Hsa-let-7a functions as a tumor suppressor in renal cell carcinoma cell lines by targeting c-myc

Liu, Yongchao; Yin, Bingde; Zhang, Changcun; Zhou, Libin; Fan, Jia

doi:10.1016/j.bbrc.2011.11.119

Cited by 54 publications

(48 citation statements)

References 37 publications

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“…It is clear from numerous subsequent studies that the let-7 miR family regulates development in many species, including mammals (31). Consistent with our data, let-7a has a well documented antiproliferative role in both in animal models and in humans (32)(33)(34) involving the targeting of MYC (34 -36) and ERK (37,38). In contrast to let-7, studies on the role of miR-377 are limited.…”

Section: Discussionsupporting

confidence: 73%

MicroRNA Regulation of Mitogenic Signaling Networks in the Human Placenta

Farrokhnia

Aplin

Westwood

et al. 2014

Journal of Biological Chemistry

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Placental cell growth depends on an adaptable combination of an endogenous developmental program and the exogenous influence of maternal growth factors, both of which may be influenced by microRNA (miR)-dependent effects on gene expression. We have previously shown that global miR suppression in placenta accelerates proliferation and enhances levels of growth factor signaling mediators in cytotrophoblast. This study aimed to identify miRs involved in regulating placental growth. An initial array revealed 58 miR species whose expression differs between first trimester, when cytotrophoblast proliferation is rapid, and term, by which time proliferation has slowed. In silico analysis defined potential growth-regulatory miRs; among these, hsa-miR-145, hsa-miR-377, and hsa-let-7a were predicted to target known placental growth genes and were higher at term than in the first trimester, so they were selected for further analysis. Overexpression of miR-377 and let-7a, but not miR-145, in first trimester placental explants significantly reduced basal cytotrophoblast proliferation and expression of ERK and MYC. PCR arrays, in silico analysis, Western blotting, and 3′-UTR luciferase reporter assays revealed targets of miR-145 within the insulin-like growth factor axis. Analysis of proliferation in placental explants overexpressing miR-145 demonstrated its role as a mediator of insulin-like growth factor-induced trophoblast proliferation. These findings identify miR-377 and let-7a in regulation of endogenous cell growth and miR-145 in the placental response to maternal stimulation and will aid the development of therapeutic strategies for problem pregnancies.

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Section: Discussionsupporting

confidence: 73%

MicroRNA Regulation of Mitogenic Signaling Networks in the Human Placenta

Farrokhnia

Aplin

Westwood

et al. 2014

Journal of Biological Chemistry

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“…(25,26) Moreover, c-MYC has also been reported to be upregulated in RCC clinical specimens. (27)(28)(29)(30) Thus, our data suggest that the identification of tumor-suppressive miR-135a-mediated cancer pathways may provide insights into potential therapeutic targets for the treatment of RCC.…”

mentioning

confidence: 78%

“…(43)(44)(45) Several reports have shown that the c-MYC pathway is activated in RCC due to the overexpression and amplification of the c-MYC gene. (27,30) For example, CCND1, which is considered a proto-oncogene, promotes the G 1 ⁄ S phase transition in the progression of the cell cycle by regulating cyclin-dependent kinase activity. (46,47) In the current study, our expression profile analysis identified CCND1 as an miR-135a regulated gene involved in cancer-related and cell cycle pathways, supporting previous studies.…”

Section: Discussionmentioning

confidence: 99%

Tumor‐suppressive microRNA‐135a inhibits cancer cell proliferation by targeting the c‐MYC oncogene in renal cell carcinoma

