Objective
Thyroid cancer (TC) is one of the fastest‐growing malignant tumors. This study sought to explore the mechanism of immune escape mediated by receptor tyrosine kinase (KIT) in TC.
Methods
The ...expression microarray of TC was acquired through the GEO database, and the difference analysis and Kyoto encyclopedia of genes and genomes pathway enrichment analysis were carried out. KIT levels in TC cell lines (K1/SW579/BCPAP) and human normal thyroid cells were detected using reverse transcription quantitative polymerase chain reaction and western blot analysis. TC cells were transfected with overexpressed (oe)‐KIT and CD8+ T cells were cocultured with SW579 cells. Subsequently, cell proliferation, migration, and invasion abilities, CD8+ T cell proliferation, cytokine levels (interferon‐γ IFN‐γ/tumor necrosis factor‐α TNF‐α) were determined using colony formation assay, Transwell assays, flow cytometry, and enzyme‐linked immunosorbent assay. The phosphorylation of MAPK pathway‐related protein (ERK) was measured by western blot analysis. After transfection with oe‐KIT, cells were treated with anisomycin (an activator of the MAPK pathway), and the protein levels of p‐ERK/ERK and programmed death‐ligand 1 (PD‐L1) were detected.
Results
Differentially expressed genes (N = 2472) were obtained from the GEO database. KIT was reduced in TC samples and lower in tumor cells than those in normal cells. Overexpression of KIT inhibited immune escape of TC cells. Specifically, the proliferation, migration, and invasion abilities of TC cells were lowered, the proliferation level of CD8+ T cells was elevated, and IFN‐γ and TNF‐α levels were increased. KIT inhibited the activation of the MAPK pathway in TC cells and downregulated PD‐L1.
Conclusion
KIT suppressed immune escape of TC by blocking the activation of the MAPK pathway and downregulating PD‐L1.
KIT suppressed immune escape of thyroid cancer by blocking the activation of the MAPK pathway and downregulating programmed death‐ligand 1.
Liver fibrosis is a worldwide clinical issue. It has been well established that activated hepatic stellate cells (HSCs) are responsible for excessive extracellular matrix (ECM) deposition in ...chronically damaged livers. The identification of key elements that control HSCs activation will help to further our understanding of liver fibrosis and improve the outcome of clinical treatment. This study demonstrates that N-Myc downstream-regulated gene 2 (NDRG2) is a potential regulator of liver fibrosis as NDRG2 mRNA and protein levels were reduced during HSCs activation. In addition, enhanced NDRG2 expression reduced Smad3 transcription and phosphorylation, which inhibited HSCs activation by blocking the TGF-β1 signal. Moreover, NDRG2 contributed to an increase in the ratio of matrix metalloproteinase 2 (MMP2) to tissue inhibitor of matrix metalloproteinase 2 (TIMP2), which may facilitate the degradation of the ECM. In dimethylnitrosamine (DMN)-induced fibrotic rat livers, adenovirus-mediated NDRG2 overexpression resulted in decreased ECM deposition and improved liver function compared with controls. In conclusion, the present findings indicate that the modulation of NDRG2 is a promising strategy for the treatment of liver fibrosis.
N‐Myc downstream‐regulated gene 2 (NDRG2), a new member of the N‐Myc downstream‐regulated gene family, has been found to be a differentially expressed gene involved in a variety of cancers. The ...present study aimed to investigate the expression of NDRG2 in esophageal squamous cell carcinoma (ESCC). Immunohistochemistry was performed in 154 samples from patients with ESCC to detect the expression level of NDRG2 and C‐MYC. Results indicated that the expression level of NDRG2 in the cancer samples was significantly lower than that in normal tissues; the trend of C‐MYC was the reverse. The Wilcoxon–Mann–Whitney test showed significant difference in the expression of NDRG2 in patients with different T stage, TNM stage, and differentiation degree of cancers (P = 0.036, 0.031, 0.001, respectively). Patients in stages I and II were followed up for 5 consecutive years and Kaplan–Meier survival analysis demonstrated that the survival time of ESCC patients with high expression of NDRG2 was longer than those with low expression during the 5‐year follow‐up period (P = 0.0018). Cox regression analysis indicated that low expression of NDRG2, cancer stage of pT1, and distant organ metastasis (pM1) were the independent poor prognostic factors of ESCC (P = 0.004, 0.019, 0.0013, respectively). Furthermore, up‐regulation of NDRG2 was introduced to ESCC cell lines (EC9706 and EC109) by plasmid transfection. In vivo and in vitro studies indicated that overexpression of NDRG2 markedly reduced proliferation and promoted the apoptosis of EC9706 and EC109 cells. In summary, our results demonstrated that NDRG2 played an important role in the proliferation of ESCC cells and the expression of NDRG2 in ESCC was closely related with the prognosis.
