Domperidone inhibits cell proliferation via targeting MEK and CDK4 in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of digestive system tumor related death in the world. Unfortunately, effective chemopreventive agent is lack for patients with ESCC in clinical practice, which leads to the extremely high mortality rate. METHODS: A library of prescribed drugs was screened for finding critical anti-tumor properties in ESCC cells. The phosphoproteomics, kinase array, pulldown assay and drug affinity responsive target stabilization assay (DARTS) were applied to explore mechanisms and searched for synergistic targets. Established models of PDX in mice were used to determine the therapeutic effect of domperidone. RESULTS: After screening a library of prescribed drugs, we discovered that domperidone has anti-tumor properties. Domperidone, acting as a gastroprokinetic agent, has been widely used in clinic for gastrointestinal motility disorders. Despite limited research, there are indications that domperidone may have anti-tumor properties. In this study, we determined that domperidone significantly inhibited ESCC proliferation in vitro and in vivo. We employed phosphoproteomics to reveal p-ERK, and p-SMAD3 down-regulation upon domperidone treatment. Then, the results of kinase assay and pulldown assay further validated that domperidone directly combined with MEK1/2 and CDK4, leading to the inhibition of their kinase activity. Furthermore, our results revealed that MEK/ERK and CDK4/SMAD3 signal pathway were major pathways in domperidone against ESCC. CONCLUSION: Collectively, these findings suggest that domperidone serves as an effective "multi-target" inhibitor of MEK1/2 and CDK4, offering potential benefits for the chemoprevention of ESCC.

Gain optimization of an erbium-ytterbium co-doped amplifier via a Si3N4 photonic platform.

Erbium-doped waveguide amplifiers enable the integration of various active functions on a silicon platform. Er3+ can provide the basis for efficient optical amplification of photonic integrated circuits, but the gain is limited by cooperative upconversion leading to doping concentration limitations and insufficient optimization of the waveguide structure. In this paper, an erbium-ytterbium co-doped Al2O3 amplifier has been innovatively implemented on a low loss Si3N4 waveguide by careful design and optimization with the finite difference method. A more accurate and comprehensive theoretical model of erbium-ytterbium co-doping is established, with consideration of upconversions, energy transfer, amplified spontaneous radiation and propagation loss to perform optimization of the high-gain erbium-ytterbium co-doped waveguide amplifier. The optimized waveguide amplifier achieves a small-signal gain of more than 36 dB at 1550 nm under Er3+ concentration of 3 × 1020 cm-3 and Yb3+ concentration of 3 × 1021 cm-3. Endowing Si3N4 photonic integrated circuits with gain can enable the miniaturization of various on-chip based active devices.

Design and optimization of GI-PCF supporting the orbital angular momentum modes based on negative curvature structure.

Based on the negative curvature structure, we design a graded-index photonic crystal fiber (GI-PCF) supporting the orbital angular momentum (OAM) mode transmission and discuss its optimization strategy. The core of the designed GI-PCF is sandwiched by three-layer inner air-hole arrays with gradually decreasing air-hole radii and a single outer air-hole array, where the inner side of the annular core forms a graded refractive index distribution. All these structures are clad with negative-curvature tubes. By optimizing characteristic structural parameters, including the air-filling fraction of the outer array, the air-hole radii of the inner arrays, and the thickness of the tubes, the GI-PCF can support 42 OAM modes and most of them have a purity greater than 85%. Compared with conventional structures, the present design of GI-PCF has better properties on an overall level, which can stably transmit multiple OAM modes with high mode purity. These results inject new interest in the flexible design of PCF and have potential applications in various fields, including but not limited to the mode division multiplexing system and terabit data transmission.

Structural stability design of an optical mirror mount adjustment mechanism.

