MicroRNA-657 promotes tumorigenesis in hepatocellular carcinoma by targeting transducin-like enhancer protein 1 through nuclear factor kappa B pathways

Zhang, Lisheng; Yang, Lixin; Liu, Xiyong; Chen, Wei; Chang, Louise; Chen, Linling; Loera, Sofia; Chu, Peiguo; Huang, Wei-Chien; Liu, Yun Ru; Yen, Yun

doi:10.1002/hep.26162

Cited by 59 publications

(38 citation statements)

References 32 publications

(39 reference statements)

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“…Liver cancer is the third leading cause of cancer mortality worldwide, with an annual death toll of 700,000 (27). More and more evidence indicates that chronic HBV infection is related to the occurrence and development of hepatoma (28).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus Inhibits Apoptosis of Hepatoma Cells by Sponging the MicroRNA 15a/16 Cluster

Liu

Zhang

Jiao

et al. 2013

J Virol

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Hepatitis B virus (HBV) causes chronic hepatitis in hundreds of millions of people worldwide, which can eventually lead to hepatocellular carcinoma (HCC). The molecular mechanisms underlying HBV persistence are not well understood. In this study, we found that HBV inhibited the chemotherapy drug etoposide-induced apoptosis of hepatoma cells. Further analysis revealed that HBV mRNAs possess a microRNA 15a/16 (miR-15a/16)-complementary site (HBV nucleotides [nt] 1362 to 1383) that acts as a sponge to bind and sequester endogenous miR-15a/16. Consequently, Bcl-2, known as the target of miR-15a/16, was upregulated in HBV-infected cells. The data from HBV-transgenic mice further confirmed that HBV transcripts cause the reduction of miR15a/16 and increase of Bcl-2. More importantly, we examined the levels of HBV transcripts and miR-15a/16 in HBV-infected HCC from patients and found that the amount of HBV mRNA and the level of miR-15a/16 were negatively correlated. Consistently, the level of Bcl-2 mRNA was upregulated in HBV-infected patients. In conclusion, we identified a novel HBV mRNAmiR-15a/16 -Bcl-2 regulatory pathway that is involved in inhibiting etoposide-induced apoptosis of hepatoma cells, which may contribute to facilitating chronic HBV infection and hepatoma development. There are approximately 350 million chronic hepatitis B virus (HBV) carriers worldwide, and chronic HBV infection is the major etiological factor in hepatocellular carcinoma (HCC) (1, 2). The relative risk for the development of HCC in chronic hepatitis B (CHB) patients is estimated to be 25 to 37 times higher than that in those without infection (1,3,4).HBV is an enveloped, partially double-stranded DNA virus with a genome size of 3.2 kb. The HBV genome contains four overlapping open reading frames (ORFs). The RNA transcripts are polyadenylated and capped and are named the pre-C/C or pregenomic RNA (pgRNA) and the pre-S, S, and X mRNAs. These mRNAs encode several viral proteins, including the polymerase, core, HBe, pre-S1, S2, S, and X proteins (5). HBV has been reported to play an important role in regulating apoptosis. For example, HBV core protein inhibits TRAIL-induced apoptosis of hepatocytes by blocking DR5 expression (6). HBx can bind to the C terminus of p53 and inhibit p53-mediated cellular processes, including transcriptional transactivation and apoptosis (7). But the HBx protein was also found to sensitize cells to apoptotic killing by tumor necrosis factor alpha (8) and to inhibit Fas-mediated apoptosis associated with upregulation of the SAPK/JNK pathway in Chang cells (9).MicroRNAs (miRNAs) are single-stranded noncoding RNAs which negatively regulate gene expression at the posttranscriptional level, primarily through base pairing to the 3=-untranslated region (UTR) of target mRNA (10). Growing evidence indicates that microRNAs control basic cell functions, ranging from proliferation to apoptosis, by direct targeting (11,12). For instance, miR-101 exerts a proapoptotic function by targeting Mcl-1 (13), and miR-29c inhibits ce...

