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Cellular and Molecular Biology

Sec61γ is a vital protein in the endoplasmic reticulum membrane promoting tumor metastasis and invasion in lung adenocarcinoma

British Journal of Cancer volume 128, pages 1478–1490 (2023)Cite this article

Subjects

Abstract

Background

Lung adenocarcinoma (LUAD) is one of the most common malignant tumors worldwide. Finding effective prognostic markers and therapeutic targets is of great significance for controlling metastasis and invasion clinically.

Methods

The open copy-number aberrations and gene expression datasets were analysed, and the data of 102 LUAD patients was used for further validation. The cell proliferation, colony formation, migration, invasion assays and mice tumor models were used to detect the function of SEC61G. The epidermal growth factor receptor (EGFR) pathway was also detected to find the mechanism of Sec61γ.

Results

Based on the open datasets, we found that the high level of SEC61G mRNA may drive LUAD metastasis. Furthermore, the overexpression of Sec61γ protein was significantly associated with poor prognosis and greater tumor cell proliferation and metastasis. The SEC61G knockdown could inhibit the EGFR pathway, including STAT3, AKT and PI3K, which can be reversed by Sec61γ overexpression and epithelial growth factor (EGF) supplement.

Conclusions

Sec61γ promoted the proliferation, metastasis, and invasion of LUAD through EGFR pathways. Sec61γ might be a potential target for the treatment of LUAD metastases.

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Fig. 1: Identification of oncogenes for LUAD metastasis in TCGA data.
Fig. 2: Survival analysis of different Sec61γ expressions in LUAD patients from different resources.
Fig. 3: Effects of Sec61γ on the proliferation of lung cell lines.
Fig. 4: Sec61γ enhanced the migration and invasion of lung cancer cells.
Fig. 5: Effects of Sec61γ on the metastatic ability of lung cancer cell lines in vivo.
Fig. 6: Sec61γ regulated the EGFR pathway through related factors.

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Data availability

The data and material presented in this article and in the Supplementary Information are available from the corresponding authors on reasonable request.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  PubMed  Google Scholar 

  2. O’Brien TD, Jia P, Caporaso NE, Landi MT, Zhao Z. Weak sharing of genetic association signals in three lung cancer subtypes: evidence at the SNP, gene, regulation, and pathway levels. Genome Med. 2018;10:16.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Seijo LM, Peled N, Ajona D, Boeri M, Field JK, Sozzi G, et al. Biomarkers in lung cancer screening: achievements, promises, and challenges. J Thorac Oncol. 2019;14:343–57.

    Article  CAS  PubMed  Google Scholar 

  4. Pieterman RM, van Putten JW, Meuzelaar JJ, Mooyaart EL, Vaalburg W, Koeter GH, et al. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med. 2000;343:254–61.

    Article  CAS  PubMed  Google Scholar 

  5. Li M, Hong G, Cheng J, Li J, Cai H, Li X, et al. Identifying reproducible molecular biomarkers for gastric cancer metastasis with the aid of recurrence information. Sci Rep. 2016;6:24869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Qi L, Li T, Shi G, Wang J, Li X, Zhang S, et al. An individualized gene expression signature for prediction of lung adenocarcinoma metastases. Mol Oncol. 2017;11:1630–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Qi L, Chen L, Li Y, Qin Y, Pan R, Zhao W, et al. Critical limitations of prognostic signatures based on risk scores summarized from gene expression levels: a case study for resected stage I non-small-cell lung cancer. Brief Bioinform. 2016;17:233–42.

    Article  PubMed  Google Scholar 

  8. Aviram N, Schuldiner M. Targeting and translocation of proteins to the endoplasmic reticulum at a glance. J Cell Sci. 2017;130:4079–85.

    Article  CAS  PubMed  Google Scholar 

  9. Rapoport TA, Li L, Park E. Structural and mechanistic insights into protein translocation. Annu Rev Cell Dev Biol. 2017;33:369–90.

    Article  CAS  PubMed  Google Scholar 

  10. Tyedmers J, Lerner M, Bies C, Dudek J, Skowronek MH, Haas IG, et al. Homologs of the yeast Sec complex subunits Sec62p and Sec63p are abundant proteins in dog pancreas microsomes. Proc Natl Acad Sci USA. 2000;97:7214–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Beckmann R, Bubeck D, Grassucci R, Penczek P, Verschoor A, Blobel G, et al. Alignment of conduits for the nascent polypeptide chain in the ribosome-Sec61 complex. Science. 1997;278:2123–6.

