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      LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer

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          Abstract

          Background

          Long noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) progression and could be a potential therapeutic target.

          Methods

          We screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact with LINRIS (Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells with LINRIS inhibited were tested in vitro and in vivo .

          Results

          LINRIS was upregulated in CRC tissues from patients with poor overall survival (OS), and LINRIS inhibition led to the impaired CRC cell line growth. Moreover, knockdown of LINRIS resulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N 6-methyladenosine (m 6A) ‘reader’. LINRIS blocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown of LINRIS attenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription of LINRIS could be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition of LINRIS suppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models.

          Conclusion

          LINRIS is an independent prognostic biomarker for CRC. The LINRIS-IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target.

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          A long noncoding RNA mediates both activation and repression of immune response genes.

          Susan Carpenter, Daniel Aiello, Maninjay Atianand … (2013)
          An inducible program of inflammatory gene expression is central to antimicrobial defenses. This response is controlled by a collaboration involving signal-dependent activation of transcription factors, transcriptional co-regulators, and chromatin-modifying factors. We have identified a long noncoding RNA (lncRNA) that acts as a key regulator of this inflammatory response. Pattern recognition receptors such as the Toll-like receptors induce the expression of numerous lncRNAs. One of these, lincRNA-Cox2, mediates both the activation and repression of distinct classes of immune genes. Transcriptional repression of target genes is dependent on interactions of lincRNA-Cox2 with heterogeneous nuclear ribonucleoprotein A/B and A2/B1. Collectively, these studies unveil a central role of lincRNA-Cox2 as a broad-acting regulatory component of the circuit that controls the inflammatory response.
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            [Report of cancer epidemiology in China, 2015].

            R. S. Zheng, K. -X. Sun, S W Zhang … (2019)
            Objective: Data from local cancer registries were pooled to estimate cancer incidence and mortality in China, 2015. Methods: Data submitted from 501 cancer registries were checked & evaluated according to the criteria of data quality control, and 368 registries' data were qualified for the final analysis. Data were stratified by area (urban/rural), sex, age group and cancer sites, and combined with national population data to estimate cancer incidence and mortality in China, 2015. Chinese population census in 2000 and Segi's population were used for age-standardized. Results: Total population covered by 368 cancer registries were 309 553 499 (148 804 626 in urban and 160 748 873 in rural areas). The percentage of morphologically verified cases (MV) and the percentage of death certificate-only cases (DCO) accounted for 69.34% and 2.09%, respectively, and the mortality to incidence ratio was 0.61. About 3 929 000 new cancer cases were reported in 2015 and the crude incidence rate was 285.83 per 100 000 population (males and females were 305.47 and 265.21 per 100 000 population). Age-standardized incidence rates by Chinese standard population (ASIRC) and by world standard population (ASIRW) were 190.64 and 186.39 per 100 000 population, respectively, with the cumulative incidence rate (0-74 age years old) of 21.44%. The cancer incidence and ASIRC were 304.96/100 000 and 196.09/100 000 in urban areas and 261.40/100 000 and 182.70/100 000 in rural areas, respectively. About 2 338 000 cancer deaths were reported in 2015 and the cancer mortality was 170.05/100 000 (210.10/100 000 in males and 128.00/100 000 in females). Age-standardized mortality rates by Chinese standard population (ASMRC) and by world standard population (ASMRW) were 106.72/100 000 and 105.84/100 000, respectively, with the cumulative incidence rate (0-74 age years old) of 11.94%. The cancer mortality and ASMRC were 172.61/100 000 and 103.65/100 000 in urban areas and 166.79/100 000 and 110.76/100 000 in rural areas, respectively. The most common cancer cases including lung, gastric, colorectal, liver and female breast, the top 10 cancer incidence accounted for about 76.70% of all cancer new cases. The most common cancer deaths including lung, liver, gastric, esophageal and colorectal, the top 10 cancer deaths accounted for about 83.00% of all cancer deaths. Conclusions: The burden of cancer showed a continuous upward trend in China. Cancer prevention and control faces the problem of the disparity in different areas and different cancer burden between men and women. The cancer pattern in China presents the coexistence of the cancer patterns in developed and developing countries. The situation of cancer prevention and control is still serious in China.
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              Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia.

              Rui-Hua Xu, Helene Pelicano, Yan Zhou … (2005)
              Cancer cells generally exhibit increased glycolysis for ATP generation (the Warburg effect) due in part to mitochondrial respiration injury and hypoxia, which are frequently associated with resistance to therapeutic agents. Here, we report that inhibition of glycolysis severely depletes ATP in cancer cells, especially in clones of cancer cells with mitochondrial respiration defects, and leads to rapid dephosphorylation of the glycolysis-apoptosis integrating molecule BAD at Ser(112), relocalization of BAX to mitochondria, and massive cell death. Importantly, inhibition of glycolysis effectively kills colon cancer cells and lymphoma cells in a hypoxic environment in which the cancer cells exhibit high glycolytic activity and decreased sensitivity to common anticancer agents. Depletion of ATP by glycolytic inhibition also potently induced apoptosis in multidrug-resistant cells, suggesting that deprivation of cellular energy supply may be an effective way to overcome multidrug resistance. Our study shows a promising therapeutic strategy to effectively kill cancer cells and overcome drug resistance. Because the Warburg effect and hypoxia are frequently seen in human cancers, these findings may have broad clinical implications.
              Article 0 comments Cited 208 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Huai-Qiang Ju: juhq@sysucc.org.cn
                Rui-Hua Xu:
                ORCID: http://orcid.org/0000-0001-9771-8534
                xurh@sysucc.org.cn
                Journal
                Journal ID (nlm-ta): Mol Cancer
                Journal ID (iso-abbrev): Mol. Cancer
                Title: Molecular Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1476-4598
                Publication date (Electronic): 2 December 2019
                Publication date PMC-release: 2 December 2019
                Publication date Collection: 2019
                Volume: 18
                Electronic Location Identifier: 174
                Affiliations
                [1 ]ISNI 0000 0004 1803 6191, GRID grid.488530.2, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, , Sun Yat-sen University Cancer Center, ; Guangzhou, China
                [2 ]ISNI 0000 0004 1803 6191, GRID grid.488530.2, Department of Medical Oncology, , Sun Yat-sen University Cancer Center, ; Guangzhou, China
                [3 ]Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
                [4 ]ISNI 0000 0004 1803 6191, GRID grid.488530.2, Department of Pathology, , Sun Yat-sen University Cancer Center, ; Guangzhou, China
                [5 ]Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China
                Author information
                http://orcid.org/0000-0001-9771-8534
                Article
                Publisher ID: 1105
                DOI: 10.1186/s12943-019-1105-0
                PMC ID: 6886219
                PubMed ID: 31791342
                SO-VID: 37f30d6f-6a50-428a-aee6-f1d99c446aab
                Copyright © © The Author(s). 2019
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 4 September 2019
                Date accepted : 12 November 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003453, Natural Science Foundation of Guangdong Province;
                Award ID: 2018B030306049
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: autophagy,crc,igf2bp2,linris,myc
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: autophagy, crc, igf2bp2, linris, myc

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