Cellular microRNA and the tumorigenesis of hepatocellular carcinoma
Yu Li, Kris V. Kowdley
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Benaroya Research Institute and Center for Liver Disease, Digestive Disease Institute Virginia, Mason Medical Center, Seattle Washington, USA
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Kowdley" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Yu" "apellidos" => "Li" ] 1 => array:4 [ "nombre" => "Kris V." "apellidos" => "Kowdley" "email" => array:1 [ 0 => "Kris.Kowdley@vmmc.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor1" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Benaroya Research Institute and Center for Liver Disease, Digestive Disease Institute Virginia, Mason Medical Center, Seattle Washington, USA" "identificador" => "aff1" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "*" "correspondencia" => "Correspondence and reprint request:" ] ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Article commented</span><p id="p0005" class="elsevierStylePara elsevierViewall">Jin-fang Zhang, Ming-liang He, Wei-ming Fu, Hua Wang, Lian-zhou Chen, Xiao Zhu, Ying Chen, Dan Xie, Paul Lai, Gong Chen, Gang Lu, Marie C.M. Lin, and Hsiang-fu Kung. Primate-specific microRNA-637 inhibits tumorigenesis in hepatocellular carcinoma by disrupting signal transducer and activator of transcription 3 signaling. <span class="elsevierStyleItalic">Hepatology</span> 2011; 54: 2137-48.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Comments</span><p id="p0010" class="elsevierStylePara elsevierViewall">Hepatocellular carcinoma (HCC) is one of the most malignant solid tumors causing over 650,000 global deaths each year.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Attributed to complex mechanisms, the tumorigenesis of HCC is associated with a broad range of risk factors, including HBV/HCV infection, heavy alcohol consumption, and non-alcoholic steatohepatitis (NASH).<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Although the underlying mechanisms of the HCC tumorigenesis is not fully understood, it should be noted that the onset of HCC is often accompanied by inflammation and aberrant proliferation of hepatocytes stimulated by pro-inflammatory cytokines in the liver.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Hence, liver inflammation and deregulated hepatocyte proliferation have been postulated as major contributing factors to the tumorigenesis of HCC. Interestingly, the signal transducer and activator of transcription 3 (STAT3) may play critical roles in HCC tumorigenesis due to its involvement in both processes.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>s<span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The phosphorylation of STAT3, induced by extracellular stimuli such as pro-inflammatory cytokines, results in its subsequent translocation into the nucleus;</p><p id="p0015" class="elsevierStylePara elsevierViewall">once in the nucleus, STAT3 regulates the transcription of many genes, some important to tu-morigenesis.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Notably, STAT3 activation is prevalent in malignant tissues in HCC tumors from patients with poor prognosis, but not in adjacent normal tissues.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>s<span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> STAT3 activation is transient in normal cells but is constitutive in cancer cells, suggesting its close association with tumorigenesis. However, it remains unclear how the constitutive activation of STAT3 is maintained throughout the tumorigenesis of HCC.</p><p id="p0020" class="elsevierStylePara elsevierViewall">As negative regulators of gene expression, microRNAs play key roles in a variety of critical biological processes, many of which are associated with the progression and prognosis as well as response to treatment of many tumors.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Interestingly, recent studies have indicated that the expression of tumor-associated microRNAs can be directly induced by STAT3.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Nevertheless, the relationship between STAT3 and microRNAs seems more complicated. Zhang, <span class="elsevierStyleItalic">et al.</span> demonstrated that a primate-specific microRNA-637 was able to negatively regulate the STAT3 activity by repressing the expression of the pro-inflammatory cytokine leukemia inhibitory factor (LIF). In this study, the authors not only provided evidence from both <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> experiments elucidating the regulatory relationship between miR-637 and LIF, but also demonstrated significant growth retardation in tumors caused by over-expression of miR-637 in a murine model.</p><p id="p0025" class="elsevierStylePara elsevierViewall">In this fine work, the authors initially demonstrated that miR-637 expression level was significantly lower in HCC cell lines and tumor specimens compared with that in non-HCC tissues. They also showed the inverse relationship between the levels of miR-637 expression and FBS-induced cell proliferation. More importantly, miR-637 over-expression in HCC cells strongly repressed cell proliferation and simultaneously induced apoptosis, which suggested an anti-tumor effect of miR-637. To elucidate the role of miR-637 in HCC tumorigenesis, the authors identified potential targets of miR-637 related to HCC formation using bioinformatic approaches. They found that both STAT3 and its activation inducer LIF were predicted targets of miR-637. To validate the regulatory relationship between miR-637 and these two