    Article  CAS  PubMed  Google Scholar 

  12. Rapoport TA, Rolls MM, Jungnickel B. Approaching the mechanism of protein transport across the ER membrane. Curr Opin Cell Biol. 1996;8:499–504.

    Article  CAS  PubMed  Google Scholar 

  13. Rapoport TA. Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes. Nature. 2007;450:663–9.

    Article  CAS  PubMed  Google Scholar 

  14. Schorr S, Klein MC, Gamayun I, Melnyk A, Jung M, Schauble N, et al. Co-chaperone specificity in gating of the polypeptide conducting channel in the membrane of the human endoplasmic reticulum. J Biol Chem. 2015;290:18621–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Huang JB, Kindzelskii AL, Clark AJ, Petty HR. Identification of channels promoting calcium spikes and waves in HT1080 tumor cells: their apparent roles in cell motility and invasion. Cancer Res. 2004;64:2482–9.

    Article  CAS  PubMed  Google Scholar 

  16. Liu B, Liu J, Liao Y, Jin C, Zhang Z, Zhao J, et al. Identification of SEC61G as a novel prognostic marker for predicting survival and response to therapies in patients with glioblastoma. Med Sci Monit. 2019;25:3624–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lu Z, Zhou L, Killela P, Rasheed AB, Di C, Poe WE, et al. Glioblastoma proto-oncogene SEC61gamma is required for tumor cell survival and response to endoplasmic reticulum stress. Cancer Res. 2009;69:9105–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Linxweiler M, Schorr S, Schauble N, Jung M, Linxweiler J, Langer F, et al. Targeting cell migration and the endoplasmic reticulum stress response with calmodulin antagonists: a clinically tested small molecule phenocopy of SEC62 gene silencing in human tumor cells. BMC Cancer. 2013;13:574.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Linxweiler M, Linxweiler J, Barth M, Benedix J, Jung V, Kim YJ, et al. Sec62 bridges the gap from 3q amplification to molecular cell biology in non-small cell lung cancer. Am J Pathol. 2012;180:473–83.

    Article  CAS  PubMed  Google Scholar 

  20. Servidei T, Meco D, Muto V, Bruselles A, Ciolfi A, Trivieri N, et al. Novel SEC61G-EGFR fusion gene in pediatric ependymomas discovered by clonal expansion of stem cells in absence of exogenous mitogens. Cancer Res. 2017;77:5860–72.

    Article  CAS  PubMed  Google Scholar 

  21. Huang Q, Wang K, Wanggou S, Tian J, Li X. A novel co-targeting strategy of EGFR/SEC61G for multi-modality fluorescence/MR/photoacoustic imaging of glioblastoma. Nanomedicine. 2022;40:102509.

    Article  CAS  PubMed  Google Scholar 

  22. Zhang B, Zhang Y, Jiang X, Su H, Wang Q, Wudu M, et al. JMJD8 promotes malignant progression of lung cancer by maintaining EGFR stability and EGFR/PI3K/AKT pathway activation. J Cancer. 2021;12:976–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Akca H, Tani M, Hishida T, Matsumoto S, Yokota J. Activation of the AKT and STAT3 pathways and prolonged survival by a mutant EGFR in human lung cancer cells. Lung Cancer. 2006;54:25–33.

    Article  PubMed  Google Scholar 

  24. Lin LL, Yang F, Zhang DH, Hu C, Yang S, Chen XQ. ARHGAP10 inhibits the epithelial-mesenchymal transition of non-small cell lung cancer by inactivating PI3K/Akt/GSK3beta signaling pathway. Cancer Cell Int. 2021;21:320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang S, Yan Y, Cheng Z, Hu Y, Liu T. Sotetsuflavone suppresses invasion and metastasis in non-small-cell lung cancer A549 cells by reversing EMT via the TNF-alpha/NF-kappaB and PI3K/AKT signaling pathway. Cell Death Discov. 2018;4:26.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Guan X. Cancer metastases: challenges and opportunities. Acta Pharm Sin B. 2015;5:402–18.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Merchant N, Nagaraju GP, Rajitha B, Lammata S, Jella KK, Buchwald ZS, et al. Matrix metalloproteinases: their functional role in lung cancer. Carcinogenesis. 2017;38:766–80.

    Article  CAS  PubMed  Google Scholar 

  28. Frezzetti D, Gallo M, Maiello MR, D’Alessio A, Esposito C, Chicchinelli N, et al. VEGF as a potential target in lung cancer. Expert Opin Ther Targets. 2017;21:959–66.

