scholarly journals miR-17-5p and miR-4443 Promote Esophageal Squamous Cell Carcinoma Development by Targeting TIMP2

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaojun Wang ◽  
Jiayi Han ◽  
Yatian Liu ◽  
Jingwen Hu ◽  
Ming Li ◽  
...  

BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most frequently diagnosed cancers in the world with a high mortality rate. The mechanism about ESCC development and whether miRNAs play a critical role remains unclear and needs carefully elucidated.Materials and MethodsHigh-throughput miRNA sequencing was used to identify the different expression miRNAs between the ESCC tissues and paired adjacent normal tissues. Next, both CCK-8, Transwell and apotosis assay were used to evaluate the role of miRNA in ESCCcells. In addition, we used bioinformatic tools to predict the potential target of the miRNAs and verified by Western Blot. The function of miRNA-target network was further identified in xenograft mice model.ResultsIn ESCC, we identified two miRNAs, miR-17-5p and miR-4443, were significantly upregulated in ESCC tissues than adjacent normal tissues. TIMP2 was proved to be the direct target of both two miRNAs. The miR-17-5p/4443- TIMP2 axis was shown to promote the tumor progression in vitro and in vivo experiments.ConclusionsThis study highlights two oncomiRs, miR-17-5p and miR-4443, and its potential role in ESCC progression by regulating TIMP2 expression, suggesting miR-17-5p and miR-4443 may serve as a novel molecular target for ESCC treatment.

Author(s):  
Xuechao Jia ◽  
Chuntian Huang ◽  
Yamei Hu ◽  
Qiong Wu ◽  
Fangfang Liu ◽  
...  

Abstract Background Esophageal squamous cell carcinoma (ESCC) is an aggressive and lethal cancer with a low 5 year survival rate. Identification of new therapeutic targets and its inhibitors remain essential for ESCC prevention and treatment. Methods TYK2 protein levels were checked by immunohistochemistry. The function of TYK2 in cell proliferation was investigated by MTT [(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and anchorage-independent cell growth. Computer docking, pull-down assay, surface plasmon resonance, and kinase assay were used to confirm the binding and inhibition of TYK2 by cirsiliol. Cell proliferation, western blot and patient-derived xenograft tumor model were used to determine the inhibitory effects and mechanism of cirsiliol in ESCC. Results TYK2 was overexpressed and served as an oncogene in ESCC. Cirsiliol could bind with TYK2 and inhibit its activity, thereby decreasing dimer formation and nucleus localization of signal transducer and activator of transcription 3 (STAT3). Cirsiliol could inhibit ESCC growth in vitro and in vivo. Conclusions TYK2 is a potential target in ESCC, and cirsiliol could inhibit ESCC by suppression of TYK2.


2021 ◽  
Vol 22 (9) ◽  
pp. 4789
Author(s):  
Shintaro Fujihara ◽  
Hideki Kobara ◽  
Noriko Nishiyama ◽  
Kayo Hirose ◽  
Hisakazu Iwama ◽  
...  

Esophageal squamous cell carcinoma (ESCC) has a poor prognosis when diagnosed at an advanced stage, and early detection and treatment are essential to improve survival. However, intraobserver and interobserver variation make the diagnosis of superficial ESCC difficult, and suitable biomarkers are urgently needed. Here, we compared the microRNA (miRNA) expression profiles of superficial ESCC tissues and adjacent normal tissues obtained immediately before esophageal endoscopic submucosal dissection. We found that ESCC and normal tissues differed in their miRNA expression profiles. In particular, miR-21-5p and miR-146b-5p were significantly upregulated and miR-210-3p was significantly downregulated in tumor tissues compared with normal tissues. We also detected significant associations between miRNA expression and ESCC invasion depth and lymphovascular invasion. The same differential expression of miR-21-5p, miR-146b-5p, and miR-210-3p was detected in ESCC cell lines compared with normal esophageal epithelial cells in vitro. However, transfection of ESCC cells with miR-210-3p and miR-21-5p mimics or inhibitors had partial effects on cell proliferation and invasion in vitro. These results indicate that miRNA expression is significantly deregulated in superficial ESCC, and suggest that the potential contribution of differentially expressed miRNAs to the malignant phenotype should be further investigated.


2020 ◽  
Author(s):  
Xin Yang ◽  
Tian Yang Zeng ◽  
Zi Yang Liu ◽  
Wan Lun He ◽  
Meng Ting Hu ◽  
...  