The stability of beam pointing in a laser system depends on the consistency of the optical mirror mount. Typically, a locking mechanism is used to secure the adjustment mechanism after beam alignment, ensuring the mount's stability. However, this process can introduce errors, causing a drift in the optical path. To mitigate this issue, in this study, an interference fit adjustment screw was designed. This development enables the mechanism to self-lock after beam alignment, thereby preventing optical path drift and enhancing overall stability. Specifically, 14 long-term thermal shock stability tests, each lasting 2500 min, were conducted to validate the proposed design. The experimental results showed that the thermal drift of the interference fit adjustment screw was reduced by 47.16%, thermal shift was reduced by 79.59%, and the long-term stability improved by at least 48.67%.

p21-activated kinase 4 promotes the progression of esophageal squamous cell carcinoma by targeting LASP1.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors of the digestive tract in humans. Several studies have indicated that PAK4 is associated with the risk of ESCC and may be a potential druggable kinase for ESCC treatment. However, the underlying mechanism remains largely unknown. The aim of our study is to identify the functional role of PAK4 in ESCC. To determine the expression of PAK4 in ESCC, Western blot analysis and immunohistochemistry were performed, and the results showed that PAK4 is significantly upregulated in ESCC tissues and cell lines compared with normal controls and normal esophageal epithelial cell line. To further investigate the role of PAK4 in ESCC, cell viability assays, anchorage-independent cell growth assays, wound healing assays, cellular invasion assays, in vivo xenograft mouse models, and metastasis assays were conducted, and the results showed that PAK4 can significantly facilitate ESCC proliferation and metastasis in vitro and in vivo. To determine the potential target of PAK4 in ESCC progression, a pull-down assay was performed, and the results showed that LASP1 may be a potential target of PAK4. An immunoprecipitation assay and confocal microscopy analysis confirmed that PAK4 can bind to and colocalize with LASP1 in vitro and in cells. Notably, rescue experiments further illustrated the mechanistic network of PAK4/LASP1. Our research reveals the oncogenic roles of PAK4 in ESCC and preliminarily elucidates the mechanistic network of PAK4/LASP1 in ESCC.

Retraction Note: Mir-655 up-regulation suppresses cell invasion by targeting pituitary tumor-transforming gene-1 in esophageal squamous cell carcinoma.

The Editor-in-Chief has retracted this article [1] because Figure 3a overlaps with Figure 2 in [2]. An investigation by Zhengzhou University has confirmed this. The data reported in this article are therefore unreliable. There is also considerable text overlap with a previously published article [3]. Guoqiang Zhao does not agree with this retraction. The other authors have not responded to correspondence from the editor about this retraction.

Correction to: TOPK promotes metastasis of esophageal squamous cell carcinoma by activating the Src/GSK3ß/STAT3 signaling pathway via γ-catenin.

Following publication of the original article [1], the authors reported the errors in Fig. 1C and D, Fig. 2, Fig. 4B and C and Fig. 6D and E.

RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth.

Metastasis is a major cause of cancer-related deaths. Approximately 80% of patients with colorectal cancer develop liver metastasis and 20% develop lung metastasis. We found that at different stages of colon cancer, IFNγ secretion from peripheral blood mononuclear cells was decreased compared with healthy controls. The ribosomal S6 kinase (RSK) family of kinases has multiple cellular functions, and we examined their roles in this observed IFNγ decrease. Flow cytometry analysis of wild-type (WT) and RSK2 knockout (KO) mice revealed significantly lower levels of IFNγ in the RSK2 KO mice compared with the WT mice. Since IFNγ is a component of immunity, which contributes to protection against metastatic carcinomas, we conducted a colon cancer liver metastasis experiment. We found significantly greater metastasis in RSK2 KO mice compared with WT mice. Transcription factor T-bet can directly activate Ifnγ gene transcription. In vitro kinase assay results showed that RSK2 phosphorylated T-bet at serines 498 and 502. We show that phosphorylation of T-bet by RSK2 is required for IFNγ expression, because knockdown of RSK2 expression or overexpression of mutant T-bet reduces IFNγ mRNA expression. To verify the function of the phosphorylation sites, we overexpressed a constitutively active mutant T-bet (S498E/S502E) in bone marrow. Mutant T-bet restored the IFNγ mRNA levels and dramatically reduced the metastasis rate in these mice. Overall, these results indicate that phosphorylation of T-bet is required for the inhibition of colon cancer metastasis and growth through a positive regulation of RSK2/T-bet/IFNγ signaling.