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Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus Inhibits Apoptosis of Hepatoma Cells by Sponging the MicroRNA 15a/16 Cluster

Liu

Zhang

Jiao

et al. 2013

J Virol

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“…TLE1, the most studied among the Groucho family proteins in mammalian systems, is widely expressed in different tissues and cell types and has been implicated in neuronal differentiation (3,4) and pancreatic beta cell development (5). TLE1 has tumor suppressor activity (6)(7)(8) as well as oncogenic functions in cancer (9,10). TLE1 associates with many important transcription factors integral for cell proliferation and differentiation, including Runx2 to block rRNA expression (11), HES1 to suppresses MASH2 expression (12), and TCF/LEF proteins to block Wnt target gene activation (13).…”

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confidence: 99%

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Ramasamy

Sáez

Mukhopadhyay

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1 Δ/Δ ) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1 Δ/Δ mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1 Δ/Δ macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1 Δ/Δ mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-κB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1 Δ/Δ mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression.T ransducin-like enhancer of split 1 (TLE1) belongs to a family of corepressor proteins called transducin-like enhancer of split, or TLEs. Groucho, the TLE homolog in Drosophila, has crucial roles in neurogenesis, segmentation, and sex determination (1). These corepressors do not bind directly to DNA but rather interact with many different classes of transcription factors and help create a repressor complex (1, 2).Vertebrates express five different TLEs (TLE1-4, AES), although the distinct functions of each of the TLEs has not been well determined. TLE1, the most studied among the Groucho family proteins in mammalian systems, is widely expressed in different tissues and cell types and has been implicated in neuronal differentiation (3, 4) and pancreatic beta cell development (5). TLE1 has tumor suppressor activity (6-8) as well as oncogenic functions in cancer (9, 10). TLE1 associates with many important transcription factors integral for cell proliferation and differentiation, including Runx2 to block rRNA expression (11), HES1 to suppresses MASH2 expression (12), and TCF/LEF proteins to block Wnt target gene activation (13). TLE1 also represses NF-κB activity (14,15). Involvement in these diverse cellular functions and diseases was studied primarily in vitro or using in vivo overexpression systems. The major physiological function of TLE1, however, remains poorly understood.A few recent studies suggest TLE1 might regulate immune function. For example, a single noncoding nucleotide polymorphism within the TLE1 locus was associated with inflammatory bowel diseases (16), and in human monocytes,...

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“…The ectopic expression of miRNAs is closely associated with carcinogenesis and cancer progression [9,10]. miR-21 and miR-657, which act as proto-oncogenes, are reported to promote cancer progression [11,12], whereas miR-29 and miR-145 are shown to be tumor-suppressor genes [13,14]. The down-regulation of miR-101 has been reported in various solid tumors, such as colorectal cancer and hepatoma [15,16].…”

Section: Introductionmentioning

confidence: 99%

miR-101 Promotes Breast Cancer Cell Apoptosis by Targeting Janus Kinase 2

Wang

Guo

et al. 2014

Cell Physiol Biochem

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Aims: microRNA-101 (miR-101) is down-regulated in several cancers. In this study, we explored the effects of dysregulated miR-101 on breast cancer cells and the underlying mechanisms. Methods: miR-101 level was quantified by real-time RT-PCR. Cell viability was analyzed by MTT assay. Apoptosis was detected by flow cytometry and TUNEL assay. Moreover, the level of protein expression was determined by Western blot. Results: miR-101 level was markedly reduced in both the human breast cancer samples and cultured breast cancer cell lines (MCF-7, MDA-MB-231). Overexpression of miR-101 inhibited the proliferation and promoted the apoptosis in cultured MCF-7 and MDA-MB-231 cells, which were reversed by co-transfection of AMO-101, the inhibitor of miR-101. We validated Janus kinase 2 (Jak2) as a direct target of miR-101. Knockdown of Jak2 induced apoptosis in cultured breast cancer cells. Moreover, the level of miR-101 is negatively correlated with Jak2 in breast cancer tissues and cell lines. Conclusions: miR-101 suppressed proliferation and promoted apoptosis in breast cancer cells by targeting Jak2. These findings indicate that manipulation of miR-101 expression may represent a novel therapeutic strategy in the treatment of breast cancer.

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MicroRNA-657 promotes tumorigenesis in hepatocellular carcinoma by targeting transducin-like enhancer protein 1 through nuclear factor kappa B pathways

Cited by 59 publications

References 32 publications

Hepatitis B Virus Inhibits Apoptosis of Hepatoma Cells by Sponging the MicroRNA 15a/16 Cluster

Hepatitis B Virus Inhibits Apoptosis of Hepatoma Cells by Sponging the MicroRNA 15a/16 Cluster

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

miR-101 Promotes Breast Cancer Cell Apoptosis by Targeting Janus Kinase 2

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