The MicroRNA let-7a modulates interleukin-6-dependent STAT-3 survival signaling in malignant human cholangiocytes

Tohoku University, Miyagi, Japan
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2007; 282(11):8256-64. DOI: 10.1074/jbc.M607712200
Source: PubMed


The inflammation-associated cytokine interleukin-6 (IL-6) can contribute to tumor growth and resistance to therapy by the
activation of survival mechanisms. In several human cancers, IL-6-activated survival signaling involves the signal transducers
and activators of transcription (Stat) factors or protein kinase cascades. microRNAs (miRNAs) are endogenous regulators of
gene expression that are altered in expression in many cancers. However, the effect of inflammatory cytokines on miRNA expression
and the role of miRNA in modulating IL-6-mediated cell survival are unknown. We investigated the involvement of miRNA in malignant
cholangiocytes stably transfected to overexpress IL-6, which enhances tumor growth in vivo by inhibition of apoptosis. We provide evidence that (i) miRNA expression both in vitro and in vivo is altered by overexpression of IL-6; (ii) selective miRNAs including let-7a are up-regulated and contribute to the survival
effects of enforced IL-6 activity; and (iii) let-7a contributes to the constitutively increased phosphorylation of Stat-3
by a mechanism involving the neurofibromatosis 2 (NF2) gene. These findings reveal a novel mechanism by which IL-6 mediates
tumor cell survival that may be therapeutically targeted and emphasize the presence of complex interrelationships between
deregulated expression of miRNA and transcription factors in human cancers.

