ABSTRACT
OBJECTIVE: Radiation therapy (RT) may increase the risk of second cancer. This study aimed to determine the association between exposure to radiotherapy for the treatment of thoracic cancer (TC) and subsequent secondary lung cancer (SLC). MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (from 1975 to 2015) was queried for TC. Univariate Cox regression analyses and multiple primary standardized incidence ratios (SIRs) were used to assess the risk of SLC. Subgroup analyses of patients stratified by latency time since TC diagnosis, age at TC diagnosis, and calendar year of TC diagnosis stage were also performed. Overall survival and SLC-related death were compared among the RT and no radiation therapy (NRT) groups by using Kaplan-Meier analysis and competitive risk analysis. RESULTS: In a total of 329 129 observations, 147 847 of whom had been treated with RT. And 6799 patients developed SLC. Receiving radiotherapy was related to a higher risk of developing SLC for TC patients (adjusted HR, 1.25; 95% CI, 1.19-1.32; P < 0.001). The cumulative incidence of developing SLC in TC patients with RT (3.8%) was higher than the cumulative incidence (2.9%) in TC patients with NRT(P). The incidence risk of SLC in TC patients who received radiotherapy was significantly higher than the US general population (SIR, 1.19; 95% CI, 1.14-1.23; P < 0.050). CONCLUSIONS: Radiotherapy for TC was associated with higher risks of developing SLC compared with patients unexposed to radiotherapy.
Subject(s)
Lung Neoplasms , Neoplasms, Second Primary , SEER Program , Thoracic Neoplasms , Humans , Male , Female , Lung Neoplasms/radiotherapy , Lung Neoplasms/epidemiology , Middle Aged , Aged , Incidence , Prognosis , Thoracic Neoplasms/radiotherapy , Thoracic Neoplasms/epidemiology , Neoplasms, Second Primary/epidemiology , Neoplasms, Second Primary/etiology , Retrospective Studies , Risk Factors , United States/epidemiology , Radiotherapy/adverse effects , Neoplasms, Radiation-Induced/epidemiology , Neoplasms, Radiation-Induced/etiology , Risk Assessment/methods , AdultABSTRACT
Natural killer (NK) cells actively participate in anti-tumor immunity and are thus regarded as a promising tool in immunotherapy against esophageal cancer (EC). However, the mechanisms regulating NK cell activation and exhaustion have not been completely elucidated. In this study, we characterized the expression and function of MLLT1 super elongation complex subunit (MLLT1) in esophageal NK cells in a mouse EC model. MLLT1 was down-regulated in esophageal NK cells, especially NK cells expressing both T cell immunoglobulin and mucin-domain containing-3 (TIM-3) and lymphocyte activation gene3(LAG-3). In vitro knockdown of MLLT1 in NK cells resulted in significant decreases in the expression of IFN-γ and perforin, as well as impaired NK cell cytotoxicity on tumor cells. Adoptive transfer of MLLT-deficient NK cells into EC-bearing mice showed consistent impairment of NK cell anti-tumor activity, as evidenced by decreases in IFN-γ and perforin but not granzyme B. Furthermore, EC tissue cells, which were enriched from the esophagus of EC-bearing mice, induced down-regulation of MLLT1 in splenic NK cells. This down-regulation was partially restored by a TIM-3 blocking antibody. Therefore, this study indicated that TIM-3 signaling down-regulated MLLT1 in esophageal NK cells, and MLLT1 down-regulation undermined the tumoricidal function of NK cells in EC. Our study unveils a novel mechanism underlying NK cell exhaustion/dysfunction in the EC microenvironment. MLLT1 could be a potential target in future NK cell-mediated immunotherapy against EC.
Subject(s)
DNA-Binding Proteins/metabolism , Esophageal Neoplasms , Hepatitis A Virus Cellular Receptor 2 , Transcription Factors/metabolism , Animals , Disease Models, Animal , Down-Regulation , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/therapy , Hepatitis A Virus Cellular Receptor 2/genetics , Hepatitis A Virus Cellular Receptor 2/metabolism , Killer Cells, Natural , Mice , Perforin/genetics , Perforin/metabolism , Tumor MicroenvironmentABSTRACT
BACKGROUND: Recent reports have indicated that circular RNA (circRNA) may regulate tumorigenesis development. However, the function of circRNAs in esophageal squamous cell carcinoma (ESCC) is unclear. MATERIAL AND METHOD: The RT-qPCR assay was performed to detect hsa_circ_0012563 expression in ESCC tissues and cell lines. Then, the MTT assay, colony formation assay, flow cytometric assay, and cell migration and invasion assay were performed to examine the function of hsa_circ_0012563. In addition, the RT-PCR and Western blot were used to detect XRCC1 and epithelial-to-mesenchymal transition (EMT) related gene expression. RESULTS: The RT-qPCR revealed that the hsa_circ_0012563 expression was remarkably upregulated in ESCC tissue and ESCC cell lines. Functionally, downregulation of hsa_circ_0012563 suppressed cell proliferation, migration, and invasion and promoted cell apoptosis. Mechanically, the knockdown of hsa_circ_0012563 inhibited XRCC1-mediated EMT pathway to suppress cell migration and invasion. CONCLUSIONS: Therefore, these results reveal hsa_circ_0012563 is a critical oncogene and may be a novel biomarker in ESCC.