Targeting the overexpressed USP7 inhibits esophageal squamous cell carcinoma cell growth by inducing NOXA-mediated apoptosis.

Increasing evidence suggests that deubiquitinase USP7 participates in tumor progression by various mechanisms and serves as a potential therapeutic target. However, its expression and role in esophageal cancer remains elusive; the anti-cancer effect by targeting USP7 still needs to be investigated. Here, we reported that USP7 was overexpressed in esophageal squamous cell carcinoma (ESCC) tissues compared with adjacent tissues, implying that USP7 was an attractive anticancer target of ESCC. Pharmaceutical or genetic inactivation of USP7 inhibited esophageal cancer cells growth in vitro and in vivo and induced apoptosis. Mechanistically, inhibition of USP7 accumulated poly-ubiquitinated proteins, activated endoplasmic reticulum stress, and increased expression of ATF4, which transcriptionally upregulated expression of NOXA and induced NOXA-mediated apoptosis. These results provide an evidence for clinical investigation of USP7 inhibitors for the treatment of ESCC.

Retraction Note: Overexpression of A613T and G462T variants of DNA polymerase ß weakens chemotherapy sensitivity in esophageal cancer cell lines.

[This retracts the article DOI: 10.1186/s12935-016-0362-x.].

TOPK promotes metastasis of esophageal squamous cell carcinoma by activating the Src/GSK3ß/STAT3 signaling pathway via γ-catenin.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a fatal disease with poor prognosis. The predominant reason for ESCC-related death is distal metastasis. A comprehensive understanding of the molecular mechanism underlying metastasis is needed for improving patient prognosis. T-LAK cell-originated protein kinase (TOPK) is a MAPKK-like kinase, which plays a vital role in various physiological and pathophysiological processes. However, the role of TOPK in ESCC metastasis is unclear. METHODS: Tissue array was used to evaluate the correlation between TOPK expression and ESCC lymph node metastasis. Wound healing assay, transwell assay, and lung metastasis mice model were used to examine the role of TOPK in the migration of ESCC cells in vitro and in vivo. Protein kinase array, mass spectrometry (MS), and molecular modeling were used to examine the pathways and direct target proteins of TOPK that are involved in ESCC metastasis. Additionally, immunofluorescence and western blotting analyses were performed to verify these findings. RESULTS: The enhanced expression of TOPK was correlated with lymph node metastasis in the ESCC tissues. TOPK knockdown or treatment with the TOPK inhibitor (HI-TOPK-032) decreased the invasion and migration of ESCC cells in vitro. HI-TOPK-032 also inhibited the lung metastasis in ESCC cell xenograft in vivo model. Moreover, TOPK promoted the invasion of ESCC cells by activating the Src/GSK3ß/STAT3 and ERK signaling pathways via γ-catenin. CONCLUSION: The findings of this study reveal that TOPK is involved in ESCC metastasis and promoted the ESCC cell mobility by activating the Src/GSK3ß/STAT3 and ERK signaling pathways. This indicated that TOPK may be a potential molecular therapeutic target for ESCC metastasis.

Retraction Note: HAX-1 Promotes the Chemoresistance, Invasion, and Tumorigenicity of Esophageal Squamous Carcinoma Cells.

The Editor-in-Chief has retracted this article [1] because Figure 3c appears to have been modified and reused as Figure 3d.

MiR-149 sensitizes esophageal cancer cell lines to cisplatin by targeting DNA polymerase ß.