    Article  CAS  PubMed  Google Scholar 

  29. Niethammer AG, Xiang R, Becker JC, Wodrich H, Pertl U, Karsten G, et al. A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nat Med. 2002;8:1369–75.

    Article  CAS  PubMed  Google Scholar 

  30. Guo H, Xing Y, Liu R, Chen S, Bian X, Wang F, et al. -216G/T (rs712829), a functional variant of the EGFR promoter, is associated with the pleural metastasis of lung adenocarcinoma. Oncol Lett. 2013;6:693–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gao H, Niu W, He Z, Gao C, Peng C, Niu J. SEC61G plays an oncogenic role in hepatocellular carcinoma cells. Cell Cycle. 2020;19:3348–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bland JM, Altman DG. The logrank test. BMJ. 2004;328:1073.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Klipper-Aurbach Y, Wasserman M, Braunspiegel-Weintrob N, Borstein D, Peleg S, Assa S, et al. Mathematical formulae for the prediction of the residual beta cell function during the first two years of disease in children and adolescents with insulin-dependent diabetes mellitus. Med Hypotheses. 1995;45:486–90.

    Article  CAS  PubMed  Google Scholar 

  34. Denisenko TV, Budkevich IN, Zhivotovsky B. Cell death-based treatment of lung adenocarcinoma. Cell Death Dis. 2018;9:117.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Rami-Porta R, Call S, Dooms C, Obiols C, Sanchez M, Travis WD, et al. Lung cancer staging: a concise update. Eur Respir J. 2018;51:1800190.

    Article  PubMed  Google Scholar 

  36. Duffy MJ, O’Byrne K. Tissue and blood biomarkers in lung cancer: a review. Adv Clin Chem. 2018;86:1–21.

    Article  CAS  PubMed  Google Scholar 

  37. Nguyen D, Stutz R, Schorr S, Lang S, Pfeffer S, Freeze HH, et al. Proteomics reveals signal peptide features determining the client specificity in human TRAP-dependent ER protein import. Nat Commun. 2018;9:3765.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Linxweiler M, Schick B, Zimmermann R. Let’s talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine. Signal Transduct Target Ther. 2017;2:17002.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zheng Q, Wang Z, Zhang M, Yu Y, Chen R, Lu T, et al. Prognostic value of SEC61G in lung adenocarcinoma: a comprehensive study based on bioinformatics and in vitro validation. BMC Cancer. 2021;21:1216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lu T, Chen Y, Gong X, Guo Q, Lin C, Luo Q, et al. SEC61G overexpression and DNA amplification correlates with prognosis and immune cell infiltration in head and neck squamous cell carcinoma. Cancer Med. 2021;10:7847–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shah P, Chaumet A, Royle SJ, Bard FA. The NAE pathway: autobahn to the nucleus for cell surface receptors. Cells. 2019;8:915.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kelkar A, Dobberstein B. Sec61beta, a subunit of the Sec61 protein translocation channel at the endoplasmic reticulum, is involved in the transport of Gurken to the plasma membrane. BMC Cell Biol. 2009;10:11.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Fa X, Song P, Fu Y, Deng Y, Liu K. Long non-coding RNA VPS9D1-AS1 facilitates cell proliferation, migration and stemness in hepatocellular carcinoma. Cancer Cell Int. 2021;21:131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang YN, Yamaguchi H, Huo L, Du Y, Lee HJ, Lee HH, et al. The translocon Sec61beta localized in the inner nuclear membrane transports membrane-embedded EGF receptor to the nucleus. J Biol Chem. 2010;285:38720–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chen MK, Du Y, Sun L, Hsu JL, Wang YH, Gao Y, et al. H2O2 induces nuclear transport of the receptor tyrosine kinase c-MET in breast cancer cells via a membrane-bound retrograde trafficking mechanism. J Biol Chem. 2019;294:8516–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jung V, Kindich R, Kamradt J, Jung M, Muller M, Schulz WA, et al. Genomic and expression analysis of the 3q25-q26 amplification unit reveals TLOC1/SEC62 as a probable target gene in prostate cancer. Mol Cancer Res. 2006;4:169–76.

    Article  CAS  PubMed  Google Scholar 

  47. Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16:284–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang Y, Fu M, Liu J, Yang Y, Yu Y, Li J, et al. Inhibition of tumor metastasis by targeted daunorubicin and dioscin codelivery liposomes modified with PFV for the treatment of non-small-cell lung cancer. Int J Nanomed. 2019;14:4071–90.

