Lung cancer is the leading cause of cancer-related deaths worldwide. Tumor suppressor genes remain to be systemically identified for lung cancer. Through the genome-wide screening of ...tumor-suppressive transcription factors, we demonstrate here that GATA4 functions as an essential tumor suppressor in lung cancer in vitro and in vivo. Ectopic GATA4 expression results in lung cancer cell senescence. Mechanistically, GATA4 upregulates multiple miRNAs targeting TGFB2 mRNA and causes ensuing WNT7B downregulation and eventually triggers cell senescence. Decreased GATA4 level in clinical specimens negatively correlates with WNT7B or TGF-β2 level and is significantly associated with poor prognosis. TGFBR1 inhibitors show synergy with existing therapeutics in treating GATA4-deficient lung cancers in genetically engineered mouse model as well as patient-derived xenograft (PDX) mouse models. Collectively, our work demonstrates that GATA4 functions as a tumor suppressor in lung cancer and targeting the TGF-β signaling provides a potential way for the treatment of GATA4-deficient lung cancer.
Cellular senescence occurs in proliferating cells as a consequence of various triggers including telomere shortening, DNA damage, and inappropriate expression of oncogenes. The senescent state is ...accompanied by failure to reenter the cell cycle under mitotic stimulation, resistance to cell death and enhanced secretory phenotype. A growing number of studies have convincingly demonstrated a paradoxical role for spontaneous senescence and therapy-induced senescence (TIS), that senescence may involve both cancer prevention and cancer aggressiveness. Cellular senescence was initially described as a physiological suppressor mechanism of tumor cells, because cancer development requires cell proliferation. However, there is growing evidence that senescent cells may contribute to oncogenesis, partly in a senescence-associated secretory phenotype (SASP)-dependent manner. On the one hand, SASP prevents cell division and promotes immune clearance of damaged cells, thereby avoiding tumor development. On the other hand, SASP contributes to tumor progression and relapse through creating an immunosuppressive environment. In this review, we performed a review to summarize both bright and dark sides of senescence in cancer, and the strategies to handle senescence in cancer therapy were also discussed.
Cancer chemoresistance and metastasis are tightly associated features. However, whether they share common molecular mechanisms and thus can be targeted with one common strategy remain unclear in ...non-small cell lung cancer (NSCLC). Here, we report that high levels of microRNA-128-3p (miR-128-3p) is key to concomitant development of chemoresistance and metastasis in residual NSCLC cells having survived repeated chemotherapy and correlates with chemoresistance, aggressiveness and poor prognosis in NSCLC patients. Mechanistically, miR-128-3p induces mesenchymal and stemness-like properties through downregulating multiple inhibitors of Wnt/β-catenin and TGF-β pathways, leading to their overactivation. Importantly, antagonism of miR-128-3p potently reverses metastasis and chemoresistance of highly malignant NSCLC cells, which could be completely reversed by restoring Wnt/β-catenin and TGF-β activities. Notably, correlations among miR-128-3p levels, activated β-catenin and TGF-β signalling, and pro-epithelial-to-mesenchymal transition/pro-metastatic protein levels are validated in NSCLC patient specimens. These findings suggest that miR-128-3p might be a potential target against both metastasis and chemoresistance in NSCLC.
Trastuzumab is a standard treatment for HER2-positive (HER2
) breast cancer, but some patients are refractory to the therapy. MicroRNAs (miRNAs) have been used to predict therapeutic effects for ...various cancers, but whether miRNAs can serve as biomarkers for HER2
metastatic breast cancer (MBC) patients remains unclear. Using miRNA microarray, we identify 13 differentially expressed miRNAs in the serum of HER2
MBC patients with distinct response to trastuzumab, and four miRNAs are selected to construct a signature to predict survival using LASSO model. Further, our data show that miR-940 is mainly released from the tumor cells and miR-451a, miR-16-5p and miR-17-3p are mainly from the immune cells. All these four miRNAs directly target signaling molecules that play crucial roles in regulating trastuzumab resistance. In summary, we develop a serum-based miRNA signature that potentially predicts the therapeutic benefit of trastuzumab for HER2
MBC patients and warrants future validation in prospective clinical trials.
Nasopharyngeal carcinoma (NPC) is characterized by a high rate of local invasion and early distant metastasis. Increasing evidence indicates that epigenetic abnormalities play important roles in NPC ...development. However, the epigenetic mechanisms underlying NPC metastasis remain unclear. Here we investigate aberrantly methylated transcription factors in NPC tissues, and we identify the HOP homeobox HOPX as the most significantly hypermethylated gene. Consistently, we find that HOXP expression is downregulated in NPC tissues and NPC cell lines. Restoring HOPX expression suppresses metastasis and enhances chemosensitivity of NPC cells. These effects are mediated by HOPX-mediated epigenetic silencing of SNAIL transcription through the enhancement of histone H3K9 deacetylation in the SNAIL promoter. Moreover, we find that patients with high methylation levels of HOPX exhibit poor clinical outcomes in both the training and validation cohorts. In summary, HOPX acts as a tumour suppressor via the epigenetic regulation of SNAIL transcription, which provides a novel prognostic biomarker for NPC metastasis and therapeutic target for NPC treatment.