Human DNA polymerase ß (polß) is a small, monomeric protein essential for short-patch base excision repair (BER). polß plays an important role in the regulation of chemotherapy sensitivity in tumour cells. In this study, we determined that the expression levels of polß mRNA and miR-149 in tumour tissues were significantly higher than in adjacent non-tumour tissues. We also found that the expression level of miR-149 in EC tumour tissues was inverse to that of polß expression. Bioinformatics analysis and dual-luciferase reporter assay predicted that miR-149 negatively regulates polß expression by directly binding to its 3'UTR. CCK-8 assay indicated that miR-149 could enhance the anti-proliferative effects of cisplatin in EC1 and EC9706 cell lines. Flow cytometry, caspase 3/7 activity, and immunofluorescence microscopy results indicated that miR-149 could enhance the apoptotic effects of cisplatin in EC1 and EC9706 cell lines. We also showed that the expression of polß lacking the 3'UTR sequence could override the proliferative and apoptotic functions of miR-149, suggesting that miR-149 negatively regulates polß expression by binding to its 3'UTR. Surface plasmon resonance results also showed that miR-149 could bind with wild-type polß. In addition, we identified a new variant of polß (C1134G). In conclusion, this study confirms that miR-149 may enhance the sensitivity of EC cell lines to cisplatin by targeting polß, and that miR-149 may be unable to regulate the C1134G variant of polß. Based on these findings, potential drugs could be developed with a focus on enhanced sensitivity of EC patients to chemotherapy.

Quercetin-3-methyl ether inhibits esophageal carcinogenesis by targeting the AKT/mTOR/p70S6K and MAPK pathways.

Esophageal squamous cell carcinoma (ESCC) is highly prevalent in Asia, especially in China. Research findings indicate that nitrosamines, malnutrition, unhealthy living habits, and genetics contribute to esophageal carcinogenesis. Currently, the 5-year survival rate for ESCC patients remains low, owing in part to a lack of a clear understanding of mechanisms involved. Chemoprevention using natural or synthesized compounds might be a promising strategy to reduce esophageal cancer incidence. The epidermal growth factor receptor (EGFR) can activate downstream pathways including the phosphatidylinositol 3-kinase (PI3K) pathway and the Ras/mitogen-activated protein kinase (MAPK) pathways. Among the important players, AKT and ERKs have an important relationship with cancer initiation and progression. Here, we found that phosphorylated (p)-AKT and p-ERKs were highly expressed in esophageal cancer cell lines and in esophageal cancer patients. Human phospho-kinase array and pull-down assay results showed that quercetin-3-methyl ether (Q3ME) is a natural flavonoid compound that interacted with AKT and ERKs and inhibited their kinase activities. At the cellular level, Q3ME attenuated esophageal cancer cell proliferation and anchorage-independent growth. Western blot analysis showed that this compound suppressed the activation of AKT and ERKs downstream signaling pathways, subsequently inhibiting activating protein-1 (AP-1) activity. Importantly, Q3ME inhibited the formation of esophageal preneoplastic lesions induced by N-nitrosomethylbenzylamine (NMBA). The inhibition by Q3ME was associated with decreased inflammation and esophageal cancer cell proliferation in vivo. Collectively, our data suggest that Q3ME is a promising chemopreventive agent against esophageal carcinogenesis by targeting AKT and ERKs.

Establishment of lung cancer patient-derived xenograft models and primary cell lines for lung cancer study.