    Article  CAS  Google Scholar 

  49. Bremnes RM, Veve R, Hirsch FR, Franklin WA. The E-cadherin cell-cell adhesion complex and lung cancer invasion, metastasis, and prognosis. Lung Cancer. 2002;36:115–24.

    Article  PubMed  Google Scholar 

  50. Greiner M, Kreutzer B, Jung V, Grobholz R, Hasenfus A, Stohr RF, et al. Silencing of the SEC62 gene inhibits migratory and invasive potential of various tumor cells. Int J Cancer. 2011;128:2284–95.

    Article  CAS  PubMed  Google Scholar 

  51. Casper M, Weber SN, Kloor M, Mullenbach R, Grobholz R, Lammert F, et al. Hepatocellular carcinoma as extracolonic manifestation of Lynch syndrome indicates SEC63 as potential target gene in hepatocarcinogenesis. Scand J Gastroenterol. 2013;48:344–51.

    Article  CAS  PubMed  Google Scholar 

  52. Appert-Collin A, Hubert P, Cremel G, Bennasroune A. Role of ErbB receptors in cancer cell migration and invasion. Front Pharm. 2015;6:283.

    Article  Google Scholar 

  53. da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011;6:49–69.

    Article  PubMed  Google Scholar 

  54. Lim SM, Syn NL, Cho BC, Soo RA. Acquired resistance to EGFR targeted therapy in non-small cell lung cancer: mechanisms and therapeutic strategies. Cancer Treat Rev. 2018;65:1–10.

    Article  CAS  PubMed  Google Scholar 

  55. Shin DY, Na II, Kim CH, Park S, Baek H, Yang SH. EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol. 2014;9:195–9.

    Article  CAS  PubMed  Google Scholar 

  56. Eustace A, Mani N, Span PN, Irlam JJ, Taylor J, Betts GN, et al. A 26-gene hypoxia signature predicts benefit from hypoxia-modifying therapy in laryngeal cancer but not bladder cancer. Clin Cancer Res. 2013;19:4879–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Miranda A, Hamilton PT, Zhang AW, Pattnaik S, Becht E, Mezheyeuski A, et al. Cancer stemness, intratumoral heterogeneity, and immune response across cancers. Proc Natl Acad Sci USA. 2019;116:9020–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.

    Article  PubMed  Google Scholar 

  59. Ma J, He Z, Zhang H, Zhang W, Gao S, Ni X. SEC61G promotes breast cancer development and metastasis via modulating glycolysis and is transcriptionally regulated by E2F1. Cell Death Dis. 2021;12:550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Meng H, Jiang X, Wang J, Sang Z, Guo L, Yin G, et al. SEC61G is upregulated and required for tumor progression in human kidney cancer. Mol Med Rep. 2021;23:427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The bioinformatics-related results shown here regarding lung adenocarcinoma are based upon data derived from The Cancer Genome Atlas (TCGA) database (http://cancergenome.nih.gov/) and Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/), accession number GSE68465, GSE31210 and GSE50081.

Funding

This research was supported by the National Natural Science Foundation of China (grant numbers: 81872396, 81572824 and 81672931).

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Author notes

  1. These authors contributed equally: Shanqi Xu, Xin Li.

Authors and Affiliations

  1. Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China

    Shanqi Xu, Jianxiong Geng, Yingyue Cao & Yan Yu

  2. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China

    Xin Li & Lishuang Qi

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  1. Shanqi Xu
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Contributions

SQX designed and performed the in vitro experiments and statistical analyses, collected clinical samples and performed IHC staining of Sec61γ in these tissues, and drafted and revised the manuscript. XL performed the Bioinformatics research and wrote and revised the manuscript. JXG performed the in vitro experiment. YYC performed the in vivo experiment and statistical analyses. LSQ and YY contributed to study design and supervision. All authors approved the final version of the paper and provided their consent for publication.

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Correspondence to Yan Yu or Lishuang Qi.

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Informed consent was obtained from all subjects. The study was conducted in accordance with the Declaration of Helsinki and the International Ethical Guidelines for Biomedical Research. All the clinical and animal experimental protocols in this study were reviewed and approved by the Ethics Committee of the Harbin Medical University Cancer Hospital.

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Xu, S., Li, X., Geng, J. et al. Sec61γ is a vital protein in the endoplasmic reticulum membrane promoting tumor metastasis and invasion in lung adenocarcinoma. Br J Cancer 128, 1478–1490 (2023). https://doi.org/10.1038/s41416-023-02150-z

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