MicroRNAs in esophageal squamous cell carcinoma: Potential biomarkers and therapeutic targets

Mei, Li-Li; Qiu, Yuntan; Zhang, Bing; Shi, Zhi‐Zhou

doi:10.3233/cbm-160240

Cited by 64 publications

(41 citation statements)

References 68 publications

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“…In addition, the combination of erlotinib with other agents, showing even greater effects in inhibition of human cancer cells through multiple molecular mechanisms, have also been reported in other studies [54][55][56]. Our findings suggest that ATL-1 might sensitize or enhance the effect of erlotinib in the controlling human lung cancer cell growth or vice versa via targeting the tumor suppressor target genes PDK1 and EZH2 [57], and HOTAIR signaling axis. This implies a potential additive synergy of these agents in EGFR-TKI resistance setting.…”

Section: Discussionsupporting

confidence: 84%

Repression of PDK1- and LncRNA HOTAIR-Mediated EZH2 Gene Expression Contributes to the Enhancement of Atractylenolide 1 and Erlotinib in the Inhibition of Human Lung Cancer Cells

Xiao

Zheng

Tang

et al. 2018

Cell Physiol Biochem

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Background/Aims: We previously showed that the major bioactive compound of Atractylodes macrocephula Koidz atractylenolide 1 (ATL-1) inhibited human lung cancer cell growth by suppressing the gene expression of 3-Phosphoinositide dependent protein kinase-1 (PDK1 or PDPK1). However, the potentially associated molecules and downstream effectors of PDK1 underlying this inhibition, particularly the mechanism for enhancing the anti-tumor effects of epidermal growth factor receptor-tyrosine-kinase inhibitors (EGFR-TKIs), remain unknown. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Western blot analyses were performed to examine the protein expressions of PDK1 and of zeste homolog 2 (EZH2). The levels of long non-coding RNA (lncRNA) and HOX transcript antisense RNA (HOTAIR) were examined via qRT-PCR. RNA-binding protein immunoprecipitation assays were used to analyze HOTAIR interaction with EZH2. The promoter activity of the EZH2 gene was determined using Secrete-Pair Dual Luminescence Assay Kit. Exogenous expressions of PDK1, HOTAIR, and EZH2 were conducted via transient transfection assays. A xenografted tumor model was used to further evaluate the effect of ATL-1 in the presence or absence of erlotinib in vivo. Results: We showed that the combination of ATL-1 and EGFR-TKI erlotinib further inhibited growth and induced cell arrest of the human lung cancer cells, determined by both MTT and flow cytometry assays. ATL-1 inhibited the protein expression and the promoter activity of EZH2, which was reversed in cells with PDK1 overexpression. Interestingly, ATL-1 inhibited the expression levels of HOTAIR. While silencing HOTAIR inhibited the expressions of PDK1 and EZH2, overexpression of HOTAIR reduced the ATL-1-reduced PDK1 and EZH2 protein expressions and EZH2 promoter activity. In addition, ATL-1 reduced the HOTAIR binding to the EZH2 protein. Moreover, we found that exogenously expressed EZH2 antagonized the effect of ATL-1 on cell growth inhibition. Consistent with the in vitro results, ATL-1 inhibited tumor growth and the expression levels of HOTAIR, protein expressions of EZH2 and PDK1 in vivo. Importantly, there was synergy of the combination of ATL-1 and erlotinib in this process. Conclusion: Here, we provide the first evidence that ATL-1 inhibits lung cancer cell growth through inhibiting not only the PDK1 but also the lncRNA HOTAIR, which results in the reduction of one downstream effector EZH2 expression. The novel interplay between the HOTAIR and EZH2, as well as repressions of the PDK1 and HOTAIR coordinate the overall effects of ATL-1. Importantly, the combination of ATL-1 and EGFR-TKI erlotinib exhibits synergy. Thus, targeting the PDK1- and HOTAIR-mediated downstream molecule EZH2 by the combination of ATL-1 and erlotinib potentially facilitates the development of an additional novel strategy to combat lung cancer.

