Regulatory Role of miR-203 in Occurrence and Progression of Kazakh Esophageal squamous cell carcinoma.
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ABSTRACT:
SUBMITTER: Hu JM
PROVIDER: S-EPMC4815010 | biostudies-other | 2016 Mar
REPOSITORIES: biostudies-other
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Project description:Dysregulation of miR-203 by promoter methylation is associated with the development of various cancers. We aimed to explore the underlying link between promoter methylation and miR-203 expression in Kazakh esophageal squamous cell carcinoma (ESCC). MassARRAY® System spectrometry was used to quantitatively analyze the DNA methylation of 32 CpG sites within miR-203 in 99 Kazakh ESCC and 46 normal esophageal tissues (NETs) with similar population characteristics. We conducted real-time PCR to detect miR-203 expression levels and evaluated their association with methylation. Eleven CpG units within miR-203 promoter were frequently hypermethylated in ESCC compared with NETs (P < 0.05). The hypermethylation of several CpG units positively correlated with age, lower esophagus, constrictive type of ESCC, and moderately differentiated ESCC. Given the involvement of human papillomavirus (HPV) in etiology of ESCC was confirmed from our previous reports, herein we found that CpG units within miR-203 in HPV16-positive ESCC are more heavily methylated. Furthermore, miR-203 expression showed a nearly 4.5-fold decrease in ESCC than NETs (0.206 ± 0.336 vs. 0.908 ± 1.424, P < 0.001) and was significantly associated with lymph node metastasis (P = 0.012). The expression of miR-203 with 11 completely hypermethylated CpG units was approximately 6.5-fold lower than that with at least 1 unmethylated CpG unit (P < 0.001) and especially the CpG_15.16 and CpG_31.32 with higher methylation levels in ESCC tissues exhibited lower expression levels of miR-203, which indicated a reverse association between miR-203 methylation and expression. Hypermethylated miR-203 is a potential biomarker and targeted delivery of miR-203 could therefore serve as a preventive or therapeutic strategy for Kazakh ESCC.
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Project description:MicroRNAs are involved in tumor initiation and progression by regulating oncogenes and tumor suppressor genes. Here we found that miR-495 are lower in clinical ESCC tissues than in adjacent non-tumor tissues. Moreover, the lower miR-495 expression correlated with increased lymph node metastasis (LNM), invasion and TNM stage. miR-495 overexpression predicted a favorable outcome in ESCC patients. miR-495 targeted a site in the 3'-UTR of Akt1, and miR-495 levels correlated inversely with Akt1 protein levels in ESCC tissue samples. Overexpression of miR-495 suppressed cell proliferation, blocked G1/S phase transition, and decreased migration and invasion by two ESCC cell lines in vitro and in vivo. Restoration of Akt1 protein levels in miR-495-overexpressing ESCC cells attenuated the inhibitory effects of miR-495. In addition, miR-495 suppressed cell cycle transition and the EMT signaling pathway through targeting Akt1, thereby inhibiting ESCC cell proliferation, migration, and invasion. Our results suggest that miR-495 may act as a tumor suppressor by targeting Akt1 in ESCC.
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Project description:BackgroundSeveral studies have documented the key role of microRNAs (miRNAs) in esophageal squamous cell carcinoma (ESCC). Although the expression of the 15-hydroxyprostaglandin dehydrogenase (HPGD) gene and miR-106b-5p are reportedly linked to cancer progression, their underlying mechanisms in ESCC remain unclear.MethodsmRNA and miRNA expression in ESCC tissues and cells were analyzed using RT-qPCR. Luciferase and RNA pull-down assays were used to identify the interaction between miR-106b-5p and HPGD. Xenograft and pulmonary metastasis models were used to assess tumor growth and metastasis. CCK-8, BrdU, colony formation, adhesion, cell wound healing, Transwell, and caspase-3/7 activity assays, and flow cytometry and western blot analyses were used to examine the function of miR-106-5p and HPGD in ESCC cell lines.ResultsThe findings revealed that miR-106b-5p expression was upregulated in ESCC tissues and cell lines. miR-106b-5p augmented cellular proliferation, colony formation, adhesion, migration, invasion, and proportion of cells in the S-phase, but reduced apoptosis and the proportion of cells in G1-phase. Silencing of miR-106-5p inhibited tumor growth in vivo and pulmonary metastasis. Although HPGD overexpression suppressed proliferation, colony formation, adhesion, migration, and invasion of ESCC cells, it promoted apoptosis and caused cell cycle arrest of the ESCC cells. The results also indicated a direct interaction of HPGD with miR-106b-5p in ESCC cells. Furthermore, miR-106b-5p inhibited HPGD expression, thereby suppressing ESCC tumorigenesis.ConclusionOur data suggest that miR-106b-5p enhances proliferation, colony formation, adhesion, migration, and invasion, and induces the cycle progression, but represses apoptosis of ESCC cells by targeting HPGD. This suggests that the miR-106b-5p/HPGD axis may serve as a promising target for the diagnosis and treatment of ESCC.
