scholarly journals Exploration of Potential Roles of a New LOXL2 Splicing Variant Using Network Knowledge in Esophageal Squamous Cell Carcinoma

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Bing-Li Wu ◽  
Guo-Qing Lv ◽  
Hai-Ying Zou ◽  
Ze-Peng Du ◽  
Jian-Yi Wu ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Splice Variant ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Splice Variants ◽  
Lysyl Oxidase ◽  
Wild Type

LOXL2 (lysyl oxidase-like 2), an enzyme that catalyzes oxidative deamination of lysine residue, is upregulated in esophageal squamous cell carcinoma (ESCC). A LOXL2 splice variant LOXL2-e13 and its wild type were overexpressed in ESCC cells followed by microarray analyses. In this study, we explored the potential role and molecular mechanism of LOXL2-e13 based on known protein-protein interactions (PPIs), following microarray analysis of KYSE150 ESCC cells overexpressing a LOXL2 splice variant, denoted by LOXL2-e13, or its wild-type counterpart. The differentially expressed genes (DEGs) of LOXL2-WT and LOXL2-e13 were applied to generate individual PPI subnetworks in which hundreds of DEGs interacted with thousands of other proteins. These two DEG groups were annotated by Functional Annotation Chart analysis in the DAVID bioinformatics database and compared. These results found many specific annotations indicating the potential specific role or mechanism for LOXL2-e13. The DEGs of LOXL2-e13, comparing to its wild type, were prioritized by the Random Walk with Restart algorithm. Several tumor-related genes such as ERO1L, ITGA3, and MAPK8 were found closest to LOXL2-e13. These results provide helpful information for subsequent experimental identification of the specific biological roles and molecular mechanisms of LOXL2-e13. Our study also provides a work flow to identify potential roles of splice variants with large scale data.

scholarly journals Splice variant of growth hormone-releasing hormone receptor drives esophageal squamous cell carcinoma conferring a therapeutic target

2020 ◽  
Vol 117 (12) ◽  
pp. 6726-6732 ◽  
Author(s):  
Xiao Xiong ◽  
Xiurong Ke ◽  
Lu Wang ◽  
Zhimeng Yao ◽  
Yi Guo ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Splice Variant ◽  
Splice Variants ◽  
Glycolytic Enzyme ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone

The extrahypothalamic growth hormone-releasing hormone (GHRH) and its cognate receptors (GHRH-Rs) and splice variants are expressed in a variety of cancers. It has been shown that the pituitary type of GHRH-R (pGHRH-R) mediates the inhibition of tumor growth induced by GHRH-R antagonists. However, GHRH-R antagonists can also suppress some cancers that do not express pGHRH-R, yet the underlying mechanisms have not been determined. Here, using human esophageal squamous cell carcinoma (ESCC) as a model, we were able to reveal that SV1, a known splice variant of GHRH-R, is responsible for the inhibition induced by GHRH-R antagonist MIA-602. We demonstrated that GHRH-R splice variant 1 (SV1) is a hypoxia-driven promoter of tumor progression. Hypoxia-elevated SV1 activates a key glycolytic enzyme, muscle-type phosphofructokinase (PFKM), through the nuclear factor kappa B (NF-κB) pathway, which enhances glycolytic metabolism and promotes progression of ESCC. The malignant actions induced by the SV1–NF-κB–PFKM pathway could be reversed by MIA-602. Altogether, our studies demonstrate a mechanism by which GHRH-R antagonists target SV1. Our findings suggest that SV1 is a hypoxia-induced oncogenic promoter which can be an alternative target of GHRH-R antagonists.

PS02.024: PRIMA-1 INDUCES P53-MEDIATED APOPTOSIS BY UPREGULATING NOXA IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA WITH TP53 MISSENSE MUTATION

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 126-127
Author(s):  
Haruna Furukawa ◽  
Tomoki Makino ◽  
Makoto Yamasaki ◽  
Koji Tanaka ◽  
Yasuhiro Miyazaki ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Missense Mutation ◽  
Cell Lines ◽  
Squamous Cell ◽  
Antitumor Effect ◽  
Xenograft Model ◽  
Wild Type ◽  
Massive Apoptosis

