6 levels. The upregulated expression of xCT in HNSCC is associated with poor prognosis. Silencing of xCT inhibited HNSCC cell proliferation in vitro and tumor growth in vivo, inducing ferroptosis. Mechanistically, IL-6 transcriptionally activates xCT expression through the JAK2/STAT3 pathway. Furthermore, IL-6 reversed ferroptosis and growth suppression that was induced by xCT knockdown or ferroptosis inducer erastin. Our results demonstrate the critical role of IL-6-induced ferroptosis resistance during HNSCC carcinogenesis. The IL-6/STAT3/xCT axis acts as a novel mechanism driving tumor progression and thus may potentially be utilized as a target for tumor prevention and therapy.
查看更多>>摘要：? 2021 Elsevier B.V.Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BCa) in which estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) are not expressed. Although TNBC cases account for approximately 15% of all BCa cases, TNBC patients' prognosis is poor compared with that of other BCa subtypes. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) plays an important role in cell proliferation and migration by negatively regulating the PI3K/Akt pathway. PTEN is one of the most commonly inactivated tumor suppressors in BCa. PTEN inactivity is associated with larger tumor sizes, multiple lymph node metastases, and an aggressive triple-negative phenotype. This review primarily focuses on two key points: (1) PTEN and its function. (2) The regulation of tumor suppressor PTEN in TNBC. We provide a summary of genomic alterations of PTEN in BCa. We further discuss the transcriptional regulation of PTEN and how PTEN is regulated by posttranscription and posttranslational modification, as well as by protein interactions. Finally, we discuss the perspectives of the PTEN protein in TNBC.
查看更多>>摘要：? 2021Metastasis is the major reason for treatment failure and accounts for cancer-related death in patients with nasopharyngeal carcinoma. However, the genetic alterations and molecular mechanisms that cause nasopharyngeal carcinoma metastasis are elusive. Herein, we performed RNA sequencing in patients with or without metastasis, and found that the early B-cell factor 3 (EBF3) was significantly elevated in the samples with metastasis. Mechanistically, EBF3 promoted metastasis by directly combining with the promoter of Vimentin and transcriptionally upregulating it. In addition, EBF3 was epigenetically silenced by EGR1/EZH2/HDAC9 complexes via sustaining the high level of H3K27–Me3 at its promoter. Clinically, there was a positive correlation between EBF3 and Vimentin in nasopharyngeal carcinoma tissues. Moreover, high expression of EBF3 or Vimentin was correlated with poor overall survival, while the combination of high EBF3 and Vimentin expression was associated with more significant poor prognosis. Therefore, specific agents targeting EBF3 or stabilizing the EGR1/EZH2/HDAC9 complex could be novel therapeutic strategies for cancer metastasis.
查看更多>>摘要：? 2021 The AuthorsGlioblastoma (GBM) is the most invasive and deadliest brain cancer in adults. Its inherent heterogeneity has been designated as the main cause of treatment failure. Thus, a deeper understanding of the diversity that shapes GBM pathobiology is of utmost importance. Single-cell RNA sequencing (scRNA-seq) technologies have begun to uncover the hidden composition of complex tumor ecosystems. Herein, a semi-systematic search of reference literature databases provided all existing publications using scRNA-seq for the investigation of human GBM. We compared and discussed findings from these works to build a more robust and unified knowledge base. All aspects ranging from inter-patient heterogeneity to intra-tumoral organization, cancer stem cell diversity, clonal mosaicism, and the tumor microenvironment (TME) are comprehensively covered in this report. Tumor composition not only differs across patients but also involves a great extent of heterogeneity within itself. Spatial and cellular heterogeneity can reveal tumor evolution dynamics. In addition, the discovery of distinct cell phenotypes might lead to the development of targeted treatment approaches. In conclusion, scRNA-seq expands our knowledge of GBM heterogeneity and helps to unravel putative therapeutic targets.
查看更多>>摘要：? 2021 Elsevier B.V.The circadian clock is an essential timekeeper that controls, for humans, the daily rhythm of biochemical, physiological, and behavioral functions. Irregular performance or disruption in circadian rhythms results in various diseases, including cancer. As a factor in cancer development, perturbations in circadian rhythms can affect circadian homeostasis in energy balance, lead to alterations in the cell cycle, and cause dysregulation of chromatin remodeling. However, knowledge gaps remain in our understanding of the relationship between the circadian clock and cancer. Therefore, a mechanistic understanding by which circadian disruption enhances cancer risk is needed. This review article outlines the importance of the circadian clock in tumorigenesis and summarizes underlying mechanisms in the clock and its carcinogenic mechanisms, highlighting advances in chronotherapy for cancer treatment.
查看更多>>摘要：? 2021 Elsevier B.V.Transient receptor potential vanilloid 1 (TRPV1) is a Ca2+-permeable ion channel that acts as cellular sensor and is implicated in the tumor microenvironment cross talk. However, the functional role of TRPV1 in colorectal cancer (CRC) is still controversial. By using a TRPV1 gain-of-function model, we previously reported that hyperfunctional TRPV1 exacerbated experimental colitis by modulating mucosal immunity. Here, we found that TRPV1 gain-of-function significantly promoted tumor initiation and progression in colitis-associated cancer, as evidenced by the increase in the number and size of tumor. Systemic TRPV1 hyperactivation fostered a tumor permissive microenvironment through altering macrophage activation status and shifting the Th1/Th2 balance towards Th2 phenotype. Mechanistically, TRPV1 gain-of-function directly potentiated M1 cytokine production in macrophage and enhanced Th2 immune response by promoting Calcineurin/nuclear factor of activated T cells (NFATc2) signaling activation. In patients with CRC, TRPV1 expression was increased in tumor immune infiltrating cells. TRPV1 level was associated with CRC progression and could impact clinical outcome. Our study reveals an important role for TRPV1 in regulating the immune microenvironment during colorectal tumorigenesis. TRPV1 might be a potential target for CRC immunotherapy.
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