BACKGROUND: The overall 5-year survival rate of lung cancer is about 15% even with therapeutic drugs like tyrosine kinase inhibitors. Ideal models are urgently needed for exploring mechanisms and finding new drugs. Patient-derived xenografts (PDX) models and primary cells are both used to screen therapeutic regimens for cancer. However, PDX models and primary cells from the same patient are difficult to establish. Their consistency to the original tumor tissue is not well studied. METHODS: 31 lung cancer patient tissues were procured to establish the lung cancer PDX models and primary cell lines. Tumor growth measurements, histological and immunohistochemistry analysis, Western blotting, EGFR and K-RAS mutation detection and gefitinib sensitive assay were performed to evaluate the characteristic of established PDX models. Immunofluorescence analysis, anchorage-independent cell growth, Western blotting and gefitinib sensitive assay were performed to assay the characteristic of established primary cell lines. The whole-exome sequencing was used to compare the characteristic of the patient's tumor tissue, established PDX and primary cell line. RESULTS: Twenty-one lung cancer PDX models (67.74%, 21/31) and ten primary cell lines (32.25%, 10/31) were established from patients' tumor tissues. The histology and pathological immunohistochemistry of PDX xenografts are consistent with the patients' tumor samples. Various signal pathways were activated in different PDX models (n = 5) and primary cell lines (n = 2). EGFR mutation PDX model and primary cell line (LG1) were sensitive to gefitinib treatment. The expression of CK8/18, TTF1 and NapsinA in LG1 and LG50 primary cells were also positive. And the activated signal pathways were activated in LG1 and LG50 primary cell lines. Furthermore, the gene mutation in PDX tumor tissues and primary cell line (LG50) was consistent with the mutation in LG50 patient's tumor tissues. CONCLUSION: These data suggested that established lung cancer PDX models and primary cell lines reserved mostly molecular characteristics of primary lung cancer and could provide a new tool to further understand the mechanisms and explore new therapeutic strategies.

RETRACTED: The long noncoding RNA CASC2 inhibits tumorigenesis through modulating the expression of PTEN by targeting miR-18a-5p in esophageal carcinoma.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. In the article Figure 3A top and center panel are duplicated and in Figure 5A elements are duplicated from previous publications from the same authors in Tumor Biol. (2014) 35:12583­12592 DOI 10.1007/s13277-014-2579-4 (Figure 3) and Dig Dis Sci (2013) 58:706­714 DOI 10.1007/s10620-012-2395-x (Figure 8). The authors recognize mishandling of these images which affects the validation of the study and would like to apologize to readers.

General self-efficacy modifies the effect of stress on burnout in nurses with different personality types.

BACKGROUND: Burnout is a health problem in nurses. Individuals with a certain personality are more susceptible to job-related burnout. General self-efficacy (GSE) is an important predictor of job-related burnout. The relationships between general self-efficacy, job-related burnout and different personality types are still not clear. This study aims to analyze the relationships of job-related burnout, stress, general self-efficacy and personality types, as well as their interactions in job-related burnout. METHOD: A cross-sectional survey of 860 nurses was conducted between June and July 2015 in China. We measured their job-related burnout using the scale of the Maslach Occupational Burnout Scale, and personality, stress, and GSE. Machine learning of generalized linear model were performed. RESULTS: Maslach Burnout Inventory (MBI) professional efficacy was significantly associated with gender, marital status, age, job title and length of service. A machine learning algorithm showed that stress was the most important factor in job-related burnout, followed by GSE, personality type (introvert unstable), and job title. Individuals with low GSE and either introversion or unstable (high neuroticism) personality seemed to have stronger burnout when they faced stress (regardless of stress intensity) compared to others. CONCLUSION: Stress, GSE and introvert unstable personality are the top three factors of job-related burnout. GSE moderates the effect of stress on burnout in nurses with extroversion or neuroticism personality. Reducing stress, increasing GSE, and more social support may alleviate job-related burnout in nurses. Nurses with introvert unstable personality should be given more social support in reducing stress and enhancing their GSE.

α-Solanine Modulates the Radiosensitivity of Esophageal Cancer Cells by Inducing MicroRNA 138 Expression.

