miR-589-5p inhibits MAP3K8 and suppresses CD90+ cancer stem cells in hepatocellular carcinoma

Zhang, Xi; Jiang, Peng; Shuai, Ling; Chen, Kai; Li, Zhong-Hu; Zhang, Yujun; Jiang, Yan; Li, Xiaowu

doi:10.1186/s13046-016-0452-6

Cited by 57 publications

(40 citation statements)

References 37 publications

(36 reference statements)

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“…Li et al reported that miR-589 was significantly downregulated in cisplatin-resistant A549, and transfection with miR-589 resulted in an increased sensitivity to cisplatin (10). A later study showed that miR-589-5p could downregulate the stemness characteristics of CD90 + cancer stem cells (CSCs) of HCC in part by silencing MAP3K8 (11). Our findings revealed that the loss of miR-589-5p by hypermethylation accelerated NSCLC development through increasing the expression of HDAC5.…”

Section: Hypermethylation Of Mirna-589 Promoter Leads To Upregulationmentioning

confidence: 58%

Hypermethylation of miRNA-589 promoter leads to upregulation of HDAC5 which promotes malignancy in non-small cell lung cancer

Liu

et al. 2017

International Journal of Oncology

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Histone deacetylases (HDACs) are crucial for regulating chromatin activity, which plays a critical role in cell proliferation, differentiation, and apoptosis of various cancers. Therefore, HDAC inhibitors have been applied as effective therapeutic agents for cancer treatment. However, the expression profiles and regulatory mechanisms of histone deacetylases in lung cancer are not well understood. In the present study, aberrant high levels of HDAC5 were observed in non-small cell lung cancer (NSCLC) and further analysis indicated a negative relationship between HDAC5 and a tumor suppressor, miR‑589‑5p, in NSCLC specimens. Consistently, miR‑589‑5p reduced the expression of HDAC5 by targeting the 3'UTR of HDAC5 mRNA in NSCLC cells. Considering the loss of miR‑589‑5p in NSCLC, the methylation status of the miR-589 gene promoter was examined. The hypermethylation of the miR-589 gene promoter was more significant in NSCLC cells compared with lung epithelial cells, and methylation inhibition by 5-aza-2-deoxycytidine (5-Aza-dC) decreased HDAC5 expression. Furthermore, several downstream gene clusters of HDAC5 were studied in the present investigation. As a result, miR‑589‑5p/HDAC5 pathway was found to regulate a number of cell cycle and epithelial-mesenchymal transition (EMT)-related genes in NSCLC cells. In vitro and in vivo phenotype experiments revealed a critical role of miR‑589‑5p/HDAC5 pathway in the migration, invasion, and tumorigenicity of NSCLC cells. These findings demonstrate a novel mechanism for deregulation of HDAC5 in NSCLC and suggest that miR‑589‑5p/HDAC5 pathway may represent a new prognostic biomarker and therapeutic target against NSCLC.

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Section: Hypermethylation Of Mirna-589 Promoter Leads To Upregulationmentioning

confidence: 58%

Hypermethylation of miRNA-589 promoter leads to upregulation of HDAC5 which promotes malignancy in non-small cell lung cancer

Liu

et al. 2017

International Journal of Oncology

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“…CD90 may be involved in HCC only under certain conditions. Although CD90 is a typical marker of CSCs in HCC and high CD90 expression has been linked to higher recurrence rate 38,39 , one study reported that CD90+ CSCs-like cells in the liver may participate only in late-stage liver cancer associated with hepatitis B virus infection 40 .…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Epcam and CD133 Correlates with Poor Prognosis in Dual-phenotype Hepatocellular Carcinoma