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Project description:KH-type splicing regulatory protein (KHSRP) is a multifunctional RNA-binding protein, which is involved in several post-transcriptional aspects of RNA metabolism, including microRNA (miRNA) biogenesis. It affects distinct cell functions in different tissues and can have an impact on various pathological conditions. In the present study, we investigated the oncogenic functions of KHSRP and their underlying mechanisms in the pathogenesis of esophageal squamous cell carcinoma (ESCC). KHSRP expression levels were elevated in ESCC tumors when compared with those in non-tumorous tissues by immunohistochemistry, and cytoplasmic KHSRP overexpression was found to be an independent prognosticator for worse overall survival in a cohort of 104 patients with ESCC. KHSRP knockdown inhibited growth, migration, and invasion of ESCC cells. KHSRP knockdown also inhibited the maturation of cancer-associated miRNAs, such as miR-21, miR-130b, and miR-301, and induced the expression of their target mRNAs, such as BMP6, PDCD4, and TIMP3, resulting in the inhibition of epithelial-to-mesenchymal transition. Our findings uncover a novel oncogenic function of KHSRP in esophageal tumorigenesis and implicate its use as a marker for prognostic evaluation and as a putative therapeutic target in ESCC.
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Project description:Long non-coding RNAs are a group of non-coding RNAs longer than 200 nucleotides and possess diverse functions and exhibit exquisite cell-specific and developmental dynamic expression patterns. The role of the long non-coding RNA PVT1 in esophageal squamous cell carcinoma remains unsolved. Here, we showed that PVT1 expression is significantly up-regulated in ESCC tumor samples compared with their normal counterparts. Knockdown of PVT1 suppressed tumor growth in vitro and in vivo. Further studies revealed that silence of PVT1 lead to up-regulation of miR-203, and vice versa. Moreover, LASP1 was found to be downregulated after knockdown of PVT1 and overexpression of LASP1 attenuated the tumor-suppressive roles of PVT1 knockdown. Our results suggest that PVT1 promote ESCC progression via functioning as a molecular sponge for miR-203 and LASP1 and provide the first evidence of dysregulated PVT1/miR-203/LASP1 axis in ESCC.
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Project description:BackgroundmiR-488-3p has been reported to play an important role in cancer progression and metastasis. The protein 53 (P53) gene serves as a mediator and biomarker of esophageal squamous cell carcinoma (ESCC). However, the molecular mechanism underlying miR-488-5p in the pathology of ESCC through the P53 pathway has not been examined.MethodsThe expression levels of miR-488-5p were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cytological experiments were performed to evaluate the biological functions of miR-488-5p. A bioinformatics analysis was performed to determine the pathways and key miR-488-5p targets associated with ESCC. Correlations between miR-488-5p and P53 signaling pathways were validated by western blotting and the dual luciferase reporter gene system. Finally, the expression level of miR-488-5p was regulated and tumor formation experiments were performed in nude mice.ResultsThe qRT-PCR analysis showed that MiR-488-5p expression was more upregulated in the KYSE-150 group than the HEEC group. In the KYSE-150 cells, the colony formation assay and flow cytometry analysis indicated that the miR-488-5p inhibitor inhibited cell viability and increased cell apoptosis; however, these effects were recovered by P53 knockdown (KD). In addition, cell invasion and cell migration were inhibited by the miR-488-5p inhibitor, but were also improved by P53 KD. Similarly, the miR-488-5p inhibitor induced the expression of P53 and P21 than normal control (NC) group in which miR-488-5p expression was normal, while P53 KD prevented the effects of the miR-488-5p inhibitor in KYSE-150 cells. Additionally, we found that tumor size was obviously smaller in miR-488-5p overexpression (OE)+ P53 OE mice than miR-488-5p OE mice. Hematoxylin and eosin and immunohistochemistry staining also revealed similar results.ConclusionsOur results suggest that miR-488-5p promotes ESCC progression by suppressing the P53 pathway. These findings should provide novel ideas for ESCC therapies.