The detection of biomarkers in blood macrophages is a new non-invasive cancer screening method, but its performance in early stage lung cancer screening remains undetermined. We evaluated the Apo10 ...and TKTL1 levels in blood macrophages of 156 early-stage lung cancer patients and 153 controls. APT (combination of Apo10 and TKTL1) level was significantly higher in the lung cancer group than that in the control group (P < 0.001). AUROC analysis showed that APT has high diagnostic value in differentiating early-stage lung cancer (AUC = 0.9132) and can be considered a biomarker for screening lung cancer patients from individuals with lung nodules.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To elucidate the role and prognostic significance of lymphocyte activation-gene-3 (LAG-3) in soft tissue sarcoma (STS).
The expression of LAG-3 in patient and matched normal blood samples was ...analyzed by flow cytometry. The localization and prognostic values of LAG-3
cells in 163 STS patients were analyzed by immunohistochemistry. In addition, the expression of tumor-infiltrating CD3
T, CD4
T, and CD8
T cells and their role in the prognosis of STS were evaluated by immunohistochemistry. The effect of LAG-3 blockade was evaluated in an immunocompetent MCA205 fibrosarcoma mouse model.
Peripheral CD8
and CD4
T cells from STS patients expressed higher levels of LAG-3 than those from healthy donors. LAG-3 expression in STS was significantly associated with a poor clinical outcome (
= 0.038 ) and was correlated with high pathological grade (
< 0.001), advanced tumor stage (
= 0.016). Additionally, LAG-3 expression was highly correlated with CD8
T-cell infiltration (
= 0.7034,
< 0.001). LAG-3 was expressed in murine tumor-infiltrating lymphocytes, and its blockade decreased tumor growth and enhanced secretion of interferon-gamma by CD8
and CD4
T cells.
LAG-3 blockade may be a promising strategy to improve the effects of targeted therapy in STS.
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FFLJ, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UL, UM, UPUK
Epstein-Barr virus-associated gastric cancer (EBVaGC) has been proposed to be a distinct subtype with a specific immune microenvironment. Here, we evaluated tumor-infiltrating T-cell subsets and the ...expression of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) in 571 gastric cancers (GCs). Tissue microarrays were stained using EBER
hybridization for EBV and using immunohistochemistry for CD4, CD8, Foxp3, PD-1 and PD-L1. GCs were categorized into four types based on CD8
infiltration and PD-L1 expression. The 5-year overall survival (OS) was evaluated according to EBV infection, T-cell subsets, PD-1 and PD-L1 expression and immune types. Thirty-two (5.3%) EBVaGCs were identified, which were more prevalent for CD8
(p<0.001) and Foxp3
(p=0.020) cell infiltration than EBV-negative GCs (EBVnGCs), suggesting a better 5-year OS (p=0.003). CD8
(p=0.001) and Foxp3
(p=0.018) cell infiltration was associated with better 5-year OS, whereas PD-L1 expression correlated with a poor 5-year OS (p=0.002). EBVaGC and EBVnGC had heterogeneous immune microenvironment, with CD8
PD-L1
GC exhibiting the best 5-year OS (p<0.001). GC was an immune ignorant dominant tumor and poor to no T-cell infiltration. An immune type classification algorithm can provide prognostic information and a rational basis for immunotherapy.
Astrocyte elevated gene-1 (AEG-1), upregulated in various types of human cancers, has been reported to be associated with the carcinogenesis of human cancer. However, the functional significance of ...AEG-1 in human esophageal squamous cell carcinoma (ESCC) remains unknown. In the present study, we showed the expression of AEG-1 was markedly upregulated in esophageal cancer cell lines and surgical ESCC specimens at both transcriptional and translational levels. Immunohistochemical analysis revealed that 80 of 168 (47.6%) paraffin-embedded archival ESCC specimens exhibited high levels of AEG-1 expression. Statistical analysis suggested the upregulation of AEG-1 was significantly correlated with the clinical staging of the ESCC patients (P = 0.001), T classification (P = 0.002), N classification (P = 0.034), M classification (P = 0.021) and histological differentiation (P = 0.035) and those patients with high AEG-1 levels exhibited shorter survival time (P < 0.001). Multivariate analysis indicated that AEG-1 expression might be an independent prognostic indicator of the survival of patients with ESCC. Furthermore, we found that ectopic expression of AEG-1 in ESCC cells could significantly enhance cell proliferation and anchorage-independent growth ability. Conversely, silencing AEG-1 by short hairpin RNAi caused an inhibition of cell growth and anchorage-independent growth ability on soft agar. Moreover, we demonstrated that the upregulation of AEG-1 could reduce the expression of p27Kip1 and induce the expression of cyclin D1 through the AKT/FOXO3a pathway. Our findings suggest that the AEG-1 protein is a valuable marker of ESCC progression and that the upregulation of AEG-1 plays an important role in the development and pathogenesis of human ESCC.
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