NUPR1 induces autophagy and promotes the progression of Esophageal squamous cell carcinoma via the MAPK-mTOR pathway.

PURPOSE: Esophageal squamous cell carcinoma (ESCC) is a dominant pathological type in China. NUPR1 is a complex molecule implicated in various physiological and biological functions whose expression is upregulated in response to stress. Furthermore, autophagy is a vital physiological mechanism in the onset and metastasis of malignancies. This study aims to uncover the influence of NUPR1 on ESCC occurrence and development by regulating autophagy while also exploring its association with the MAPK signaling pathway. METHODS: First, the differences in NUPR1 between ESCC and normal tissues were analyzed through online databases. Subsequently, the pathological tissues of clinical samples were stained and scored using immunohistochemistry. And NUPR1 expression in ESCC cells was investigated, as was the function of NUPR1 in the modulation of ESCC's malignant behavior. Furthermore, a nude mouse ESCC xenograft model was developed. Finally, RNA sequencing was performed on NUPR1-downregulated ESCC cells, which was verified using WB. RESULTS: Our findings initially uncovered differences in the expression of NUPR1 in ESCC and normal tissues. In vitro experiments demonstrated that NUPR1 downregulation significantly inhibited ESCC cell proliferation, invasion, and migration, as well as promoted their apoptosis. Our xenograft model exhibited significant inhibition of ESCC tumors upon NUPR1 downregulation. Subsequently, RNA sequencing uncovered that NUPR1 regulates its malignant biological behavior through MAPK-mTOR signaling pathway. Finally, we found that NUPR1 downregulation can inhibit autophagic flux in ESCC. CONCLUSION: Collectively, our findings show that NUPR1 enhances the progression of ESCC by triggering autophagy and is associated with the MAPK-mTOR signaling pathway.

MUC1 promotes lymph node metastasis in esophageal squamous cell carcinoma by downregulating DNAJB6 expression.

BACKGROUND: Aberrant expression of MUC1 correlates with the progression of esophageal squamous cell carcinoma (ESCC), this study aimed to explore the effect of targeting MUC1 by Go-203 on malignant behavior of ESCC and the underlying mechanism. METHODS AND RESULTS: IHC was used to examine the expression of MUC1 and DNAJB6 in ESCC samples. qRT-PCR and western blotting were used to examine the expression of MUC1 and DNAJB6 in ESCC cell lines. CCK8, wound healing, and transwell assays were used to determine the effect of regulating MUC1/DNAJB6 on the proliferation, migration, and invasion of ESCC cells. The effect of overexpressing/targeting MUC1 on the activation of the AKT/HSF-1 pathway was determined by western blotting. A negative correlation was confirmed between the expression of DNAJB6 and MUC1 in ESCC tissue samples by IHC, and high expression of MUC1 and low expression of DNAJB6 correlated with lymph node metastasis in ESCC patients. Overexpressing MUC1 downregulated the expression of DNAJB6, promoted ESCC proliferation, invasion, migration and activated the AKT pathway, while targeting MUC1 suppressed proliferation, invasion, migration, and the AKT pathway and up-regulated DNAJB6 expression in vitro. Moreover, MUC1 increased the phosphorylation of HSF-1 via the AKT pathway, and inhibiting AKT-HSF-1 increased the expression of DNAJB6 in vitro. CONCLUSIONS: This study indicated that MUC1 could promote tumorigenesis and metastasis in ESCC by downregulating DNAJB6 expression through AKT-HSF-1 pathway.

2022 Multiple-country Monkeypox Outbreak and Its Importation Risk into China: An Assessment Based on the Risk Matrix Method.

