Mannose enhances the radio-sensitivity of esophageal squamous cell carcinoma with low MPI expression by suppressing glycolysis

Background To investigate the effect of mannose on radio-sensitivity of human esophageal squamous cell carcinoma (ESCC) cell line and its possible mechanism. Methods The expression of mannose phosphate isomerase (MPI) in human esophageal cancer cell lines were detected by Western blot. The inhibitory effect of mannose on human esophageal cancer cell lines were observed by MTT assay. Plate clone formation assay was performed to investigate the efficacy of mannose on radio-sensitivity of human esophageal cancer cells. The apoptosis rates of tumor cells treated with mannose and/or radiation therapy was calculated by flow cytometry. Furthermore, we analyzed intracellular metabolites using liquid chromatography mass spectrometry to identify selective sugar metabolites. Results MPI expression was various in human esophageal cancer cells. KYSE70 cells was associated with the highest MPI expression whereas KYSE450 cells had the lowest MPI expression level. When administrated with 11.1 mM/L mannose, the same inhibitory effect was observed in both KYSE70 and KYSE450 cell lines. Moreover, the inhibitory effect was significant on KYSE450 cell lines with an increased mannose concentration. The application of 11.1 mM/L mannose could significantly enhance the radio-sensitivity of KYSE450 cell line; and tumor cell apoptosis rate was also increased. However, there was limited efficacy of mannose on the radio-sensitivity and apoptosis rate of KYSE70 cell line. Additionally, intracellular metabolites analyzation revealed that glycolysis could be disturbed by mannose when combined with radiation therapy in esophageal cancer cells. Conclusion In esophageal cancer cell lines with low MPI expression, the administration of mannose was associated with enhanced radio-sensitivity.

KRT17 Facilitates Proliferation, Migration and Invasion in Esophageal Squamous Cell Carcinoma by Regulating mTOR/S6K1 pathway

BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies worldwide which originates from the malignant transformation of esophageal epithelial cells. Dysregulated expression of Keratin17 (KRT17) has been claimed in a variety of malignancies, while its role in ESCC remains unclear. Therefore, our study aimed to explore the potential function and underlying molecular mechanism of KRT17 in ESCC.MethodsData-independent acquisition-mass spectrometry (DIA-MS) workflow was used to analysis KRT17 expression between ESCC and adjacent non-cancerous esophageal tissues. The online database gene expression profiling interactive analysis (GEPIA) was used to further determine the differential expression of KRT17 in tissues. The function of KRT17 in ESCC was tested on two human esophageal cancer cell lines (EC9706 and ECA109). Small interfering RNA (siRNA) was used to inhibit KRT17 expression. Cell proliferation was examined by cell counting kit 8 (CCK8) reagent, colony formation assay, cell cycle distribution analysis and apoptosis. Cell migration was examined by transwell and wound healing assay. Cell invasion was also examined by transwell assay. Western blot and quantitative real-time PCR (qRT-PCR) was used to evaluate protein and mRNA levels, respectively.ResultsKRT17 expression was higher in cancer tissues compared with normal tissues. Transfected with siKRT17 attenuated protein and mRNA levels of KRT17, inhibited proliferation, migration and invasion, and decreased mTOR/S6K1 phosphorylation levels in EC9706 and ECA109.ConclusionKRT17 facilitates proliferation, migration and invasion in ESCC cells, and these cell viability functions were mediated by mTOR/S6K1 pathway.

Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer

Tumors with elevated c-Myc expression often exhibit a highly aggressive phenotype, and c-Myc amplification has been shown to be frequent in esophageal cancer. Emerging data suggests that synthetic lethal interactions between c-Myc pathway activation and small molecules inhibition involved in cell cycle signaling can be therapeutically exploited to preferentially kill tumor cells. We therefore investigated whether exploiting elevated c-Myc expression is effective in treating esophageal cancer with the CDK inhibitor flavopiridol. We found frequent overexpression of c-Myc in human esophageal cancer cell lines and tissues. c-Myc overexpression correlated with accelerated esophageal cancer subcutaneous xenograft tumor growth. Esophageal cancer cells with elevated c-Myc expression were found preferentially more sensitive to induction of apoptosis by the CDK inhibition flavopiridol compared to esophageal cancer cells with lower c-Myc expression. In addition, we observed that flavopiridol alone or in combination with the chemotherapeutic agent nanoparticle albumin-bound paclitaxel (NPT) or in combinations with the targeted agent BMS-754807 significantly inhibited esophageal cancer cell proliferation and subcutaneous xenograft tumor growth while significantly enhancing overall mice survival. These results indicate that aggressive esophageal cancer cells with elevated c-Myc expression are sensitive to the CDK inhibitor flavopiridol, and that flavopiridol alone or in combination can be a potential therapy for c-Myc overexpressing esophageal cancer.