(Cancer Sci 2010; 101: 1292–1299)
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•Cu-In-Zr-O as CO2 hydrogenation catalyst exhibited high CH3OH selectivity (80%).•Enhanced CH3OH selectivity due to incorporation of In2O3.•Cu-In2O3 synergy described, Cu promotes H2 ...dissociation, In facilitates methanol.•Hydrogenation of CO2(ads) and methoxy species identified as possible RDS.•Defective In2O3 with strong CO2 adsorption led to selective CH3OH formation.
Methanol synthesis via CO2 hydrogenation has attracted intensive research efforts, but is challenged with development of active and selective catalyst materials that would allow the reaction occurs under milder conditions and being economically more viable. Herein we report the use of bifunctional active sites and their synergy in promoting CO2 hydrogenation kinetics and selectivity. A series of Cu-In-Zr-O mixed oxide nanomaterials containing Cu and defective In2O3 active sites were synthesized and studied for the catalytic properties. Significantly higher CO2 conversion and methanol selectivity were achieved using the Cu-In-Zr-O compared to its non-copper counterpart In-Zr-O, revealing synergy between the two active sites. Insights into the mechanism and functionality of the two actives in CO2 hydrogenation catalysis were obtained with in situ DRIFTS study. A formate-methoxy-methanol pathway and the possible rate-limiting steps were discovered. The excellent selectivity property of the Cu-In-Zr-O was attributed to strong adsorption of CO2 to defective In2O3, which creates a large energy barrier that suppresses CO2 dissociation into CO. The promotion in CO2 hydrogenation kinetics was attributed to cooperation between the bifunctional active sites, with Cu sites adsorb and provide active hydrogen atoms that hydrogenate adsorbed CO2 at adjacent defective In2O3 sites. The findings confirmed synergy between bifunctional sites in CO2 hydrogenation catalysis and provided a new concept in development of active and selective catalyst materials.
Abstract N-myc downstream regulated gene 2 (NDRG2) was reported to be widely expressed in the nervous system. However, the expression and potential role of NDRG2 in focal cerebral ischemia brain ...remain unclear. Herein, we investigated spatial–temporal expression of NDRG2 in the rat brain following transient focal cerebral ischemia. Male Sprague–Dawley rats underwent a 120-min transient occlusion of middle cerebral artery. Rats were killed and brain samples were harvested at 4, 12, 24, and 72 h after reperfusion. Expression of NDRG2 in the brain was determined by reverse transcriptase–polymerase chain reaction (RT-PCR), Western blot analysis and immunohistochemical staining. Cellular apoptosis was assessed by TUNEL staining. The results showed that NDRG2 was expressed on cells with an astrocytes-like morphology in ischemic penumbra. NDRG2 mRNA and protein expression began to increase at 4 h after reperfusion and peaked at 24 h in the ischemic penumbra. By using immunofluorescence, NDRG2 signals were co-localized with GFAP-positive astrocytes, and NDRG2 expression in astrocytes translocated from a cytoplasm to a nuclear localization at 24 h after reperfusion. Double immunofluorescent staining for TUNEL and NDRG2 showed that some NDRG2 signals co-localized with TUNEL-positive cells, and that the apoptotic cells increased with enhancement of NDRG2-positive signals. In conclusion, NDRG2 expression is up-regulated in ischemic penumbra following transient focal cerebral ischemia. NDRG2 expression in astrocytes may play important pathological roles in cell apoptosis after stroke.
We have investigated the expression and role of the 58‐kDa microspherule protein (MSP58) in colorectal carcinoma (CRC). By immuhistochemistry and immunofluorescence, we observed MSP58 in the nucleus ...and cytoplasm of CRC cells, and found MSP58 to be present in CRC specimens more often than in adjacent non‐tumor tissues (92.5 vs 36.3%, P < 0.01). The average staining score in adjacent non‐tumor tissues was significantly lower than in CRC tissues (2.05 ± 1.13 vs 5.23 ± 1.38, P < 0.01). Moreover, MSP58 mRNA and protein appeared to be upregulated in six fresh CRC samples compared to their adjacent non‐cancerous tissues. MSP58 expression was also detected in the human CRC‐derived cell lines LoVo, CoLo205, HCT116, HT‐29, SW620, and SW480. Downregulation of MSP58 inhibited in vitro growth and attenuated tumor growth in animal models by induction of cell cycle arrest, and was associated with reduced levels of cyclin D1, cyclin‐dependent kinase 4, phosphorylation‐Rb (p‐Rb), p21, and Retino blastoma (Rb) proteins. These results indicated that MSP58 might play an important role in the carcinogenesis of CRC via regulation of the cyclin D1–cyclin‐dependent kinase 4–p21 pathway. (Cancer Sci 2009; 100: 1585–1590)
The tumor suppressor, p53, is a transcription factor which can modulate the transcription of a number of target genes that are involved in cell-cycle arrest and apoptosis. However, the apoptotic ...pathway mediated by p53 is not fully understood. Here, we showed that N-Myc downstream-regulated gene 2 (NDRG2) is a new target gene that is regulated by p53. NDRG2 mRNA and protein levels can be upregulated in a p53-dependent manner. The first intron of the NDRG2 gene contains a site that binds p53 directly and mediates wild-type p53-dependent transactivation. In addition, silencing of NDRG2 attenuates p53-mediated apoptosis, whereas overexpression of NDRG2 suppresses tumor cell growth, regardless of the presence or absence of p53. Our results indicate that NDRG2 is a novel p53-inducible target that is involved in the p53-mediated apoptosis pathway.
