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      LncRNA NEAT1 knockdown attenuates autophagy to elevate 5‐FU sensitivity in colorectal cancer via targeting miR‐34a

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          Abstract

          Backgrounds

          Colorectal carcinoma (CRC) is a common malignant tumor. Increasing evidences indicated that CRC showed a resistance to 5‐fluorouracil (5‐FU) and further resulted in a poor prognosis. In this study, we aim to investigate the effect of long noncoding RNA nuclear paraspeckle assembly transcript 1 (LncRNA NEAT1) on cell viability, sensitivity to 5‐FU, and autophagy of CRC cell lines.

          Methods

          MTT (3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐Htetrazolium bromide) was used to detect cell viability, immunofluorescent staining was used to detect autophagy puncta, and luciferase reporter system was used to determine binding ability between miR‐34a and NEAT1 or putative targets. Additionally, indicated mRNAs and protein expressions were determined by qRT‐PCR or western blotting, respectively.

          Results

          We found that NEAT1 expression was increased in CRC tissues and cells, which showed a negative correlation with miR‐34a expression. In addition, NEAT1 knockdown noticeably inhibited the proliferation of CRC cells and enhanced 5‐FU sensitivity. It revealed that NEAT1 knockdown suppressed the LC3 puncta and the expressions of Beclin‐1, ULK1, and ratio of LC3II/I. Overexpression of miR‐34a showed similar trends with NEAT1 knockdown. miR‐34a was validated to target the putative binding sites in 3′‐UTR of HMGB1, ATG9A, and ATG4B, which are involved in the activation of autophagy. Inhibition of miR‐34a or overexpression of HMGB1 could effectively reverse elevated 5‐FU sensitivity upon NEAT1 knockdown. In addition, 3‐MA reversed NEAT1 overexpression‐induced resistance in HT29 cells.

          Conclusion

          These findings indicate that LncRNA NEAT1 could target miR‐34a and promote autophagy to facilitate 5‐FU chemoresistance in CRC.

          Abstract

          NEAT1 knockdown attenuates autophagy to elevate 5‐FU sensitivity in CRC cell lines. NEAT1 is an endogenous compete RNA of miR‐34a in CRC.

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          Most cited references25

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          The role of autophagy in cancer development and response to therapy.

          Autophagy is a process in which subcellular membranes undergo dynamic morphological changes that lead to the degradation of cellular proteins and cytoplasmic organelles. This process is an important cellular response to stress or starvation. Many studies have shed light on the importance of autophagy in cancer, but it is still unclear whether autophagy suppresses tumorigenesis or provides cancer cells with a rescue mechanism under unfavourable conditions. What is the present state of our knowledge about the role of autophagy in cancer development, and in response to therapy? And how can the autophagic process be manipulated to improve anticancer therapeutics?
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            Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy.

            Autophagy or "self eating" is frequently activated in tumor cells treated with chemotherapy or irradiation. Whether autophagy represents a survival mechanism or rather contributes to cell death remains controversial. To address this issue, the role of autophagy in radiosensitive and radioresistant human cancer cell lines in response to gamma-irradiation was examined. We found irradiation-induced accumulation of autophagosomes accompanied by strong mRNA induction of the autophagy-related genes beclin 1, atg3, atg4b, atg4c, atg5, and atg12 in each cell line. Transduction of specific target-siRNAs led to down-regulation of these genes for up to 8 days as shown by reverse transcription-PCR and Western blot analysis. Blockade of each autophagy-related gene was associated with strongly diminished accumulation of autophagosomes after irradiation. As shown by clonogenic survival, the majority of inhibited autophagy-related genes, each alone or combined, resulted in sensitization of resistant carcinoma cells to radiation, whereas untreated resistant cells but not sensitive cells survived better when autophagy was inhibited. Similarly, radiosensitization or the opposite was observed in different sensitive carcinoma cells and upon inhibition of different autophagy genes. Mutant p53 had no effect on accumulation of autophagosomes but slightly increased clonogenic survival, as expected, because mutated p53 protects cells by conferring resistance to apoptosis. In our system, short-time inhibition of autophagy along with radiotherapy lead to enhanced cytotoxicity of radiotherapy in resistant cancer cells.
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              Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer.

              Autophagy is an evolutionarily conserved lysosomal pathway for degrading cytoplasmic proteins, macromolecules, and organelles. While autophagy has become one of the most attractive topics in cancer research, the current autophagy literature is often viewed as confusing, because of its association with apparently contradictory roles, such as survival and cell death. Autophagy can serve as a tumor suppressor, as a partial reduction in autophagic capacity or defective autophagy (e.g., heterozygous knockdown BECN1 (+/-) in mice) provides an oncogenic stimulus, causing malignant transformation and spontaneous tumors. In addition, autophagy seems to function as a protective cell survival mechanism against environmental and cellular stress (e.g., nutrient deprivation, hypoxia and therapeutic stress) and causes resistance to antineoplastic therapies. Recent studies have demonstrated that the inhibition of autophagy in cancer cells may be therapeutically beneficial in some circumstances, as it can sensitize cancer cells to different therapies, including DNA-damaging agents, antihormone therapies (e.g., tamoxifen), and radiation therapy. This supports the hypothesis that inhibiting autophagy can negatively influence cancer cell survival and increase cell death when combined with anticancer agents, providing a therapeutic advantage against cancer. On the other hand, the induction of autophagy by the inhibition of anti-autophagic proteins, such as Bcl-2, PKCdelta, and tissue transglutaminase 2 (TG2), may lead to autophagic cell death in some apoptosis-resistant cancers (i.e., breast and pancreatic cancers), indicating that the induction of autophagy alone may also be used as a potential therapy. Overall, the data suggest that, depending on the cellular features, either the induction or the inhibition of autophagy can provide therapeutic benefits to patients and that the design and synthesis of the first-generation modulators of autophagy may provide the tools for proof of concept experiments and the impetus for translational studies that may ultimately lead to new therapeutic strategies in cancer.
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                Author and article information

                Contributors
                cslsj169@163.com
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                05 December 2019
                February 2020
                : 9
                : 3 ( doiID: 10.1002/cam4.v9.3 )
                : 1079-1091
                Affiliations
                [ 1 ] Department of Gastroenterology The Third Xiangya Hospital of Central South University Changsha P.R. China
                [ 2 ] Hunan Key Laboratory of Nonresolving Inflammation and Cancer Changsha P.R. China
                Author notes
                [*] [* ] Correspondence

                Shao‐Jun Liu, Department of Gastroenterology, The Third Xiangya Hospital of Central South University, No. 138, Tongzipo Road, Yuelu District, Changsha, Hunan Province 410013, P.R. China.

                Email: cslsj169@ 123456163.com

                Author information
                https://orcid.org/0000-0001-5374-1302
                Article
                CAM42746
                10.1002/cam4.2746
                6997058
                31802650
                0e61c80c-e1fc-4ccb-8baa-d08ea7e778ef
                © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 July 2019
                : 07 November 2019
                : 15 November 2019
                Page count
                Figures: 8, Tables: 0, Pages: 13, Words: 5618
                Funding
                Funded by: Hunan Natural Science Foundation of Youth Fund Project
                Award ID: 2018JJ3802
                Categories
                Original Research
                Cancer Biology
                Original Research
                Custom metadata
                2.0
                February 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:03.02.2020

                Oncology & Radiotherapy
                autophagy,colorectal carcinoma,hmgb1,lncrna neat1,mir‐34a
                Oncology & Radiotherapy
                autophagy, colorectal carcinoma, hmgb1, lncrna neat1, mir‐34a

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