Abstract Background: Recent studies have shown that Long non-coding RNAs (lncRNAs) are crucial in the invasion, angiogenesis, progression, and metastasis of esophageal squamous cell carcinoma (ESCC). However, the biological functions and potential molecular mechanism of LncRNA GK-IT1 in esophageal squamous cell carcinoma has not been reported.Methods: We analysed the expression of GK-IT1 in ESCC and their adjacent normal tissues in the TCGA database. The quantitative real-time-PCR (qRT-PCR) was used to detect the expression of GK-IT1 in Clinical specimens. The Kaplan-Meier method was employed to draw the survival curve and then the statistical significance was calculated using the logarithmic rank test. a range of functional experiments in vivo and in vitro were used to explore the role of GK-IT1 in the carcinogenesis and development of ESCC. RNA pull down assay, RNA immunoprecipitation (RIP), fluorescence in situ hybridisation (FISH), agarose gel electrophoresis and immunofluorescence were all employed to explore the interaction mechanism between GK-IT1 and MAPK1 (mitogen activated protein kinase 1).Results: The expression of GK-IT1 was higher in ESCC than adjacent normal tissues, which was positively correlated with the clinical stage and shorter survival time. The knockout of the GK-IT1 gene significantly attenuated the abilities of ESCC cell proliferation, invasion and migration, induced apoptosis and autophagy in ESCC cells and inhibited tumour growth and tumour metastasis in vivo. on the contrary, the upregulation of GK-IT1 had the opposite effect. Further studies have shown that GK-IT1 can regulate the biological process of ESCC by regulating the phosphorylation of MAPK1.Conclusion: Our study reveals that GK-IT1 mediated the phosphorylation of MAPK1 improve the carcinogenesis and development of esophageal squamous cell carcinoma through ERK/MAPK pathway which indicates that GK-IT1 possesses substantial potential as a novel biomarker for ESCC prognosis and therapy.


2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaodan Wu ◽  
Yihui Fan ◽  
Yupeng Liu ◽  
Biao Shen ◽  
Haimin Lu ◽  
...  

Long non-coding RNAs (lncRNAs) have been shown to play important roles in human cancers, including esophageal squamous cell carcinoma (ESCC). In the current study, we identified CCAT2 as a relevant lncRNA and investigated its role in the progression of ESCC. RT-qPCR was adopted to detect CCAT2 expression in collected clinical samples, ESCC cell lines, and a normal cell line. We tested the correlation between CCAT2 expression and the prognosis of ESCC. RT-qPCR or immunoblotting was adopted to detect the expression of relevant factors in ESCC tissues or cells. Cell proliferation, apoptosis, migration, and invasion were examined by colony formation assay, flow cytometry, scratch assay, and Transwell assay, respectively, while subcutaneous tumorigenesis in nude mice was adopted to examine the role of CCAT2 in tumorigenesis of ESCC cells in vivo. Bioinformatics analysis, dual luciferase reporter assay, and RIP were conducted for the target relationship profiling. Me-RIP was adopted to detect m6A modification level of TK1 in ESCC tissues or cells. Upregulated CCAT2, IGF2BP2, and TK1 expression and inhibited miR-200b expression were observed in ESCC cells and tissues. CCAT2 bound to miR-200b and reduced its expression, leading to upregulated IGF2BP2 expression. IGF2BP2 improved TK1 mRNA stability to enhance its expression by recognizing its m6A modification. CCAT2 promoted the migration and invasion of ESCC cells in vitro, and tumorigenesis in vivo by upregulating TK1 expression, while overexpression of miR-200b reversed these effects of CCAT2. Overall, this study suggests that CCAT2 competitively binds to miR-200b to alleviate its inhibitory effects on IGF2BP2 expression, resulting in elevated TK1 expression, and an ensuing promotion of the development of ESCC.


2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Wei Gao ◽  
Yuliang Zhang ◽  
Hongjie Luo ◽  
Min Niu ◽  
Xiwang Zheng ◽  
...  