Abstract Background TP53 is associated with the resistance of cytotoxic treatment and patient prognosis, and the mutation rate of TP53 in esophageal squamous cell carcinoma (ESCC) is extraordinarily high, at over 90%. PRIMA-1 (p53 re-activation and induction of massive apoptosis) has recently been reported to restore wild type activity to mutant p53 and induce massive p53-dependent apoptosis. APR-246 (methylated PRIMA-1) has been tested in a phase I/II clinical trial with promising results; however, the effects and mechanism in ESCC remain unknown. This study was designed to assess the antitumor effect of PRIMA-1 treatment in both ESCC cell lines with different TP53 status and an ESCC xenograft model and uncover the molecular mechanism of PRIMA-1. Methods After evaluating the TP53 mutation status of a panel of eleven ESCC cell lines by Sanger sequencing, we assessed the in vitro effect of PRIMA-1 administration on cells with different p53 status by conducting cell viability and apoptosis assays. The expression levels of proteins in TP53-related pathways were examined by Western blotting, while knockdown studies were conducted to investigate the mechanism underlying PRIMA-1’s function. An ESCC xenograft model was further used to evaluate the therapeutic effect of PRIMA-1 in vivo. Results PRIMA-1 markedly inhibited cell growth and induced apoptosis by upregulating Noxa expression in ESCC cell lines with a TP53 missense mutation, whereas no apoptosis was induced in ESCC with wild type TP53 and with TP53 frameshift and nonsense mutations. Importantly, the knockdown of Noxa cancelled the apoptosis induced by PRIMA treatment in ESCC cell lines with a TP53 missense mutation. PRIMA-1 administration, compared with placebo, showed a significant antitumor effect by inducing Noxa in the xenograft model of an ESCC cell line with a TP53 missense mutation. Conclusion PRIMA-1 exhibits a significant antitumor effect, inducing massive apoptosis through the upregulation of Noxa in ESCC with a TP53 missense mutation. Disclosure All authors have declared no conflicts of interest.

scholarly journals LINC00261 Suppresses Cisplatin Resistance of Esophageal Squamous Cell Carcinoma Through miR-545-3p/MT1M Axis

2021 ◽  
Vol 9 ◽  
Author(s):  
Lijun Wang ◽  
Xiaojun Wang ◽  
Pengwei Yan ◽  
Yatian Liu ◽  
Xuesong Jiang
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Molecular Mechanisms ◽  
Cure Rate ◽  
Downstream Target ◽  
Downstream Target Gene ◽  
Non Coding Rnas ◽  
New Treatment

To improve the survival rate and cure rate of patients, it is necessary to find a new treatment scheme according to the molecular composition of (ESCC) in esophageal squamous cell carcinoma. Long non-coding RNAs (lncRNAs) regulate the progression of ESCC by various pathophysiological pathways. We explored the possible function of the lncRNA LINC00261 (LINC00261) on cisplatin (DDP) resistance of ESCC and its relative molecular mechanisms. In the study, we found that LINC00261 was downregulated in ESCC tissues, cell lines, and DDP-resistant ESCC patients. Besides, overexpression of LINC00261 not only inhibited cell proliferation, and DDP resistance but also promotes cell apoptosis. Further mechanistic research showed that LINC00261 sponged miR-545-3p which was negatively correlated with the expression of LINC00261. In addition, functional experiments revealed that upregulation of miR-766-5p promoted proliferation and enhanced DDP resistance. Subsequently, MT1M was testified to be the downstream target gene of miR-545-3p. Rescue experiments revealed that overexpression of MT1M largely restores miR-545-3p mimics-mediated function on ESCC progression. Our results demonstrate that the LINC00261 suppressed the DDP resistance of ESCC through miR-545-3p/MT1M axis.

Anterior gradient 2 regulates cancer progression in TP53‑wild‑type esophageal squamous cell carcinoma

2021 ◽  
Vol 46 (6) ◽  
Author(s):  
Kazuya Takabatake ◽  
Hirotaka Konishi ◽  
Tomohiro Arita ◽  
Satoshi Kataoka ◽  
Jun Shibamoto ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cancer Progression ◽  
Squamous Cell ◽  
Wild Type

scholarly journals Dihydroartemisinin Inhibits the Proliferation of Esophageal Squamous Cell Carcinoma Partially by Targeting AKT1 and p70S6K

2020 ◽  
Vol 11 ◽  
Author(s):  
Lili Zhu ◽  
Xinhuan Chen ◽  
Yanyan Zhu ◽  
Jiace Qin ◽  
Tingting Niu ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Molecular Mechanisms ◽  
Kinase Assay ◽  
Anticancer Effects ◽  
Tumor Tissues