Objective: To analyze the 2022 multiple-country monkeypox outbreak and assess its importation risk into China. Methods: Data was from United States Centers for Disease Control and Prevention. We described the global epidemic and calculated concentration index to measure economic-related inequality. Importation risk into China was evaluated and ranked by using risk matrix method and Borda count method, respectively. Results: As of July 29, 2022, of 79 countries or territories, 39 (49.37%, 39/79), 17 (21.52%, 17/79), 6 (7.59%, 6/79), 12 (15.19%, 12/79), and 5 (6.33%, 5/79) country or territories identified cases < 10, 10-, 51-, 101-, and > 1,000. There were economic-related health disparities exist in the distribution of cases (the concentration index = 0.42, P = 0.027), and the inequality disadvantageous to the rich (pro-poor). There were 12 (15.38%, 12/78), 15 (19.23%, 15/78), 6 (7.69%, 6/78), and 45 (57.69%, 45/78) countries or territories with extremely high, high, moderate, and low importation risk. United States and France ranked first with the highest Borda points of 156, and counts of zero. Conclusion: Of 78 countries or territories, the key attention need be paid to the United States and France, relatively. As the epidemic progresses, preparing prevention and control measures to further reduce importation risk was crucial.

Downregulation of fibulin-4 inhibits autophagy and promotes the sensitivity of esophageal squamous cell carcinoma cells to apatinib by activating the Akt-mTOR signaling pathway.

BACKGROUND: Fibulin-4, namely, EFEMP2, is an essential matricellular protein associated with a variety of malignancies. The aim of this study was to explore the role of fibulin-4 in the progression of esophageal squamous cell carcinoma (ESCC), as well as its effect on ESCC sensitivity to apatinib treatment. METHODS: The expression of fibulin-4 in ESCC tissues and cell lines was detected. Stably transfected ESCC cells were established by transducing lentiviral vectors for silencing or overexpressing the fibulin-4 gene into ESCC cells, and a subcutaneous xenograft tumor model of ESCC in mice was successfully established. IHC, RT-qPCR and western blotting were used to detect the expression of related genes and proteins. The CCK8 assay, EdU cell proliferation assay, wound healing assay, transwell assay and flow cytometry were used to evaluate the proliferation, invasion, migration and apoptosis of ESCC cells. After mice were sacrificed, the transplanted tumors were resected, and their volumes were measured. RESULTS: The expression of fibulin-4 was significantly increased in both ESCC tissues and cell lines, and the high expression was closely related to the poor clinicopathological features. Downregulation of fibulin-4 inhibited the proliferation, invasion and migration of ESCC cells in vitro and in vivo. Meanwhile, fibulin-4 knockdown inhibited autophagy of tumor cells by activating the Akt-mTOR signaling pathway and significantly promoted apatinib-induced apoptosis of ESCC cells. CONCLUSION: Our study showed that fibulin-4 is an oncogene that can promote ESCC progression and inhibit apoptosis. Downregulation of fibulin-4 enhances the sensitivity of ESCC cells to apatinib by inhibiting cellular protective autophagy through activating the Akt-mTOR signaling pathway.

Hypoxia-inducible factor-2α promotes EMT in esophageal squamous cell carcinoma through the Notch pathway.

BACKGROUND: Esophageal cancer is one of the most lethal tumors worldwide. The most common histological type in China is esophageal squamous cell carcinoma (ESCC), accounting for 90% of cases. Esophageal cancer occurs at a high incidence in certain areas, among which China has the highest incidence. Although various therapeutic strategies have been used in clinical treatment, the 5-year survival rate is still not satisfactory, as it is only 15-20%. The reason for the poor prognosis of ESCC is that the distant metastasis easily occurs in these tumors. However, the mechanism of metastasis has not been studied clearly. OBJECTIVES: To investigate the function of hypoxia-inducible factor-2α (hif-2α) in ESCC. MATERIAL AND METHODS: Immunohistochemistry and immunofluorescence were used to detect the expression of hif-2α in tissues and cells. Clinicopathological data from 100 ESCC patients were used to investigate the relationship between hif-2α and prognosis. Cell experiments (Cell Counting Kit-8 (CCK-8) assay and transwell migration assays) were utilized to verify the roles of hif-2α on the ESCC cells. Western blotting was used to explore the mechanism of hif-2α in ESCC. Mouse model was used to clarify the effect of hif-2α on ESCC cells in vivo. RESULTS: The hif-2α was overexpressed both in ESCC tissues and cells, and was related with poor prognosis in ESCC patients. The CCK-8 assay evidenced that silencing hif-2α suppressed the proliferation of ESCC cells, while transwell assay - that overexpression of hif-2α promoted the migration of ESCC cells. Western blot assay indicated that hif-2α regulated epithelial-mesenchymal transition (EMT) through Notch pathway in ESCC cells. Mouse model showed that silencing hif-2α significantly suppressed the proliferation of ESCC cells in vivo. CONCLUSIONS: The hif-2α promotes EMT in ESCC through the Notch pathway.