The N-myc downstream-regulated gene 2 (NDRG2) is involved in tumor cell differentiation and apoptosis, but its function in tumor angiogenesis remains to be established. Here, we employed adenovirus ...overexpressing NDRG2 (Ad-NDRG2) to efficiently up-regulate target gene expression in the NDRG2-low-expressing, breast cancer cell line MCF-7. Moreover, VEGF secretion was decreased in MCF-7 cells infected by Ad-NDRG2, and medium conditioned by these infected cells could significantly inhibit the proliferation, tube formation and invasion of human umbilical vein endothelial cells (HUVECs). Further study indicated that the angiogenesis promoting factors VEGF and HIF-1α were down-regulated, whereas the angiogenesis suppressing factors p53 and VHL were up-regulated in MCF-7 cells infected by Ad-NDRG2. Finally, in a nude mouse model, intratumoral injections of Ad-NDRG2 every 3 days for 20 days significantly inhibited the growth and angiogenesis of xenografted MCF-7 tumors. In summary, these data indicate that NDRG2 may be involved in angiogenesis by impacting the expression of angiogenesis related factors. Thus, specific overexpression of NDRG2 by adenovirus represents a promising approach for the treatment of tumor angiogenesis.
The aim of thos study was to understand the experience of social alienation in elderly lung cancer patients, to explore its causes, and to propose targeted intervention strategies.
From July to ...August 2023, 16 elderly lung cancer patients attending the respiratory department of a tertiary hospital in Changsha City, Hunan Province, were selected for semistructured interviews using a purposive sampling method. The Colaizzi 7-step method was used to analyze the data.
A total of four themes were distilled: the experience of social alienation in elderly lung cancer patients (pessimistic feelings, inferiority complex, and heavy psychological burden), subjective causes (disease-included shame, avoidant social behavior, and stigmatized labels), objective causes (isolated social states, and reduced amount of socialization), and rehabilitation support.
The causes of social alienation in elderly lung cancer patients include multiple aspects of personal, family, and social support, and symptom management and psychological guidance should be strengthened for this population to construct a hospital–society–family triple-linkage care program to help patients recover.
NDRG2, a member of N-Myc downstream regulated gene family, plays some roles in cellular stress, cell differentiation and tumor suppression. We have found that NDRG2 expression in cervical cancer Hela ...cells increases significantly upon stimulation with cisplatin, the most popular chemotherapeutic agent currently used for the treatment of advanced cervical cancer. This interesting phenomenon drove us to evaluate the role of NDRG2 in chemosensitivity of Hela cells.
In the present study, RNA interference was employed to down-regulate NDRG2 expression in Hela cells. RT-PCR and Western blot were used to detect expression of NDRG2, Bcl-2 and Bax in cancer cells. Real-time PCR was applied to detect miR-15b and miR-16 expression levels. Drug sensitivity was determined with MTT assay. Cell cloning efficiency was evaluated by Colony-forming assay. Apoptotic cells were detected with annexin V staining and flow cytometry.
In vitro drug sensitivity assay revealed that suppression of NDRG2 could sensitize Hela cells to cisplatin. Down-regulation of NDRG2 didn't influence the colony-forming ability but promoted cisplatin-induced apoptosis of Hela cells. Inhibition of NDRG2 in Hela cells was accompanied by decreased Bcl-2 protein level. However, Bcl-2 mRNA level was not changed in Hela cells with down-regulation of NDRG2. Further study indicated that miR-15b and miR-16, two microRNAs targetting Bcl-2, were significantly up-regulated in NDRG2-suppressed Hela cells.
These data suggested that down-regulation of NDRG2 could enhance sensitivity of Hela cells to cisplatin through inhibiting Bcl-2 protein expression, which might be mediated by up-regulating miR-15b and miR-16.
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