Abstract Spindle and kinetochore-associated complex subunit 3 (SKA3) is a well-known regulator of chromosome separation and cell division, which plays an important role in cell proliferation. However, the mechanism of SKA3 regulating tumor proliferation via reprogramming metabolism is unknown. Here, SKA3 is identified as an oncogene in laryngeal squamous cell carcinoma (LSCC), and high levels of SKA3 are closely associated with malignant progression and poor prognosis. In vitro and in vivo experiments demonstrate that SKA3 promotes LSCC cell proliferation and chemoresistance through a novel role of reprogramming glycolytic metabolism. Further studies reveal the downstream mechanisms of SKA3, which can bind and stabilize polo-like kinase 1 (PLK1) protein via suppressing ubiquitin-mediated degradation. The accumulation of PLK1 activates AKT and thus upregulates glycolytic enzymes HK2, PFKFB3, and PDK1, resulting in enhancement of glycolysis. Furthermore, our data reveal that phosphorylation at Thr360 of SKA3 is critical for its binding to PLK1 and the increase in glycolysis. Collectively, the novel oncogenic signal axis “SKA3-PLK1-AKT” plays a critical role in the glycolysis of LSCC. SKA3 may serve as a prognostic biomarker and therapeutic target, providing a potential strategy for proliferation inhibition and chemosensitization in tumors, especially for LSCC patients with PLK1 inhibitor resistance.


Author(s):  
Zhirong Li ◽  
Xuebo Qin ◽  
Wei Bian ◽  
Yishuai Li ◽  
Baoen Shan ◽  
...  

Abstract Background In recent years, long non-coding RNAs (lncRNAs) are of great importance in development of different types of tumors, while the function of lncRNA ZFAS1 is rarely discussed in esophageal squamous cell carcinoma (ESCC). Therefore, we performed this study to explore the expression of exosomal lncRNA ZFAS1 and its molecular mechanism on ESCC progression. Methods Expression of ZFAS1 and miR-124 in ESCC tissues was detected. LncRNA ZFAS1 was silenced to detect its function in the biological functions of ESCC cells. A stable donor and recipient culture model was established. Eca109 cells transfected with overexpressed and low expressed ZFAS1 plasmid and miR-124 inhibitor labeled by Cy3 were the donor cells, and then co-cultured with recipient cells to observe the transmission of Cy3-ZFAS1 between donor cells and recipient cells. The changes of cell proliferation, apoptosis, invasion, and migration in recipient cells were detected. The in vivo experiment was conducted for verifying the in vitro results. Results LncRNA ZFAS1 was upregulated and miR-124 was down-regulated in ESCC tissues. Silencing of ZFAS1 contributed to suppressed proliferation, migration, invasion and tumor growth in vitro and induced apoptosis of ESCC cells. LncRNA ZFAS1 was considered to be a competing endogenous RNA to regulate miR-124, thereby elevating STAT3 expression. Exosomes shuttled ZFAS1 stimulated proliferation, migration and invasion of ESCC cells and restricted their apoptosis with increased STAT3 and declined miR-124. Furthermore, in vivo experiment suggested that elevated ZFAS1-exo promoted tumor growth in nude mice. Conclusion This study highlights that exosomal ZFAS1 promotes the proliferation, migration and invasion of ESCC cells and inhibits their apoptosis by upregulating STAT3 and downregulating miR-124, thereby resulting in the development of tumorigenesis of ESCC.


Author(s):  
Wei Cui ◽  
Tingting Fang ◽  
Zhaoheng Duan ◽  
Dongfang Xiang ◽  
Yanxia Wang ◽  
...  

Platinum-based regimens have been routinely used in the clinical treatment of patients with esophageal squamous cell carcinoma (ESCC). However, administration of these drugs is frequently accompanied by drug resistance. Revealing the underlying mechanisms of the drug resistance and developing agents that enhance the sensitivity to platinum may provide new therapeutic strategies for the patients. In the present study, we found that the poor outcome of ESCC patients receiving platinum-based regimens was associated with co-expression of Shh and Sox2. The sensitivity of ESCC cell lines to cisplatin was related to their activity of Shh signaling. Manipulating of Shh expression markedly changed the sensitivity of ESCC cells to platinum. Continuous treatment with cisplatin resulted in the activation of Shh signaling and enhanced cancer stem cell-like phenotypes in ESCC cells. Dihydroartemisinin (DHA), a classic antimalarial drug, was identified as a novel inhibitor of Shh pathway. Treatment with DHA attenuated the cisplatin-induced activation of the Shh pathway in ESCC cells and synergized the inhibitory effect of cisplatin on proliferation, sphere and colony formation of ALDH-positive ESCC cells in vitro and growth of ESCC cell-derived xenograft tumors in vivo. Taken together, these results demonstrate that the Shh pathway is an important player in cisplatin-resistant ESCC and DHA acts as a promising therapeutic agent to sensitize ESCC to cisplatin treatment.


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