Identification of an Innate Immune-Related Prognostic Signature in Early-Stage Lung Squamous Cell Carcinoma.

BACKGROUND: Early-stage lung squamous cell carcinoma (LUSC) progression is accompanied by changes in immune microenvironments and the expression of immune-related genes (IRGs). Identifying innate IRGs associated with prognosis may improve treatment and reveal new immunotherapeutic targets. METHODS: Gene expression profiles and clinical data of early-stage LUSC patients were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases and IRGs from the InnateDB database. Univariate and multivariate Cox regression and LASSO regression analyses were performed to identify an innate IRG signature model prognostic in patients with early-stage LUSC. The predictive ability of this model was assessed by time-dependent receiver operator characteristic curve analysis, with the independence of the model-determined risk score assessed by univariate and multivariate Cox regression analyses. Overall survival (OS) in early-stage LUSC patients was assessed using a nomogram and decision curve analysis (DCA). Functional and biological pathways were determined by gene set enrichment analysis, and differences in biological functions and immune microenvironments between the high- and low-risk groups were assessed by ESTIMATE and the CIBERSORT algorithm. RESULTS: A signature involving six IRGs (SREBF2, GP2, BMX, NR1H4, DDX41, and GOPC) was prognostic of OS. Samples were divided into high- and low-risk groups based on median risk scores. OS was significantly shorter in the high-risk than in the low-risk group in the training (P < 0.001), GEO validation (P = 0.00021) and TCGA validation (P = 0.034) cohorts. Multivariate Cox regression analysis showed that risk score was an independent risk factor for OS, with the combination of risk score and T stage being optimally predictive of clinical benefit. GSEA, ESTIMATE, and the CIBERSORT algorithm showed that immune cell infiltration was higher and immune-related pathways were more strongly expressed in the low-risk group. CONCLUSION: A signature that includes these six innate IRGs may predict prognosis in patients with early-stage LUSC.

EPB41L5 promotes EMT through the ERK/p38 MAPK signaling pathway in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors worldwide and is characterized by activation of epithelial-mesenchymal transition (EMT). EPB41L5 is regarded as a key factor in the progression of EMT and metastasis in various kinds of cancers, although the role and mechanism of EPB41L5 in ESCC have not yet been elucidated. In addition, tumor cells can acquire enhanced aggressiveness and a mesenchymal phenotype through phosphorylation of MAPK signaling pathway components. Here, we intend to explore whether EPB41L5 can regulate the EMT process in ESCC and reveal whether the MAPK signaling pathway is involved. METHODS: We compared the expression level of EPB41L5 with the prognostic characteristics of 100 ESCC patients to hypothesize the role of EPB41L5 in the progression of ESCC. Furthermore, in vivo and in vitro experiments were conducted to verify the conclusions from the analysis of clinical specimens and investigate the underlying mechanism by which EPB41L5 contributes to ESCC. RESULTS: We discovered that EPB41L5 was overexpressed in ESCC and that higher EPB41L5 expression was related to higher TNM stage, a higher incidence of lymphatic metastasis and worse prognosis. Moreover, using ESCC cells and nude mouse models, we found that EPB41L5 promoted EMT, proliferation, migration and invasion in ESCC. Mechanistically, activation of phosphorylation in the ERK/p38 MAPK signaling pathway was involved in the EPB41L5-mediated regulation of EMT. CONCLUSION: In conclusion, our findings suggest that EPB41L5 plays a critical role in the regulation of EMT and the progression of ESCC.