Dihydroartemisinin (DHA), a sesquiterpene lactone with endoperoxide bridge, is one of the derivatives of artemisinin. In addition to having good antimalarial properties, DHA exhibits anticancer effects including against malignant solid tumors. However, the mechanism by which DHA inhibits the progression of esophageal cancer, especially esophageal squamous cell carcinoma (ESCC), is unclear. In this study, DHA was found to inhibit the proliferation of ESCC, and the underlying molecular mechanisms were explored. DHA inhibited ESCC cells proliferation and anchorage-independent growth. Flow cytometry analysis revealed that DHA significantly blocked cell cycle in the G1 phase. The results of human phospho-kinase array revealed that DHA downregulated the levels of p70S6KT389 and p70S6KT421/S424. Furthermore, the levels of mTORS2448, p70S6KT389, p70S6KT421/S424 and RPS6S235/S236 were decreased after DHA treatment in KYSE30 and KYSE150 cells. We then explored the proteins targeted by DHA to inhibit the mTOR-p70S6K-RPS6 pathway. Results of the in vitro kinase assay revealed that DHA significantly inhibited phosphorylation of mTORS2448 by binding to AKT1 and p70S6K kinases. In vivo, DHA inhibited the tumor growth of ESCC patient-derived xenografts and weakened p-mTOR, p-p70S6K, and p-RPS6 expression in tumor tissues. Altogether, our results indicate that DHA has antiproliferative effects in ESCC cells and can downregulate mTOR cascade pathway partially by binding to AKT1 and p70S6K. Thus, DHA has considerable potential for the prevention or treatment of ESCC.

PS02.157: ESOPHAGEAL SQUAMOUS CELL CARCINOMA IS ASSOCIATED WITH CHRONIC DISEASES AS WELL AS UNHEALTHY LIFESTYLES

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 166-166
Author(s):  
Jun Nakamura ◽  
Noriaki Manabe ◽  
Ken Haruma ◽  
Rui Nakato ◽  
Takahisa Murao ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Medical History ◽  
Chronic Diseases ◽  
Squamous Cell ◽  
Large Scale ◽  
Conflicts Of Interest ◽  
Gastrointestinal Diseases ◽  
History Of

Abstract Background Cancer and other chronic diseases such as cardiovascular disease, diabetes, chronic kidney disease, and respiratory disease share common risk factors, including aging and unhealthy lifestyles (eg, smoking and alcohol misuse). Although the recent prospective cohort large-scale study showed chronic diseases contributed to more than one fifth of the risk for incident cancer and more than one third of the risk for cancer death, the relation between esophageal squamous cell carcinoma (ESCC) and non-cancer chronic diseases (NCCD) still remain unknown. The aim of this study is to assess the independent and joint associations of major NCCD and ESCC. Methods From April 2011 to March 2017, 406 consecutive patients with ESCC diagnosed pathologically were enrolled. Their medical records as to patients’ background, the reason for their consultation, lifestyles, and medical history were investigated retrospectively in detail. Results As to the reason for their consultation, 45 patients (25.3%) were diagnosed at annual medical checkup (no symptoms), 125 (70.2%) consulted a doctor for any symptoms such as dysphagia, and 8 (4.5%) had other reasons. As to lifestyles, 304 (78.1%) were drinkers of alcohol (daily amount of alcohol consumption > 20g) and 302 (77.4%) were smokers (Brinkman index > 200), respectively. As to the medical history related to cancer or gastrointestinal diseases, 25 (6.8%) had a history of laryngopharyngeal cancer, 20 (5.1%) had a history of gastric cancer, 2 (0.5%) had a history of breast cancer, one (0.3%) had a history of sclerodema, and one (0.3%) had a history of esophageal achalasia. Of the 406 ESCC patients, 305 were early ESCC and the remaining 101 were advanced ESCC. As to the medical history in patients with advanced ESCC, 22 (21.8%) had a history of cancer of other organs, and 48 (47.5%) had NCCD including hypertension (35 patients), diabetes (18 patients), and hyperlipidemia (12 patients). Conclusion NCCD is an overlooked risk factor for ESCC, as important as two major lifestyle factors combined (drinkers of alcohol and smokers). General physicians who follow up NCCD patients should pay attention to the coexistence of ESCC. Disclosure All authors have declared no conflicts of interest.

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