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    • "In the embryonic stage the let-7 miRNAs were found to be barely detectable, but having an increased expression in differentiated cells [20, 27]. Furthermore, aberrant let-7 expression was associated with a variety of human diseases as, for example, cardiovascular diseases [28], liver fibrosis [29], lung diseases [30], and cancer [9–12, 26, 31–34]. Interestingly several let-7 family members were found to be located at fragile sites of human chromosomes potentially contributing to aberrant let-7 transcript levels [35]. "
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    ABSTRACT: Prostate cancer is worldwide the sixth leading cause of cancer related death in men thus early detection and successful treatment are still of major interest. The commonly performed screening of the prostate-specific antigen (PSA) is controversially discussed, as in many patients the prostate-specific antigen levels are chronically elevated in the absence of cancer. Due to the unsatisfying efficiency of available prostate cancer screening markers and the current treatment outcome of the aggressive hormone refractory prostate cancer, the evaluation of novel molecular markers and targets is considered an issue of high importance. MicroRNAs are relatively stable in body fluids orchestrating simultaneously the expression of many genes. These molecules are currently discussed to bear a greater diagnostic potential than protein-coding genes, being additionally promising therapeutic drugs and/or targets. Herein we review the potential impact of the microRNA let-7 family on prostate cancer and show how deregulation of several of its target genes could influence the cellular equilibrium in the prostate gland, promoting cancer development as they do in a variety of other human malignant neoplasias.
    Full-text · Article · Sep 2014 · BioMed Research International
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    • "Our findings are in agreement with some previous studies. For example, aberrant expression of let-7 has been proven by a number of groups and in various types of tumors, such as cholangiocarcinoma [22], lung cancer [15], epithelial ovarian cancer [23], breast cancer [24], and colon cancer [17]. Reduced let-7 expression has also been associated with tumor progression and shortened postoperative survival in lung and ovarian cancer patients [15,16,23]. "
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    ABSTRACT: Background MicroRNA let-7i has been proven to be down-regulated in many human malignancies and correlated with tumor progression and anticancer drug resistance. Our study aims to characterize the contribution of miRNA let-7i to the initiation and malignant progression of locally advanced gastric cancer (LAGC), and evaluate its possible value in neoadjuvant chemotherapeutic efficacy prediction. Methods Eighty-six previously untreated LAGC patients who underwent preoperative chemotherapy and radical resection were included in our study. Let-7i expression was examined for pairs of cancer tissues and corresponding normal adjacent tissues (NATs), using quantitative RT-PCR. The relationship of let-7i level to clinicopathological characteristics, pathologic tumor regression grades after chemotherapy, and overall survival (OS) was also investigated. Results Let-7i was significantly down-regulated in most tumor tissues (78/86: 91%) compared with paired NATs (P < 0.001), and low levels of let-7i were significantly correlated with local invasion, lymphatic metastasis, and poor pathologic tumor response. Multivariate Cox regression analysis revealed that low let-7i expression was an unfavorable prognostic factor of OS (hazard ratio (HR) = 2.316, P =0.024) independently of other clinicopathological factors, including tumor node metastasis (TNM) stage (HR = 3.226, P = 0.013), depth of infiltration (HR = 4.167, P < 0.001), and lymph node status (HR = 2.245, P = 0.037). Conclusions These findings indicate that let-7i may be a good candidate for use a therapeutic target and a potential tissue marker for the prediction of chemotherapeutic sensitivity and prognosis in LAGC patients.
    Full-text · Article · Oct 2012 · World Journal of Surgical Oncology
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    • "Our results also indicate that the reduced expression and functional activity of SOCS3 is of relevance for HNSCC cell proliferation, migration and invasion suggesting SOCS3 has a role in HNSCC tumor progression. However, the influence of SOCS3 in these processes may be mediated, in part by a prominent role of STAT3 activation in the tumor cells, as the decrease in cell proliferation and invasion in vitro by overexpression of SOCS3 was less marked in a cell line (OSCC3) in which a biochemical STAT3 inhibitor was also less effective; other mechanisms may be compensating for the inhibitory function of SOCS3 and of the biochemical inhibitor on STAT3 activation, such as let-7a microRNA which contributes to constitutive STAT3 phosphorylation in malignant cholangiocytes [32]. STAT3 relevance in oncogenesis/tumor progression is widely acknowledged, via regulating apoptosis-related genes (Bcl-XL, Mcl-1 and Survivin) [33], proliferation- (c-myc and cyclin D1) and invasion-promoting genes (VEGF, MMP-9) [34], [35]. "
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    ABSTRACT: Background Suppressor of cytokine signaling 3 (SOCS3) is an inducible endogenous negative regulator of signal transduction and activator of transcription 3 (STAT3). Epigenetic silencing of SOCS3 has been shown in head and neck squamous cell carcinoma (HNSCC), which is associated with increased activation of STAT3. There is scarce information on the functional role of the reduction of SOCS3 expression and no information on altered subcellular localization of SOCS3 in HNSCC. Methodology/Principal Findings We assessed endogenous SOCS3 expression in different HNSCC cell lines by RT-qPCR and western blot. Immunofluorescence and western blot were used to study the subcellular localization of endogenous SOCS3 induced by IL-6. Overexpression of SOCS3 by CMV-driven plasmids and siRNA-mediated inhibition of endogenous SOCS3 were used to verify the role of SOCS3 on tumor cell proliferation, viability, invasion and migration in vitro. In vivo relevance of SOCS3 expression in HNSCC was studied by quantitative immunohistochemistry of commercially-available tissue microarrays. Endogenous expression of SOCS3 was heterogeneous in four HNSCC cell lines and surprisingly preserved in most of these cell lines. Subcellular localization of endogenous SOCS3 in the HNSCC cell lines was predominantly nuclear as opposed to cytoplasmic in non-neoplasic epithelial cells. Overexpression of SOCS3 produced a relative increase of the protein in the cytoplasmic compartment and significantly inhibited proliferation, migration and invasion, whereas inhibition of endogenous nuclear SOCS3 did not affect these events. Analysis of tissue microarrays indicated that loss of SOCS3 is an early event in HNSCC and was correlated with tumor size and histological grade of dysplasia, but a considerable proportion of cases presented detectable expression of SOCS3. Conclusion Our data support a role for SOCS3 as a tumor suppressor gene in HNSCC with relevance on proliferation and invasion processes and suggests that abnormal subcellular localization impairs SOCS3 function in HNSCC cells.
    Full-text · Article · Sep 2012 · PLoS ONE
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