Targeting MUC1-C reverses the cisplatin resistance of esophageal squamous cell carcinoma in vitro and in vivo.

BACKGROUND: The efficacy of chemotherapeutic treatment of esophageal squamous cell carcinoma (ESCC) is limited by drug resistance during. This severely compromises the long-term survival rate of patients. Therefore, reversing chemotherapy resistance in ESCC may improve the therapeutic outcome. Here, we investigated the molecular mechanism of MUC1-C, the C-terminal transmembrane subunit of MUC1 (a transmembrane heterodimer protein), and its role in the reversal of cisplatin sensitivity in ESCC cells. METHODS: We assessed the efficacy of GO-203, a cell-penetrating peptide, as a chemotherapeutic target of MUC1-C using cell proliferation, colony-forming, and transwell assays. Apoptosis was analyzed in GO-203-treated cells by flow cytometry. Tumor xenograft assay was performed in nude mice to corroborate our in vitro findings. RESULTS: GO-203 treatment inhibited cell proliferation and restrained the migration and invasion of cisplatin-resistant ESCC. Moreover, targeting MUC1 resulted in enhanced apoptosis in GO-203-treated cells. These in vitro pro-apoptotic and anti-proliferative effects of GO-203 in combination with cisplatin were validated by in vivo models. Significantly smaller tumor volumes were observed in ESCCs-xenografted nude mice treated with GO-203 in combination with cisplatin compared with mice treated with monotherapy or their control counterparts. We found that blocking MUC1-C with GO-203 significantly reversed the cisplatin resistance in ESCC via modulating Akt and ERK pathways. CONCLUSIONS: Our findings suggest that GO-203 may hold potential as an ancillary therapeutic molecule and a chemosensitizer to improve the outcomes of cisplatin-based chemotherapy especially in patients with cisplatin-resistant ESCC.

Nanopatterned silk-coated AZ31 magnesium alloy with enhanced antibacterial and corrosion properties.

Because of unique properties such as the lightweight, natural biodegradability, and biocompatibility, magnesium alloys are promising in biomedical implants. However, inadequate corrosion resistance in the physiological environment remains a technical hurdle and application of coatings is a viable means to overcome the deficiency. Also, the antibacterial properties are very important in order to mitigate post-implantation complications arising from bacterial infection. In this study, a biocompatible silk film is deposited on AZ31 Mg alloy to enhance the corrosion resistance and by means of oxygen plasma etching, nature-inspired nanopatterns are fabricated on the surface of the silk film to improve the inherent antibacterial properties. The biocompatibility and antibacterial properties are determined with MC3T3-E1 osteoblast cells and E. coli and S. aureus, respectively. The antimicrobial properties of the silk coated AZ31 are better than those of the bare alloy probably due to the combined effects of the nanopatterns and alkalinity associated with leaching of Mg ions. The ß-sheets formed on the silk film is found to result in 104 times reduction in the corrosion current density and 50% reduction in Mg leaching after 1 day. Although degradation of the ß-sheets is observed to begin after 1 day, the amount of Mg ions leached to the medium from silk-coated AZ31 is still 17% lower than that from the bare one. The biomimicking nanopatterns on the natural silk film improve the corrosion resistance, biocompatibility, and antibacterial properties simultaneously and have large clinical potential.

RUNX3 inhibits the invasion and migration of esophageal squamous cell carcinoma by reversing the epithelial­mesenchymal transition through TGF­ß/Smad signaling.

