miR‐486 regulates metastasis and chemosensitivity in hepatocellular carcinoma by targeting <i>CLDN10</i> and <i>CITRON</i>

Sun, Huiyan; Chu, Chun-Ping; Xiao, Fengjun; Wang, Hua; Xu, Jun; Shi, Xuefeng; Yang, Yuefeng; Zhang, Qunwei; Zheng, Xiaofei; Yang, Xiaoming; Wu, Chutse; Wang, Lisheng

doi:10.1111/hepr.12500

Cited by 52 publications

(43 citation statements)

References 28 publications

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“…However, treatment outcomes are poor due to unfavorable pharmacokinetics, low tumor accumulation and high rates of sorafenib resistance in HCC patients (5). Evidence has shown that, some miRNAs increased sorafenib sensitivity to HCC cells (13,(38)(39)(40). In addition, inhibition of the activation of Akt may be a valid approach to treating human malignancies and overcoming the resistance of cancer cells to chemotherapy (41).…”

Section: Discussionmentioning

confidence: 99%

miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN

et al. 2015

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Abstract. acts as an oncomiR and is involved in tumor development, progression and metastasis, and confers resistance to chemotherapeutic drugs by targeting a number of molecules in several human cancers. However, the function and underlying molecular mechanism of miR-494 in hepatocellular carcinoma (HCC) has not been totally elucidated. In the present study, we determined the role played by miR-494 in HCC tissues and HCC cell lines using quantitative RT-PCR (RT-qPCR). The results showed that, miR-494 was significantly upregulated in HCC tissues and HCC cell lines. Additionally, a high miR-494 expression positively correlated with tumor differentiation (P<0.01), TNM stage (P<0.01) and lymph node metastasis (P<0.01). Luciferase reporter assays confirmed that miR-494 binds to the 3'-untranslated region (3'-UTR) of the phosphatase and tensin homolog (PTEN) mRNA and represses its translation. Functional analyses indicated that the upregulation of miR-494 promoted cell viability, migration and invasion, decreased cell apoptosis and cell cycle arrest at G1 stage, and conferred sorafenib resistance to HCC cell lines. Underexpression of PTEN by siRNA significantly attenuated the inhibitory effects of anti-miR-494 on the proliferation, migration and invasion of liver cancer cells. Mechanistic investigations revealed that miR-494 suppressed the expression of PTEN but increased the expression of PI3K and p-Akt, which contribute to the promotion of proliferation, migration and invasion, and increased sorafenib resistance to HCC cell lines. These findings suggested that miR-494 is a potential candidate for HCC therapeutics.

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Section: Discussionmentioning

confidence: 99%

miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN

et al. 2015

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“…Among miR-486-5p target oncogenes that get activated following its downregulation in lung cancer include: CDK4, which promote cell cycle progression [3], ARHGAP5, which regulates cellular adhesion, motility, and polarity to promote cell migration and invasion [10], the growth promoting IGF signaling genes IGF1, IGF1R, and PIK3R1 [9], and the proto-oncogene serine/threonine kinase PIM-1 [8]. The tumor-suppressor role of miR-486-5p is also demonstrated in other cancers where it targets PIM-1 in breast cancer [43], SNAI1 in prostate cancer [44], and CLDN10, CITRON, and PIK3R1 in HCC [45,46] [45]. Although downregulation of this important tumor-suppressor miR in various cancer types is well-known, the mechanism of repression had not been delineated.…”

Section: Discussionmentioning

confidence: 99%

ANK1 Methylation regulates expression of MicroRNA-486-5p and discriminates lung tumors by histology and smoking status

et al. 2017

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The intragenic tumor-suppressor microRNA miR-486-5p is often down-regulated in non-small cell lung cancer (NSCLC) but the mechanism is unclear. This study investigated epigenetic co-regulation of miR-486-5p and its host gene ANK1. MiR-486-5p expression in lung tumors and cell lines was significantly reduced compared to normal lung (p<0.001) and is strongly correlated with ANK1 expression. In vitro, siRNA-mediated ANK1 knockdown in NSCLC cells also reduced miR-486-5p while the DNA methylation inhibitor 5-aza-2′-deoxycytidine induced expression of both. ANK1 promoter CpG island was unmethylated in normal lung but methylated in 45% (118/262) lung tumors and 55% (17/31) NSCLC cell lines. After adjustment for tumor histology and smoking, methylation was significantly more prevalent in adenocarcinoma (101/200, 51%) compared to squamous cell carcinoma (17/62, 27%), p<0.001; HR=3.513 (CI: 1.818–6.788); and in smokers (73/128, 57%) than never-smokers (28/72, 39%), p=0.014; HR=2.086 (CI: 1.157–3.759). These results were independently validated using quantitative methylation data for 809 NSCLC cases from The Cancer Genome Atlas project. Together, our data indicate that aberrant ANK1 methylation is highly prevalent in lung cancer, discriminate tumors by histology and patients’ smoking history, and contributes to miR-486-5p repression.

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“…Overexpression of the NAD+-dependent histone deacetylases, Sirtuin 1, is detected in HCCs with a higher tumor grade and is associated with poor survival as well as resistance to sorafenib [53]. Finally, expression of miRs that are considered to have tumor suppressor functions, such as miR-425-3p and miR-486, may also predict the effect of sorafenib [54,55]. Given the fact that a single miR targets multiple kinds of mRNA, constitutive activation of multiple molecules may act in concert to restore the sensitivity of HCC to sorafenib [56].…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism and Prediction of Sorafenib Chemoresistance in Human Hepatocellular Carcinoma

Nishida

Kitano

Sakurai

et al. 2015

Dig Dis

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, and prognosis remains unsatisfactory when the disease is diagnosed at an advanced stage. Many molecular targeted agents are being developed for the treatment of advanced HCC; however, the only promising drug to have been developed is sorafenib, which acts as a multi-kinase inhibitor. Unfortunately, a subgroup of HCC is resistant to sorafenib, and the majority of these HCC patients show disease progression even after an initial satisfactory response. To date, a number of studies have examined the underlying mechanisms involved in the response to sorafenib, and trials have been performed to overcome the acquisition of drug resistance. The anti-tumor activity of sorafenib is largely attributed to the blockade of the signals from growth factors, such as vascular endothelial growth factor receptor and platelet-derived growth factor receptor, and the downstream RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade. The activation of an escape pathway from RAF/MEK/ERK possibly results in chemoresistance. In addition, there are several features of HCCs indicating sorafenib resistance, such as epithelial-mesenchymal transition and positive stem cell markers. Here, we review the recent reports and focus on the mechanism and prediction of chemoresistance to sorafenib in HCC.

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miR‐486 regulates metastasis and chemosensitivity in hepatocellular carcinoma by targeting CLDN10 and CITRON

Abstract: Our data indicated that miR-486 may function as a novel tumor suppressor in HCC.

Cited by 52 publications

References 28 publications

miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN

miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN

ANK1 Methylation regulates expression of MicroRNA-486-5p and discriminates lung tumors by histology and smoking status

Molecular Mechanism and Prediction of Sorafenib Chemoresistance in Human Hepatocellular Carcinoma

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