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      SEC23A confers ER stress resistance in gastric cancer by forming the ER stress-SEC23A-autophagy negative feedback loop

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          Abstract

          Background

          Sec23 homolog A (SEC23A), a core component of coat protein complex II (COPII), has been reported to be involved in several cancers. However, the role of SEC23A in gastric cancer remains unclear.

          Methods

          The expression of SEC23A in gastric cancer was analyzed by using qRT-PCR, western blotting and IHC staining. The role of SEC23A in ER stress resistance was explored by functional experiments in vitro and vivo. The occupation of STAT3 on the SEC23A promoter region was verified by luciferase reporter plasmids and CHIP assay. The interaction between SEC23A and ANXA2 was identified by Co-IP and mass spectrometry analysis.

          Results

          We demonstrated that SEC23A was upregulated in gastric cancer and predicted poor prognosis in patients with gastric cancer. Mechanistically, SEC23A was transcriptional upregulated by ER stress-induced pY705-STAT3. Highly expressed SEC23A promoted autophagy by regulating the cellular localization of ANXA2. The SEC23A-ANXA2-autophay axis, in turn, protected gastric cancer cells from ER stress-induced apoptosis. Furthermore, we identified SEC23A attenuated 5-FU therapeutic effectiveness in gastric cancer cells through autophagy-mediated ER stress relief.

          Conclusion

          We reveal an ER stress-SEC23A-autophagy negative feedback loop that enhances the ability of gastric cancer cells to resist the adverse survival environments. These results identify SEC23A as a promising molecular target for potential therapeutic intervention and prognostic prediction in patients with gastric cancer.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s13046-023-02807-w.

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          Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

          Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)
          This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
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            Gastric cancer

            Elizabeth Smyth, Magnus Nilsson, Heike I Grabsch … (2020)
            Gastric cancer is the fifth most common cancer and the third most common cause of cancer death globally. Risk factors for the condition include Helicobacter pylori infection, age, high salt intake, and diets low in fruit and vegetables. Gastric cancer is diagnosed histologically after endoscopic biopsy and staged using CT, endoscopic ultrasound, PET, and laparoscopy. It is a molecularly and phenotypically highly heterogeneous disease. The main treatment for early gastric cancer is endoscopic resection. Non-early operable gastric cancer is treated with surgery, which should include D2 lymphadenectomy (including lymph node stations in the perigastric mesentery and along the celiac arterial branches). Perioperative or adjuvant chemotherapy improves survival in patients with stage 1B or higher cancers. Advanced gastric cancer is treated with sequential lines of chemotherapy, starting with a platinum and fluoropyrimidine doublet in the first line; median survival is less than 1 year. Targeted therapies licensed to treat gastric cancer include trastuzumab (HER2-positive patients first line), ramucirumab (anti-angiogenic second line), and nivolumab or pembrolizumab (anti-PD-1 third line).
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              The unfolded protein response: from stress pathway to homeostatic regulation.

              Peter Walter, David Ron (2011)
              The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum (ER), where they fold and assemble. Only properly assembled proteins advance from the ER to the cell surface. To ascertain fidelity in protein folding, cells regulate the protein-folding capacity in the ER according to need. The ER responds to the burden of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways, collectively termed the unfolded protein response (UPR). Together, at least three mechanistically distinct branches of the UPR regulate the expression of numerous genes that maintain homeostasis in the ER or induce apoptosis if ER stress remains unmitigated. Recent advances shed light on mechanistic complexities and on the role of the UPR in numerous diseases.
              Article 0 comments Cited 1038 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Li Yang:
                ORCID: http://orcid.org/0000-0001-5456-1944
                pwkyangli@njmu.edu.cn
                Journal
                Journal ID (nlm-ta): J Exp Clin Cancer Res
                Journal ID (iso-abbrev): J Exp Clin Cancer Res
                Title: Journal of Experimental & Clinical Cancer Research : CR
                Publisher: BioMed Central (London )
                ISSN (Print): 0392-9078
                ISSN (Electronic): 1756-9966
                Publication date (Electronic): 5 September 2023
                Publication date PMC-release: 5 September 2023
                Publication date Collection: 2023
                Volume: 42
                Electronic Location Identifier: 232
                Affiliations
                [1 ]GRID grid.412676.0, ISNI 0000 0004 1799 0784, Department of General Surgery, , the First Affiliated Hospital of Nanjing Medical University, ; 300 Guangzhou Road, Nanjing, 210029 Jiangsu Province China
                [2 ]Department of General Surgery, Liyang People’s Hospital, Liyang Branch Hospital of Jiangsu Province Hospital, Liyang, Jiangsu Province China
                Author information
                http://orcid.org/0000-0001-5456-1944
                Article
                Publisher ID: 2807
                DOI: 10.1186/s13046-023-02807-w
                PMC ID: 10478313
                PubMed ID: 37670384
                SO-VID: 27d7f924-8f88-4aa2-9932-b0f3d59092b9
                Copyright © © Italian National Cancer Institute ‘Regina Elena’ 2023
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.

                History
                Date received : 6 June 2023
                Date accepted : 22 August 2023
                Funding
                Funded by: Project of Cultivating Innovation in Science and Technology Plan of Liyang City
                Award ID: Grant No.LC2021001
                Award Recipient :
                Funded by: Jiangsu Province Capability Improvement Project through Science, Technology and Education
                Award ID: Jiangsu Provincial Medical Key Discipline
                Award ID: ZDXK202222
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: Grant No. 81874219
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © Italian National Cancer Institute ‘Regina Elena’ 2023

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: 5-fu,apoptosis,autophagy,er stress,gastric cancer,sec23a
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: 5-fu, apoptosis, autophagy, er stress, gastric cancer, sec23a

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