Runt­related transcription factor 3 (RUNX3) is a candidate tumor suppressor, and its inactivation may play a crucial role in the carcinogenesis process of numerous cancer types, including esophageal squamous cell carcinoma (ESCC). We previously revealed that RUNX3 inactivation was correlated with lymph node metastasis (LNM) and ESCC recurrence. However, the exact mechanisms of this process are still under investigation. The aim of the present study was to examine the potential roles and underlying molecular mechanisms of RUNX3 in ESCC metastasis and the epithelial­mesenchymal transition (EMT). According to the results, RUNX3 expression in ESCC tissue was significantly reduced compared with that in adjacent normal tissue (0.50±0.20 vs. 0.83±0.16; P<0.001). In addition, statistical analysis revealed a close association between decreased RUNX3 expression and T status (P=0.027) and LNM (P=0.017) in ESCC patients. Pearson's correlation coefficient analysis was then used to evaluate correlations between RUNX3 and EMT­related marker expression. The results revealed that RUNX3 expression in ESCC tissues was negatively correlated with the expression of N­cadherin (r=­0.429; P<0.01) and Snail (r=­0.364; P<0.01) and positively correlated with the expression of E­cadherin (r=0.580; P<0.01). Moreover, Eca109 and EC9706 cell invasion, migration, MMP­9 expression and EMT were significantly inhibited by RUNX3 overexpression. Notably, further analysis revealed that RUNX3 overexpression markedly inhibited the phosphorylation of Smad2/3; RUNX3­overexpressing cells also displayed less sensitivity to TGF­ß1­induced EMT than control cells. Thus, RUNX3 may inhibit the invasion and migration of ESCC cells by reversing EMT through TGF­ß/Smad signaling and may be useful as a therapeutic target.

EFEMP2 Suppresses the Invasion of Lung Cancer Cells by Inhibiting Epithelial-Mesenchymal Transition (EMT) and Down-Regulating MMPs.

BACKGROUND: Epidermal growth factor-containing fibulin-like extracellular matrix protein 2 (EFEMP2), also known as fibulin-4, MBP1 and UPH1, is an extracellular matrix protein associated with a variety of tumors. The purpose of this study was to investigate the prognostic value and the function of EFEMP2 in lung cancer. METHODS: The mRNA and protein expression of EFEMP2 in lung normal and cancer tissues, lung cancer cell lines (A549, H460, H1299 and H1650) and normal epithelial cell line BEAS-2B were evaluated by immunohistochemistry, RT-qPCR and Western blotting. The Public databases (Oncomine and Kaplan-Meier plotter) were used to investigate the prognostic value of EFEMP2 in lung cancer. RNA interference (RNAi) and overexpression transfection were performed to detect the effects of EFEMP2 up- or down-regulation on lung normal and cancer cell proliferation, invasion and metastasis in vitro and in vivo. RESULTS: EFEMP2 was lowly expressed in lung cancer tissues and cells, and its low expression was associated with malignant phenotype and poor prognosis of lung cancer. The same conclusion had been drawn from the Public databases. EFEMP2 overexpression significantly inhibited the invasion of lung cancer cells, hampered the process of EMT, and decreased the expression and activity of MMP2 and MMP9, while EFEMP2 knockdown remarkably enhanced the invasion of lung cancer cells, promoted EMT, and increased the expression and activity of MMP2 and MMP9. CONCLUSION: The low expression of EFEMP2 was detected in lung cancer and was positively correlated with the poor prognosis of patients. EFEMP2 was a tumor suppressor gene that inhibited the progress of lung cancer, which suggested a new research objective for the future studies.

Impact of epidural analgesia during labor on breastfeeding initiation and continuation: a retrospective study.

Objective: Although epidural analgesia is widely used during labor, its impact on breastfeeding has not yet reached a consensus. This retrospective cohort study was to investigate the association of patient-controlled epidural analgesia (PCEA) during labor with breastfeeding initiation and continuation.Methods: Medical records from 1 February, 2016 to 31 December, 2016 at Guangzhou Women and Children's Medical Center, China were reviewed for women received PCEA or not. Breastfeeding continuation was assessed by a questionnaire at 6 months after hospital discharge.Results: Nine hundred twenty-two women were enrolled in the study, with 527 of these women received PCEA for labor analgesia. The proportion of timely initiation of breastfeeding (within 1 h after birth), and exclusive or partial breastfeeding at any of the evaluation time points (1, 3, and 6 months) between two groups showed no statistically significant difference.Conclusion: Our data do not support an association between the PCEA and discontinuation of breastfeeding within 6 months postpartum.

