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      High expression of Lin28 is associated with tumour aggressiveness and poor prognosis of patients in oesophagus cancer

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          Abstract

          Background:

          Lin28 is a negative regulator of the tumour suppressor microRNA, let-7, suggesting its role in tumourigenesis. However, the clinical significance of Lin28 expression in oesophageal cancer has not been elucidated.

          Methods:

          Lin28 and Lin28B expression was examined by immunohistochemistry in 161 tissues from patients with oesophageal cancer who had undergone curative surgery. The relationship between the expressions of Lin28 and Lin28B and various clinicopathological factors was examined. In vitro assays were conducted to determine the role of Lin28 in aggressiveness of oesophageal cancers using oesophageal cancer cell line.

          Results:

          Lin28 and Lin28B were overexpressed in oesophageal cancer cells compared with non-cancerous epithelial cells, especially in the invasive front. High expression of Lin28 and Lin28B correlated significantly with lymph node metastasis and poor prognosis. High expression of Lin28B expression correlated significantly with low expression of let-7. Multivariate analysis also identified Lin28B expression as an independent prognostic factor. In vitro assays showed that the proliferative and invasive activities were significantly reduced in Lin28B-knockdown cells, compared with control cells.

          Conclusion:

          High expression of Lin28 is associated with poor prognosis and high tumour aggressiveness in oesophageal cancer and these effects are mediated through increased proliferation and invasiveness of oesophageal cancer cells.

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          Most cited references17

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          Reporting results of cancer treatment.

          On the initiative of the World Health Organization, two meetings on the Standardization of Reporting Results of Cancer Treatment have been held with representatives and members of several organizations. Recommendations have been developed for standardized approaches to the recording of baseline data relating to the patient, the tumor, laboratory and radiologic data, the reporting of treatment, grading of acute and subacute toxicity, reporting of response, recurrence and disease-free interval, and reporting results of therapy. These recommendations, already endorsed by a number of organizations, are proposed for international acceptance and use to make it possible for investigators to compare validly their results with those of others.
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            Selective blockade of microRNA processing by Lin28.

            MicroRNAs (miRNAs) play critical roles in development, and dysregulation of miRNA expression has been observed in human malignancies. Recent evidence suggests that the processing of several primary miRNA transcripts (pri-miRNAs) is blocked posttranscriptionally in embryonic stem cells, embryonal carcinoma cells, and primary tumors. Here we show that Lin28, a developmentally regulated RNA binding protein, selectively blocks the processing of pri-let-7 miRNAs in embryonic cells. Using in vitro and in vivo studies, we found that Lin28 is necessary and sufficient for blocking Microprocessor-mediated cleavage of pri-let-7 miRNAs. Our results identify Lin28 as a negative regulator of miRNA biogenesis and suggest that Lin28 may play a central role in blocking miRNA-mediated differentiation in stem cells and in certain cancers.
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              Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA.

              The precise control of microRNA (miRNA) biogenesis is critical for embryonic development and normal cellular functions, and its dysregulation is often associated with human diseases. Though the birth and maturation pathway of miRNA has been established, the regulation and death pathway remains largely unknown. Here, we report the RNA-binding proteins, Lin28a and Lin28b, as posttranscriptional repressors of let-7 miRNA biogenesis. We observe that the Lin28 proteins act mainly in the cytoplasm by inducing uridylation of precursor let-7 (pre-let-7) at its 3' end. The uridylated pre-let-7 (up-let-7) fails Dicer processing and undergoes degradation. We provide a mechanism for the posttranscriptional regulation of miRNA biogenesis by Lin28 which is highly expressed in undifferentiated cells and certain cancer cells. The Lin28-mediated downregulation of let-7 may play a key role in development, stem cell programming, and tumorigenesis.
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                Author and article information

                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                10 April 2012
                20 March 2012
                : 106
                : 8
                : 1415-1423
                Affiliations
                [1 ]Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine , Suita, Yamadaoka 2-2, Osaka 565-0871, Japan
                Author notes
                Article
                bjc201290
                10.1038/bjc.2012.90
                3326671
                22433967
                9481920a-0754-4666-a3e7-fc7f6eb45270
                Copyright © 2012 Cancer Research UK
                History
                : 12 October 2011
                : 23 January 2012
                : 23 February 2012
                Categories
                Molecular Diagnostics

                Oncology & Radiotherapy
                lin28,lin28b,oesophageal cancer,let-7
                Oncology & Radiotherapy
                lin28, lin28b, oesophageal cancer, let-7

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