targets, a reporter system was used to confirm the miR-637 mediated repression on LIF and STAT3 expressions. It turned out that LIF, but not STAT3, was a direct target of miR-637. The repression of LIF by miR-637 resulted in down-regulation of STAT3 phosphorylation and therefore its activity. More importantly, STAT3 phosphorylation could be restored by supplementing exogenous LIF in the culture, suggesting that miR-637 was able to regulate STAT3 activity by controlling the level of LIF expression. In addition, the authors used a murine model to investigate the role of miR-637 in the context of HCC. In nude mice injected with hepatoma cells that over-expressed miR-637, the tumors remained significantly smaller than the tumors in the controls. A closer look at the levels of activated STAT3 in these tumors clearly revealed that increased miR-637 expression correlated with decreased STAT3 phosphorylation. Although the authors did not provide data indicating an inverse relationship between LIF and miR-637 in mice, they demonstrated this relationship in human HCC samples. Taken together, the evidence from this study strongly points to a protective role of miR-637 against HCC tumorigenesis and development.</p><p id="p0030" class="elsevierStylePara elsevierViewall">The work of Zhang, <span class="elsevierStyleItalic">et al.</span> is particularly interesting because they provided a mechanistic model potentially useful for developing siRNA-based HCC therapeutics. As most anti-cancer drugs with the exception of sorafenib are largely ineffective in treating HCC, siRNA-based therapeutics may be a viable alternative as they are effective, safe, easy to design and amenable to commercial production. Furthermore, a number of siRNA drugs have demonstrated their efficacy in treating advance cancer,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> viral diseases,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and hypercholesterolemia with more clinical trials planned.</p><p id="p0035" class="elsevierStylePara elsevierViewall">Several caveats must be considered in interpreting the results of Zhang, <span class="elsevierStyleItalic">et al.</span>, to address the toxicity and safety of miR-637 as an anti-tumor drug candidate. First, the effect of miR-637 over-expression in hepatocytes needs to be assessed in a broader scope. Since a microRNA is able to repress the expression of dozens or even hundreds of cellular genes, other pathways associated with the predicted miR-637 targets could be analyzed by bioinformatics to identify potential adverse effects. In addition, high-throughput genomics and next-generation sequencing technologies could be used to detect non-</p><p id="p0040" class="elsevierStylePara elsevierViewall">specific effects of miR-637 over-expression that cannot be identified by bioinformatics alone. Second, it would be useful to identify other cellular microRNAs that also repress the LIF expression for designing siRNA drugs with fewer “off-target” effects. Combination therapy using multiple microRNAs targeting the same gene would likely require a lower effective dose, relative to the use of just a single microRNA at a high dosage, but with minimized off-target effects.</p><p id="p0045" class="elsevierStylePara elsevierViewall">In conclusion these exciting findings offer new promise in understanding the pathogenesis of HCC and may open new avenues to novel therapeutics against this important liver disease.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Article commented" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Comments" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0005" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1." 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 1 | 0 | 1 |
| 2024 October | 3 | 4 | 7 |
| 2024 September | 20 | 2 | 22 |
| 2024 August | 7 | 1 | 8 |
| 2024 July | 11 | 6 | 17 |
| 2024 June | 7 | 10 | 17 |
| 2024 May | 8 | 3 | 11 |
| 2024 April | 9 | 6 | 15 |
| 2024 March | 9 | 3 | 12 |
| 2024 February | 7 | 5 | 12 |
| 2024 January | 9 | 4 | 13 |
| 2023 December | 2 | 5 | 7 |
| 2023 November | 4 | 2 | 6 |
| 2023 October | 4 | 6 | 10 |
| 2023 August | 6 | 2 | 8 |
| 2023 July | 2 | 4 | 6 |
| 2023 June | 3 | 3 | 6 |
| 2023 May | 5 | 5 | 10 |
| 2023 April | 2 | 2 | 4 |
| 2023 March | 6 | 1 | 7 |
| 2023 February | 1 | 4 | 5 |
| 2023 January | 2 | 5 | 7 |
| 2022 December | 7 | 3 | 10 |
| 2022 November | 5 | 4 | 9 |
| 2022 October | 6 | 7 | 13 |
| 2022 September | 7 | 5 | 12 |
| 2022 August | 8 | 6 | 14 |
| 2022 July | 7 | 6 | 13 |
| 2022 June | 6 | 6 | 12 |
| 2022 May | 6 | 7 | 13 |
| 2022 April | 6 | 9 | 15 |
| 2022 March | 4 | 9 | 13 |
| 2022 February | 5 | 4 | 9 |
| 2022 January | 11 | 7 | 18 |
| 2021 December | 4 | 6 | 10 |
| 2021 November | 6 | 4 | 10 |
| 2021 October | 6 | 12 | 18 |
| 2021 September | 6 | 6 | 12 |
| 2021 August | 5 | 4 | 9 |
| 2021 July | 8 | 8 | 16 |
| 2021 June | 5 | 12 | 17 |
| 2021 May | 10 | 10 | 20 |
| 2021 April | 21 | 5 | 26 |
| 2021 March | 4 | 6 | 10 |
| 2021 February | 5 | 5 | 10 |
| 2021 January | 5 | 10 | 15 |
| 2020 December | 3 | 4 | 7 |
| 2020 November | 0 | 4 | 4 |
| 2020 October | 1 | 5 | 6 |
| 2020 September | 5 | 6 | 11 |
| 2020 August | 6 | 1 | 7 |
| 2020 July | 4 | 1 | 5 |
| 2020 June | 3 | 3 | 6 |
| 2020 May | 3 | 3 | 6 |
| 2020 April | 1 | 1 | 2 |
| 2020 March | 3 | 3 | 6 |
| 2020 February | 2 | 2 | 4 |
| 2020 January | 5 | 4 | 9 |
| 2019 December | 4 | 3 | 7 |
| 2019 November | 3 | 3 | 6 |
| 2019 October | 2 | 2 | 4 |
| 2019 September | 6 | 3 | 9 |
| 2019 August | 6 | 1 | 7 |
| 2019 July | 0 | 3 | 3 |
| 2019 June | 1 | 9 | 10 |
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