DNAJB6 Promotes Ferroptosis in Esophageal Squamous Cell Carcinoma.

BACKGROUND: DnaJ/Hsp40 homolog, subfamily B, member 6 (DNAJB6) is significantly down-regulated in esophageal squamous cell carcinoma (ESCC), while its complicated molecular mechanisms are still unknown. AIMS: To investigate the relationship between DNAJB6 and ESCC. METHODS: The expression of DNAJB6 was detected in ESCC patient by Western blot and immunohistochemistry. To overexpress DNAJB6a by lentivirus infection, colony-forming, CCK-8, transwell, mouse xenograft assays were utilized to verify the proliferous, invasive, and migratory role of DNAJB6a in ESCC cells. The MDA and GSH assays determine whether DNAJB6a participates in cell redox reaction. The variation of AKT and GPX4 was detected by Western blot. RESULTS: The correlation between DNAJB6 level and lymph node metastasis in ESCC patient was negative. Overexpressing DNAJB6a shows tumor-suppressive effects in vitro and in vivo. In addition, DNAJB6a overexpression was accompanied together with a remarkable reduction in the protein levels of GPX4 and phosphorylated AKT (p-AKT). CONCLUSION: DNAJB6 plays an important anti-oncogenic role in ESCC evolvement via ferroptosis.

Atypical calcific tendinitis involving the long biceps tendon: A rare cause of hemiplegic shoulder pain.

BACKGROUND AND OBJECTIVE: Calcific tendinitis is commonly found in the rotator cuff; however, it is very rare in the long biceps tendon (LBT). Furthermore, calcific tendinitis involving the LBT in the hemiplegic shoulder after a stroke has not been previously reported. MATERIALS AND METHOD: We present a case of a 63-year-old man who suffers from a stroke and atypical calcific tendinitis involving the LBT as a rare cause of hemiplegic shoulder pain. The patient had experienced intractable pain in the right hemiplegic shoulder for more than 6 months with a waxing and waning course. Marked tenderness to palpation was present at the biceps tendon adjacent to the bicipital groove. Ultrasound (US) and computed tomography revealed a long, blade-shaped, circumscribed, cloudy and irregular dense calcific deposit in the LBT site, distal to the bicipital groove. The patient underwent US-guided corticosteroid injection at the posterior intra-articular joint. The symptoms failed to resolve; we injected an additional corticosteroid into the biceps tendon sheath adjacent to the calcific deposit. This procedure provided satisfactory relief, and follow-up US revealed mild diminution of the calcification through absorption. CONCLUSION: This is the first report on atypical calcific tendinitis involving the LBT causing hemiplegic shoulder pain after a stroke.

Inhibition of MUC1-C regulates metabolism by AKT pathway in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common digestive tumors worldwide. The Mucin 1 (MUC1) heterodimeric protein has been confirmed that is overexpressed in ESCC and induced adverse outcomes. However, the detailed mechanism(s) remained challenging. So, we investigated the relationship between MUC1-C and metabolism in ESCC cells. In the results, TP53-induced glycolysis and apoptosis regulator (TIGAR) was overexpressed and correlative with MUC1-C positively in ESCC tissue. Targeting MUC1-C inhibits AKT-mTORC-S6K1 signaling and blocks TIGAR translation. We found that the inhibitory effect of GO-203 on TIGAR was mediated by inhibition of AKT-mTOR-S6K1 pathway. The findings also demonstrated that the suppressive effect of GO-203 on TIGAR is related to the decrease of glutathione level, the increase of reactive oxygen species and the loss of mitochondrial transmembrane membrane potential. In xenograft tissues, GO-203 inhibited the growth of ESCC cells and lead to the low expression of transmembrane C-terminal subunit (MUC1-C) and TIGAR. This evidence supports the contention that MUC1-C is significant for metabolism in ESCC and indicated that MUC1-C is a potential target for the treatment of ESCC.

Blocking FGFR4 exerts distinct anti-tumorigenic effects in esophageal squamous cell carcinoma.