Loss of grand histone H3 lysine 27 trimethylation domains mediated transcriptional activation in esophageal squamous cell carcinoma

Trimethylation of histone H3 lysine 27 trimethylation (H3K27me3) may be recruited by repressive Polycomb complexes to mediate gene silencing, which is critical for maintaining embryonic stem cell pluripotency and differentiation. However, the roles of aberrant H3K27me3 patterns in tumorigenesis are not fully understood. Here, we discovered that grand silencer domains (breadth > 50 kb) for H3K27me3 were significantly associated with epithelial cell differentiation and exhibited high gene essentiality and conservation in human esophageal epithelial cells. These grand H3K27me3 domains exhibited high modification signals involved in gene silencing, and preferentially occupied the entirety of topologically associating domains and interact with each other. We found that widespread loss of the grand H3K27me3 domains in of esophageal squamous cell carcinomas (ESCCs) were enriched in genes involved in epithelium and endothelium differentiation, which were significantly associated with overexpression with increase of active modifications of H3K4me3, H3K4me1, and H3K27ac marks, as well as DNA hypermethylation in the gene bodies. A total of 208 activated genes with loss of grand H3K27me3 domains in ESCC were identified, where the higher expression and mutation of T-box transcription factor 20 (TBX20) were associated with worse patients’ outcomes. Our results showed that knockdown of TBX20 may have led to a striking defect in esophageal cancer cell growth and carcinogenesis-related pathway, including cell cycle and homologous recombination. Together, our results reveal that loss of grand H3K27me3 domains represent a catalog of remarkable activating regulators involved in carcinogenesis.

MiR-195-5p Reduces Esophageal Cancer Cell Proliferation Through The IGF-1R/AKT Axis

Background Esophageal cancer (ECa) remains a major cause of mortality across the globe. The expression of MiR-195-5p is altered in a plethora of tumors, but its role in ECa development and progression are undefined. Result Here, we show that miR-195-5p is downregulated in ECa and associated with poor survival in ECa. Function assays indicated that MiR-195-5p inhibited ECa progression. Mechanistically, we identified IGF-1R as a downstream target of miR-195-5p, and miR-195-5p/IGFR axis caused a loss of GLUT1 expression, reduced glucose uptake, reduced lactate production, and low levels of ATP production. Conclusion Collectively, miR-195-5p as a Eca suppressor impaired glycolysis. This highlighting miR-195-5p as a novel target for much needed anti-ECa therapeutics.

The Photodynamic Anti-Tumor Effects of New PPa-CDs Conjugate with pH Sensitivity and Improved Biocompatibility

Background: Photodynamic therapy has been increasingly used to cope with the alarming problem of cancer. Porphyrins and its derivatives are widely used as potent photosensitizers (PS) for PDT. However, hydrophobicity of porphyrins poses a challenge for their use in clinics, while most of the carbon dots (CDs) are known for good biocompatibility, solubility, and pH sensitivity. Objective: To improve the properties/biocompatibility of the pyropheophorbide-α for PDT. Methods: Methods: PPa-CD conjugate was synthesized through covalent interaction using amide condensation. The structure of synthesized conjugate was confirmed by TEM, 1HNMR, and FTIR. The absorption and emission spectra were studied. In vitro, cytotoxicity of the conjugate was examined in the Human esophageal cancer cell line (Eca-109). Results: The results showed that the fluorescence of the drug was increased from its precursor. CD based conjugate could generate ROS as well as enhanced the biocompatibility by decreasing the cytotoxicity. The conjugated drug also showed pH sensitivity in different solutions. Conclusion: The dark toxicity, as well as hemocompatibility, were improved.