BACKGROUND: Esophageal cancer (EC) is one of the most common malignant tumors in the world. Due to difficulties with performing the operation, most patients choose to have palliative treatment instead. Radiotherapy is one of the main palliative treatments of EC. However, the clinical efficacy of radiotherapy is not satisfactory α-Solanine is a bioactive component of steroidal glycoalkaloids which has been demonstrated to exhibit anti-metastasis activity in different cancers. In the present study, we determined the effect of α-solanine on the radiosensitivity of EC cells and priliminarily explored the underlying molecular mechanisms. METHODS: Cell Counting Kit-8 (CCK-8) assay was conducted to found the cytotoxic effect of α-solanine on EC cells. CCK-8 assay and colony-forming survival assays were performed to explore the effect of α-solanine on cell viability and proliferation of EC cells after irradiation. Immunofluorescence and comet assays were used to detect the effect of α-solanine on DNA repair capacity of EC cells after irradiation. The flow cytometry (FCM) and Hoechst/PI staining were conductd to study the effect of α-solanine on apoptosis of EC cells after irradiation. RESULTS: The cytotoxic effect of α-solanine to EC cells was dose-dependent. The results of CCK-8, colony-forming survival assay, immunofluorescence, comet assay, FCM and Hoechst/PI staining showed that α-solanine could enhance the radiosensitivity of EC cells. α-Solanine could downregulate Survivin expression level by upregulating miR-138 expression in EC cells. Upregulation of miR-138 and knock down Survivin both enhanced the radiosensitivity of EC cells. Moreover, Survivin could restore the effect of α-solanine and miR-138 on radiosensitivity of EC cells. CONCLUSIONS: α-solanine could enhance the radiosensitivity of esophageal cancer cells by inducing microRNA-138 expression, and probably be an effective radiosensitizer in treating EC.

Caveolin-1 affects tumor drug resistance in esophageal squamous cell carcinoma by regulating expressions of P-gp and MRP1.

Esophageal squamous cell carcinoma (ESCC) is the most common cancer in China, and multidrug resistance (MDR) remains one of the biggest problems in ESCC chemotherapy. In this study, we aimed to investigate the mechanism of Caveolin-1, an integral membrane protein, on regulating ESCC MDR. First, immunohistochemistry was used to check the protein expression of Caveolin-1, MDR-related protein of P-glycoprotein (P-gp), and multidrug resistance protein 1 (MRP1) in 84 pathologically characterized ESCC tissues, matched adjacent tumor, and adjacent normal-looking tissues. The results showed that Caveolin-1 expression level was elevated in ESCC tissues than that of matched adjacent tumor and adjacent normal-looking tissues (P < 0.05), and the expression of Caveolin-1 has close correlation with P-gp and MRP1 during tumor genesis of ESCC (P = 0.034, P = 0.009, respectively). Then, Caveolin-1 overexpression and knockdown were used to investigate its effect on expressions of P-gp and MRP1 in ESCC cell line Ec9706. The messenger RNA (mRNA) and protein expression levels of P-gp and MRP1 were checked by real-time quantitative reverse transcription-PCR (qRT-PCR) and Western blot (WB). The results showed that Caveolin-1 overexpression significantly promotes the mRNA and protein expression of MRP1 (P < 0.05), while almost has no effect on the mRNA and protein expression of P-gp (P > 0.05); Cavoelin-1 knockdown inhibits the mRNA and protein expressions of both P-gp and MRP1 (P < 0.05). The similar result was found in another ESCC cell line Eca109. So, it is concluded that Caveolin-1 affects ESCC MDR by regulating the expressions of P-gp and MRP1; therefore, it can be taken as a significant marker and target in tumor therapy.

G648C variant of DNA polymerase ß sensitizes esophageal cancer to chemotherapy.

Human DNA polymerase ß (polß) is a small monomeric protein that is essential for short-patch base excision repair. It plays an important role in regulating the sensitivity of tumor cells to chemotherapy. We have previously identified a G to C point mutation at nucleotide 648 (G648C) of polß in esophageal cancer (EC). In this study, we evaluated the mutation of polß in a larger cohort of EC patients by RT-PCR and sequencing analysis. The function of the mutation was evaluated by MTT, in vivo tumor growth, and flow cytometry assays. The G648C mutation occurred in 15 (3.45 %) of 435 EC patients. In addition, patients with this mutation had significantly longer survival time than those without, following postoperative chemotherapy. Cell lines with G648C mutation in polß gene were more sensitive to treatment with 5-fluorouracil and cisplatin than those with wild-type polß. These results suggest that polß gene with G648C mutation in surgically resected esophagus may be clinically useful for predicting responsiveness to chemotherapy in patients with EC. The polß gene alteration may serve as a prognostic biomarker for EC.