BACKGROUND: The FGFR family can be activated by FGFs and plays important roles in regulating cell growth, differentiation, migration, and angiogenesis. Recent studies have suggested that FGFR4 could regulate several processes, including tumor progression. Esophageal squamous cell carcinoma (ESCC) is a malignancy with high global occurrence. However, the molecule mechanism and the potential roles of FGFR4 in ESCC remain unknown. METHODS: Immunohistochemistry and Western blotting were used to detect FGFR4 expression in ESCC samples and cell lines. Cell counting kit-8, and clonogenic, transwell, flow cytometric, and tumor xenograft in nude mice assays were utilized to determine the effect of blocking FGFR4 in proliferation, invasion, migration, and apoptosis of ESCC cells. RESULTS: FGFR4 is frequently overexpressed in ESCC tissue and cell lines. in vitro assays have shown that blocking FGFR4 by a specific blocker, H3B-6527, significantly decreases proliferation, invasion, and migration, and alters epithelial-mesenchymal transition markers in ESCC cells. In addition, FGFR4 blockade is associated with the induction of apoptosis and affects PI3K/Akt and MAPK/ERK pathways. Moreover, FGFR4 blockade could significantly inhibit the growth of xenograft tumors in vivo. CONCLUSION: Our findings suggest that blocking FGFR4 significantly suppresses the malignant behaviors of ESCC and indicate that FGFR4 is a potential target for the treatment of ESCC.

Inhibition of MUC1-C entering nuclear suppresses MYC expression and attenuates malignant growth in esophageal squamous cell carcinoma.

BACKGROUND: The mucin 1 (MUC1) heterodimeric protein (N-terminal subunit and C-terminal subunit) is aberrantly overexpressed in esophageal squamous cell carcinoma (ESCC) and has been linked to poor outcomes in this disease. The detailed mechanism(s), however, remains unclear. In this article, we investigate the effects of the MUC1 C-terminal transmembrane subunit (MUC1-C) through the inhibitor GO-201, which inhibits MUC1-C targeting to nuclear. PATIENTS AND METHODS: The expression of MUC1-C and MYC in the ESCC samples and cell lines was detected by immunohistochemistry, immunofluorescence and western blotting. MYC mRNA level was determined by using quantitative real-time polymerase chain reaction. In addition, Cell Counting Kit-8, clonogenic assay, transwell assay and tumor xenograft in nude mice assay were utilized to determine the role of MUC1-C in proliferation, invasion and migration of ESCC cells. RESULTS: The level of MUC1-C in nuclear and MYC in whole cells in the ESCC tissue is significantly higher than that in the noncancerous tissue. Treatment of MUC1-C-overexpressing ESCC cells with GO-201 was associated with downregulation of MYC expression and induction of apoptosis. Besides, in vitro and in vivo assays have both shown that inhibiting MUC1-C targeting to the nucleus by the GO-201 significantly decreased the abilities of proliferation, invasion and migration in ESCC cells. CONCLUSION: Our findings suggest that MUC1-C targeting to the nucleus plays an important role in suppressing the malignant growth of ESCC and indicate that MUC1-C is a potential target for the treatment of ESCC.

Selecting Bacterial Antagonists for Cucurbit Downy Mildew and Developing an Effective Application Method.

To identify new bacterial antagonists for cucurbit downy mildew (CDM) caused by Pseudoperonospora cubensis, 163 bacterial isolates were recovered from different microenvironments of field-grown cucumber plants. In the greenhouse, 19 representative isolates were applied to cucumber plants as a foliar spray (FS); 7 isolates achieved the efficacy over 60% against CDM, with 5 (DS22, HS10, DP14, HP4, and DS57) identified as Bacillus pumilus, B. licheniformis, Enterobacter sp., Bacillus sp., and Stenotrophomonas maltophilia, respectively. Strains DP14, DS22, and HS10 were assessed for their biocontrol effect on naturally occurring CDM in 2-year field trials (2010 and 2011), in which their overall efficacy relative to that of propamocarb was 106.25 to 117.17% with foliar spray plus root drench (FS+RD) but only 70.98 to 84.03% with FS. Coincidently, DP14 and HS10 applied as root drench (RD) alone also significantly reduced CDM. Under field conditions, DP14, DS22, and HS10 all successfully colonized cucumber leaves and the rhizosphere, and also significantly increased fruit yield by 37.60 to 51.03%, as well as nutrient levels. Taken together, Enterobacter sp. DP14, B. licheniformis HS10, and B. pumilus DS22 are plant-growth-promoting rhizobacteria effective in controlling CDM in the field, whose efficacy increased with FS+RD compared with FS alone.