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Project description:BackgroundThis study was performed to investigate the effect of microRNA-203 (miR-203) and ?Np63 on cell proliferation and the functional connection between miR-203 and ?Np63 in ESCC.MethodsWe employed 2 human ESCC cell lines, Eca109 and TE-1, as the model system. The effect of miR-203 and ?Np63 on cell proliferation was determined in cells transfected with miR-203 mimic and ?Np63 small interfering RNA (siRNA), respectively. The regulation of ?Np63 expression in ESCC cells by miR-203 was studied by luciferase reporter assay, RT-PCR and western blot analysis in cells transfected with miR-203. The effect of ?Np63 re-expression on miR-203 induced inhibition of cell proliferation was studied by cell proliferation assay in cells cotransfected with miR-203 and pcDNA-?Np63 plasmid (without the 3'-UTR of ?Np63).ResultsWe found that both miR-203 and ?Np63 siRNA signicantly inhibited cell proliferation in ESCC. MiR-203 could down-regulate endogenous ?Np63 expression at the posttranscriptional level. Moreover, re-expression of ?Np63 in cells transfected with miR-203 significantly attenuated the miR-203 induced inhibition of cell proliferation.ConclusionsOur data implied that miR-203 could inhibit cell proliferation in human ESCC through ?Np63-mediated signal pathway. Therefore, we propose that miR-203 might be used as a therapeutic agent for human ESCC.
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Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is a prevalent malignant tumor worldwide. Circular RNA (circRNA) is of great value in tumorigenesis progression. However, the mechanism of circFNDC3B in ESCC remains to be clarified.MethodsFirstly, the circular characteristics of circFNDC3B were evaluated by Actinomycin D and RNase R measurements. The functions of circFNDC3B in ESCC cells were examined by CCK-8, EdU and flow cytometry. Subsequently, the molecular mechanism of circFNDC3B was explained using luciferase reporter gene detection. Finally, we constructed xenograft model to prove the role of circFNDC3B in vivo.ResultsOur study revealed that circFNDC3B was more stable than its linear RNA and prominently upregulated in ESCC. Functional findings suggested that silencing of circFNDC3B reduced the proliferation and enhanced apoptosis of ESCC cells in vitro. Meanwhile, knockdown of circFNDC3B attenuated tumor progression in vivo. Next, miR-370-3p/miR-136-5p was discovered to bind circFNDC3B. miR-370-3p/miR-136-5p reversed the promotive effect on cell proliferation and the inhibitory effect on cell apoptosis of circFNDC3B. MYO5A was a downstream target of miR-370-3p/miR-136-5p. CircFNDC3B served as a sponge for miR-370-3p/miR-136-5p and alleviated the prohibitory effect of miR-370-3p/miR-136-5p on MYO5A, which accelerated ESCC progression.ConclusioncircFNDC3B positively adjusted the MYO5A expression via spongy miR-370-3p/miR-136-5p, hence achieving the cancer-promoting effect on ESCC. circFNDC3B was a prospective diagnosis marker for ESCC.
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Project description:BackgroundDysregulation of the cell cycle has been implicated in esophageal squamous cell carcinoma (ESCC) progression. This study aimed to evaluate the role of miR-424 in cell cycle regulation and ESCC proliferation.MethodsThe role of miR-424 in cell proliferation was evaluated in vitro and in vivo. Transcriptional activation of miR-424 was determined using chromatin immunoprecipitation, and binding of miR-424 to targets was verified using miRNA ribonucleoprotein complex immunoprecipitation.FindingsmiR-424 was upregulated and correlated with poor survival in ESCC patients. Repression or overexpression of miR-424 respectively decreased or increased ESCC cell proliferation in vitro and in vivo. miR-424 expression is transcriptionally regulated by E2F1 and increased during G1/S transition. Knockdown or overexpression of miR-424 respectively inhibited or promoted both G1/S and G2/M cell cycle transitions in ESCC cells, and these effects were mediated by two newly identified miR-424 targets, PRKCD and WEE1, respectively. Consequently, elevation of PRKCD by miR-424 knockdown led to enhanced stability of the p21Cip1 protein via increased activation of PRKCD and downstream p38 MAPK and JNK signaling to block CDK2 activation and G1/S transition, while elevated WEE1 maintained CDC2 in an inactive state to block G2/M transition. However, circLARP4 could sponge the binding of miR-424 to PRKCD, thus compromising the regulation of G1/S progression by miR-424.InterpretationmiR-424 coordinates a previously unknown, multilayered regulation of ESCC cell cycle progression to promote ESCC proliferation, and may be used as a novel prognostic marker and an effective therapeutic target for ESCCs. FUND: National Natural Science Foundation of China.
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