Zhang

et al. 2020

J. Cancer

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Background: Dual-phenotype hepatocellular carcinoma (DPHCC) is associated with high rate of post-operative recurrence and low rate of survival, which may reflect the post-operative persistence of cancer stem cells (CSCs). Here we explored the potential correlation between DPHCC and expression of CSCs markers. Methods: In this retrospective study, we included 19 patients with DPHCC and 61 patients with non-DPHCC treated in 2015 by liver resection. Paraffin-embedded tumor tissue specimens were analyzed using immunohistochemistry as well as immunofluorescence double-staining. Rates of recurrence-free survival and overall survival were compared between the two groups using the Kaplan-Meier method, and expression of the CSC markers CD133, CD90, and EpCAM were compared using real-time quantitative PCR and western blotting. Results: Overall survival rates were significantly lower for patients with DPHCC than patients with non-DPHCC at 1 year (78.9% vs 93.4%), 2 years (52.6% vs 72.1%), and 3 years (42.1% vs 67.2%) (P = 0.019). Multivariate Cox proportional hazard modeling identified CK19 positivity (P = 0.016) and multiple nodules (P = 0.023) as independent predictors of poor recurrence-free survival. Independent predictors of poor overall survival were CK19 positivity (P = 0.032), Barcelona Clinic Liver Cancer stage C (P = 0.025) and carbohydrate antigen 19-9 (CA19-9) >37 ng/ml (P = 0.016). Expression of CD133 and EpCAM mRNA and protein were significantly higher in DPHCC tissue than non-DPHCC tissue, while CD90 expression was similar between the groups. Conclusions: These results suggest that DPHCC is associated with significantly lower overall survival than non-DPHCC, and that the poor prognosis among DPHCC patients may be related to the presence of CSCs expressing CD133 and EpCAM.

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“…Further, miR-1, miR-21, miR-122, miR-221, miR-29, miR-500 and many other microRNA are reported to be aberrantly expressed in HCC and can act as biomarkers [16][17][18][19][20][21]. Although MiR-589-5p is a poorly studied microRNA in cancer, there is the following research; (1) Zhang et al demonstrated that it inhibits MAP3K8 and suppresses CD90+ cancer stem cells in HCC [22]; (2) Long et al found that it promotes the cancer stem cell characteristics and chemo-resistance of HCC cells by targeting multiple negative regulators of the STAT3 signaling pathway [23] and (3) Huang et al reported that the expression of miR-589-5p is down-regulated in radiated laryngeal squamous carcinoma stem cells [24]. However, more biological effects of miR-589-5p need to be revealed.…”

Section: Discussionmentioning

confidence: 99%

MiR-589-5p is a potential prognostic marker of hepatocellular carcinoma and regulates tumor cell growth by targeting MIG-6

Wang

et al. 2018

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MicroRNAs (miRNAs) are small noncoding RNAs approximately with 22 nucleotides. Accumulating evidence indicates that microRNAs are involved in carcinogenesis and tumor progression. Some recent investigations have also reported that several microRNAs could act as biomarkers in cancer diagnosis and prognosis. MicroRNA-589-5p (miR-589-5p) is a less studied microRNA, in this study, we explored its roles in hepatocellular carcinoma (HCC). We analyzed miR-589-5p expression in HCC tissues by sequencing data and proved the expression in liver cancer cell lines by quantitative real-time PCR (qRT-PCR). We studied the effect of miR-589-5p on the growth of liver cancer cells by MTT assay, colony formation and flow cytometry, and identified its target gene by luciferase reporter assay. We found that miR-589-5p was commonly overexpressed in HCC specimens. High expression of miR-589-5p was a risk factor for HCC patient (Hazard ratio [HR] = 1.434; 95% confidence intervals [CI] = 1.006-2.044; p = 0.046). We also found miR-589-5p had higher expression in hepatocarcinoma cell lines HepG2 and HuH-7 than did in normal hepatocyte Lo-2. We identified that suppression of miR-589-5p inhibited cell proliferation and cell cycle progression by loss-of-function studies. Furthermore, we found mitogen-inducible gene 6 (MIG-6) to be a target of miR-589-5p. Our study demonstrated that miR-589-5p facilitated the growth of liver cancer cells by targeting MIG-6 and could be a prognosis biomarker for HCC. Suppression of miR-589-5p may be a feasible approach for inhibiting HCC progress.

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miR-589-5p inhibits MAP3K8 and suppresses CD90+ cancer stem cells in hepatocellular carcinoma

Cited by 57 publications

References 37 publications

Hypermethylation of miRNA-589 promoter leads to upregulation of HDAC5 which promotes malignancy in non-small cell lung cancer

Hypermethylation of miRNA-589 promoter leads to upregulation of HDAC5 which promotes malignancy in non-small cell lung cancer

Overexpression of Epcam and CD133 Correlates with Poor Prognosis in Dual-phenotype Hepatocellular Carcinoma

MiR-589-5p is a potential prognostic marker of hepatocellular carcinoma and regulates tumor cell growth by targeting MIG-6

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