Association of fibroblast growth factor receptor 1 gene amplification with poor survival in patients with esophageal squamous cell carcinoma.

PURPOSE: To investigate whether FGFR1 gene amplification is associated with clinicopathologic characteristics and its potential impact on survival in patients with resected esophageal squamous cell carcinoma (ESCC). METHODS: Five hundred fifty-six ESCC patients undergoing curative resection of ESCC were retrospectively studied. FGFR1 gene copy number was determined in microarrayed tumor samples using fluorescent in situ hybridization (FISH) analysis. FGFR1 gene amplification status was prespecified as copy number ≥ 6 or FGFR1/CEN 8 ratio ≥ 2.2. FGFR1 expression was evaluated by immunohistochemistry. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method followed by the log rank test. Correlation with survival was examined using multivariate Cox regression. RESULTS: FGFR1 amplification was identified in 67 (12.1%) patients; these patients had significantly shorter OS (50.0 vs 32.0 months; log rank; P<0.001) as well as shorter DFS (47.0 vs 28.0 months; log rank; P<0.001) than those without FGFR1 amplification. Under a Cox proportional hazard model, FGFR1 amplification was associated with significantly shorter OS (adjusted hazard ratio [AHR]=1.61; 95% CI, 1.10-2.43, P=0.004) and DFS (AHR=1.72; 95%CI, 1.15-2.48; P<0.001). Moreover, cases with high intratumoral FGFR1 expression showed significantly shorter OS and DFS than those with low FGFR1 expression. The frequency of FGFR1 amplification was significantly higher in heavy drinkers than in moderate and light drinkers. CONCLUSION: FGFR1 amplification is an independent adverse prognostic factor in surgically resected ESCC. FGFR1 may be a promising therapeutic target in patients with ESCC.

RUNX3 reverses cisplatin resistance in esophageal squamous cell carcinoma via suppression of the protein kinase B pathway.

BACKGROUND: Preoperative chemoradiation combined with surgery has been of focus recently in order to improve prognosis in esophageal squamous cell carcinoma (ESCC) patients. Finding biological markers that may assist in predicting the therapeutic effect of chemoradiation may benefit the treatment effect. In this study, the role of RUNX3 in the formation of cisplatin resistance in ESCC was examined. METHODS: The study enrolled 103 stage IIa-IIIb ESCC patients who had undergone esophagectomy. RUNX3 expression in ESCC tissue was detected. RESULTS: A higher expression of RUNX3 in ESCC patients correlated with a more sensitive response to cisplatin-based chemotherapy. A consistently lower expression of RUNX3 was found in the ESCC tissues of patients who agreed to perioperative chemotherapy compared with patients who had undergone no preoperative treatment. A lower RUNX3 expression in cisplatin-resistant ESCC cell lines, Eca109 and TE-1, was observed compared with parental cell lines. Heterologous RUNX3 expression significantly suppressed cisplatin resistance in Eca109 and TE-1, both in vitro and vivo. Meanwhile, heterologous RUNX3 expression could inhibit growth and induce apoptosis in cisplatin resistant Eca109 and TE-1 cell lines in vitro. Remarkable inhibition of the Akt pathway was observed in heterologous RUNX3 expression in Eca109 and TE-1. Silencing Akt1 could reverse cisplatin resistance in Eca109 and TE-1. CONCLUSION: Our results confirmed that a loss of RUNX3 in ESCC may contribute to cisplatin-resistance. RUNX3 could reverse cisplatin resistance via suppression of the Akt pathway in ESCC patients.