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Section: Discussionsupporting

confidence: 84%

Repression of PDK1- and LncRNA HOTAIR-Mediated EZH2 Gene Expression Contributes to the Enhancement of Atractylenolide 1 and Erlotinib in the Inhibition of Human Lung Cancer Cells

Xiao

Zheng

Tang

et al. 2018

Cell Physiol Biochem

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“…Several reports point to miRNAs to be involved in Barrett's carcinogenesis 5,6 and in the development of the esophageal squamous cell carcinoma. 7 Recently, Shoji and colleagues performed a miRNA expression profile on esophageal mucosal biopsies from 8 patients with achalasia and 4 healthy volunteers and showed the miRNA-130a highly expressed in patients. 8 In this study, we used miRNA microarrays to identify miRNAs with altered expression in esophageal mucosa of achalasic patients.…”

mentioning

confidence: 99%

microRNA‐mRNA network model in patients with achalasia

Palmieri

Mazza

Bassotti

et al. 2019

Neurogastroenterology Motil

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Background Achalasia is a rare idiopathic disease with a complex etio‐pathogenesis still unknown. This study aimed to identify microRNA (miRNA)‐mRNA regulatory networks underlying achalasia. Methods The investigation was performed in tissue specimens from 11 patients and five controls using the microarray technology followed by an integrated bioinformatics analysis. Key Results One hundred and six miRNAs were significantly up‐regulated and 64 were down‐regulated in achalasia patients. The expression of the most 10 differential expressed miRNAs (miR‐122‐5p, miR‐133a‐3p, miR‐504‐5p, miR‐187‐3p, miR‐133b, miR‐200c‐3p, miR‐375, miR‐200b‐5p, miR‐200b‐3p, and miR203a) was confirmed by droplet digital PCR in an independent cohort. The interactions between the significant miRNAs and their targets uncovered 14 miRNA‐mRNA interacting pairs with experimentally predicted genes (ie, FN1, ROCK2, DPYSL2), and 35 pairs with not experimentally target genes (ie, SULF1, MRVI1, PRKG1); all genes were involved in immune cell trafficking, skeletal and muscular system development, nervous system development macro‐processes. Conclusion & Inferences The mRNA–miRNA regulatory networks described in this study provide new insights in the genetic background of the disease, suggesting further investigations in novel pathogenic mechanisms.

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“…7,22 There are many serological tumor markers in diagnosing and monitoring the malignant tumors. Furthermore, many studies suggested that the abnormal expression of miRNAs could set off adverse clinical and pathological features 29 and cause the invasion and metastasis of ESCC. [23][24][25] miRNAs are known to play a vital role in the occurrence and development of many malignant tumors, [26][27][28] including ESCC.…”

Section: Discussionmentioning

confidence: 99%

miR‐32 promotes esophageal squamous cell carcinoma metastasis by targeting CXXC5

Liu

Jiang

et al. 2018

J of Cellular Biochemistry

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MicroRNA‐32 (miR‐32) functioned as a tumor oncogene in some cancer, which control genes involved in important biological and pathological functions and facilitate the tumor growth and metastasis. However, the role of miR‐32 modulates esophageal squamous cell carcinoma (ESCC) malignant transformation has not been clarified. Here, we focused on the function and the underlying molecular mechanism of miR‐32 in ESCC. Results discovered a significant increased expression of miR‐32 in ESCC tissues and cells. Downregulation of miR‐32 inhibited the migration, invasion, adhesion of ESCC cell lines (EC9706 and KYSE450), and the levels of EMT protein in vitro. In vivo, miR‐32 inhibitors decrease tumor size, tumor weight, and the number of metastatic nodules. Hematoxylin and eosin (H&E) results revealed that inhibition of miR‐32 attenuate lung metastasis. Immunohistochemistry and immunofluorescence assay showed increased level of E‐cadherin and decreased level of N‐cadherin and Vimentin with treatment of miR‐32 inhibitors. Furthermore, miR‐32 targeted the 3′‐untranslated region (3′‐UTR) of CXXC5, and inhibited the level of mRNA and protein of CXXC5. There is a negative correlation between the expressions of CXXC5 and miR‐32. Then, after EC9706 and KYSE450 cells cotransfected with si‐CXXC5 and miR‐32 inhibitors, the ability of cell migration, invasion, and adhesion was significantly reduced. In addition, the protein expression of EMT and TGF‐β signaling was also depressed. Collectively, these data supply an insight into the positive role of miR‐32 in ESCC progression and metastasis, and its biological effects may attribute the inhibition of TGF‐β signaling mediated by CXXC5.

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MicroRNAs in esophageal squamous cell carcinoma: Potential biomarkers and therapeutic targets

Cited by 64 publications

References 68 publications

Repression of PDK1- and LncRNA HOTAIR-Mediated EZH2 Gene Expression Contributes to the Enhancement of Atractylenolide 1 and Erlotinib in the Inhibition of Human Lung Cancer Cells

Repression of PDK1- and LncRNA HOTAIR-Mediated EZH2 Gene Expression Contributes to the Enhancement of Atractylenolide 1 and Erlotinib in the Inhibition of Human Lung Cancer Cells

microRNA‐mRNA network model in patients with achalasia

miR‐32 promotes esophageal squamous cell carcinoma metastasis by targeting CXXC5

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