et al. 2012

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Recently, many studies have suggested that microRNAs (miRNAs) are involved in cancer cell development, invasion, and metastasis of various types of human cancers. In a previous study, miRNA expression signatures from renal cell carcinoma (RCC) revealed that expression of microRNA-135a (miR-135a) was significantly reduced in cancerous tissues. The aim of this study was to investigate the functional significance of miR-135a and to identify miR-135a-mediated molecular pathways in RCC cells. Restoration of mature miR-135a significantly inhibited cancer cell proliferation and induced G 0 ⁄ G 1 arrest in the RCC cell lines caki2 and A498, suggesting that miR-135a functioned as a potential tumor suppressor. We then examined miR-135a-mediated molecular pathways using genome-wide gene expression analysis and in silico analysis. A total of 570 downregulated genes were identified in miR-135a transfected RCC cell lines. To investigate the biological significance of potential miR-135a-mediated pathways, we classified putative miR-135a-regulated genes according to the Kyoto Encyclopedia of Genes and Genomics pathway database. From our in silico analysis, 25 pathways, including the cell cycle, pathways in cancer, DNA replication, and focal adhesion, were significantly regulated by miR-135a in RCC cells. Moreover, based on the results of this analysis, we investigated whether miR-135a targeted the c-MYC gene in RCC. Gain-of-function and luciferase reporter assays showed that c-MYC was directly regulated by miR-135a in RCC cells. Furthermore, c-MYC expression was significantly upregulated in RCC clinical specimens. Our data suggest that elucidation of tumor-suppressive miR-135a-mediated molecular pathways could reveal potential therapeutic targets in RCC. (Cancer Sci 2013; 104: 304-312) R enal cell carcinoma (RCC) is the most common neoplasm of the adult kidney, and approximately 80% of RCC patients are diagnosed with the clear cell RCC (ccRCC) subtype.(1) In the USA, the incidence and mortality rates of RCC have increased in recent years, with approximately 58 000 new cases and 13 000 deaths in 2010.(2) Although surgery is curative for localized disease, a significant percentage of patients developed relapses or metastases with poor prognosis.(3,4) Therefore, researchers have become interested in elucidating the molecular mechanisms of RCC oncogenesis and metastasis, which could lead to development of better prognostic, diagnostic, and therapeutic interventions for the disease.RNA can be divided into two categories, protein-coding RNAs and non-coding RNAs (ncRNAs). It is important to examine the functions of ncRNAs in both normal and diseased tissues and to elucidate their involvement in human diseases, including cancer. MicroRNAs (miRNAs) are endogenous small ncRNA molecules (19-22 bases) that regulate protein-coding gene expression by repressing translation of RNA or cleaving RNA transcripts in a sequence-specific manner.(5) A growing body of evidence suggests that miRNAs are aberrantly expressed in many human cancers and ...

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“…The let-7 family members act as tumor suppressor molecules by binding target oncogenes, such as Ras (30), HMGA2 (31) and c-Myc (32). In addition, Liu et al reported that let-7a reduced c-Myc and the c-Myc target gene cyclin d1, leading to cell cycle arrest and the inhibition of proliferation (33). These events suggest that the suppression of cancer cell proliferation by gemcitabine may result, in part, from the upregulation of let-7a.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of gemcitabine-induced suppression of human cholangiocellular carcinoma cell growth

Toyota

Iwama

Kato

et al. 2015

International Journal of Oncology

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Abstract. Although gemcitabine (2',2'-difluorocytidine monohydrochloride) is a common anticancer agent of cholangiocellular carcinoma (CCC), its growth inhibitory effects and gemcitabine resistance in CCC cells are poorly understood. Our aims were to uncover the mechanism underlying the antitumor effect of gemcitabine and to analyze the mechanism regulating in vitro CCC cell gemcitabine resistance. In addition, we sought to identify miRNAs associated with the antitumor effects of gemcitabine in CCCs. Using a cell proliferation assay and flow cytometry, we examined the ability of gemcitabine to inhibit cell proliferation in three types of human CCC cell lines (HuCCT-1, Huh28, TKKK). We also employed western blotting to investigate the effects of gemcitabine on cell cycle-related molecules in CCC cells. In addition, we used array chips to assess gemcitabine-mediated changes in angiogenic molecules and activated tyrosine kinase receptors in CCC cells. We used miRNA array chips to comprehensively analyze gemcitabine-induced miRNAs and examined clusters of differentially expressed miRNAs in cells with and without gemcitabine treatment. Gemcitabine inhibited cell proliferation in a dose-and time-dependent manner in HuCCT-1 cells, whereas cell proliferation was unchanged in Huh28 and TKKK cells. Gemcitabine inhibited cell cycle progression in HuCCT-1 cells from G0/G1 to S phase, resulting in G1 cell cycle arrest due to the reduction of cyclin D1 expression. In addition, gemcitabine upregulated the angiogenic molecules IL-6, IL-8, ENA-78 and MCP-1. In TKKK cells, by contrast, gemcitabine did not arrest the cell cycle or modify angiogenic molecules. Furthermore, in gemcitabine-sensitive HuCCT-1 cells, gemcitabine markedly altered miRNA expression. The miRNAs and angiogenic molecules altered by gemcitabine contribute to the inhibition of tumor growth in vitro.

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Hsa-let-7a functions as a tumor suppressor in renal cell carcinoma cell lines by targeting c-myc

Cited by 54 publications

References 37 publications

MicroRNA Regulation of Mitogenic Signaling Networks in the Human Placenta

MicroRNA Regulation of Mitogenic Signaling Networks in the Human Placenta

Tumor‐suppressive microRNA‐135a inhibits cancer cell proliferation by targeting the c‐MYC oncogene in renal cell carcinoma

Mechanism of gemcitabine-induced suppression of human cholangiocellular carcinoma cell growth

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