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Journal of Cancer Research and Clinical Oncology

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Open Access 01-05-2024 | Gastric Cancer | Research

Cystatin SA attenuates gastric cancer cells growth and increases sensitivity to oxaliplatin via PI3K/AKT signaling pathway

Authors: Yida Lu, Huizhen Wang, Sihan Chen, Bo Yang, Yaxian Li, Yongxiang Li

Published in: Journal of Cancer Research and Clinical Oncology | Issue 5/2024

Abstract

Purpose

Cystatin SA (CST2) belongs to the superfamily of cysteine protease inhibitors. Emerging research indicates that CST2 is often dysregulated across various cancers. Its role and molecular mechanisms in gastric cancer remain underexplored. This study aims to explore the expression and function of CST2 in gastric cancer.

Methods

CST2 expression was analyzed and validated through Western blot. CST2 overexpression was induced by lentivirus in GC cells, and the correlation between CST2 expression levels and downstream signaling pathways was assessed. In addition, multiple assays, including cell proliferation, colony formation, wound-healing, and transwell migration/invasion, were considered to ascertain the influence of CST2 overexpression on gastric cancer. The cell cycle and apoptosis were detected by flow cytometry.

Results

CST2 expression at the protein level was decreased to be reduced in both gastric cancer tissues and cell lines, and CST2 expression attenuate gastric cancer growth, an effect restricted to gastric cancer cells and absent in gastric epithelial GES-1 cells. Furthermore, CST2 was demonstrated to improve chemosensitivity to Oxaliplatin in gastric cancer cells through the PI3K/AKT signaling pathway.

Conclusion

These findings indicate that CST2 is downregulated at the protein level in gastric cancer tissues and cell lines. Additionally, CST2 was found to attenuate the growth of gastric cancer cells and to enhance sensitivity to Oxaliplatin through the PI3K/AKT signaling pathway, specific to gastric cancer cell lines. CST2 may serve as a tumor suppressor gene increasing sensitivity to Oxaliplatin in gastric cancer.

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Altomare DA, Testa JR (2005) Perturbations of the AKT signaling pathway in human cancer. Oncogene 24:7455–7464CrossRefPubMed

Alzahrani AS (2019) PI3K/Akt/mTOR inhibitors in cancer: at the bench and bedside. Semin Cancer Biol 59:125–132CrossRefPubMed

Bao Y, Wang L, Shi L, Yun F, Liu X, Chen Y, Chen C, Ren Y, Jia Y (2019) Transcriptome profiling revealed multiple genes and ECM-receptor interaction pathways that may be associated with breast cancer. Cell Mol Biol Lett 24:38CrossRefPubMedPubMedCentral

Braicu C, Zanoaga O, Zimta AA, Tigu AB, Kilpatrick KL, Bishayee A, Nabavi SM, Berindan-Neagoe I (2022) Natural compounds modulate the crosstalk between apoptosis- and autophagy-regulated signaling pathways: controlling the uncontrolled expansion of tumor cells. Semin Cancer Biol 80:218–236CrossRefPubMed

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

Campbell PT, Sloan M, Kreiger N (2007) Physical activity and stomach cancer risk: the influence of intensity and timing during the lifetime. Eur J Cancer 43:593–600CrossRefPubMed

Casamayor M, Morlock R, Maeda H, Ajani J (2018) Targeted literature review of the global burden of gastric cancer. Ecancermedicalscience 12:883CrossRefPubMedPubMedCentral

Chen YF, Ma G, Cao X, Luo RZ, He LR, He JH, Huang ZL, Zeng MS, Wen ZS (2013) Overexpression of cystatin SN positively affects survival of patients with surgically resected esophageal squamous cell carcinoma. BMC Surg 13:15CrossRefPubMedPubMedCentral

Cheng A, Zhao S, FitzGerald LM, Wright JL, Kolb S, Karnes RJ, Jenkins RB, Davicioni E, Ostrander EA, Feng Z et al (2019) A four-gene transcript score to predict metastatic-lethal progression in men treated for localized prostate cancer: development and validation studies. Prostate 79:1589–1596CrossRefPubMedPubMedCentral

Clements WM, Wang J, Sarnaik A, Kim OJ, MacDonald J, Fenoglio-Preiser C, Groden J, Lowy AM (2002) beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res 62:3503–3506PubMed

Cui Y, Sun D, Song R, Zhang S, Liu X, Wang Y, Meng F, Lan Y, Han J, Pan S et al (2019) Upregulation of cystatin SN promotes hepatocellular carcinoma progression and predicts a poor prognosis. J Cell Physiol 234:22623–22634CrossRefPubMedPubMedCentral

Feng R, Chen X, Yu Y, Su L, Yu B, Li J, Cai Q, Yan M, Liu B, Zhu Z (2010) miR-126 functions as a tumour suppressor in human gastric cancer. Cancer Lett 298:50–63CrossRefPubMed

Fong C, Johnston E, Starling N (2022) Neoadjuvant and adjuvant therapy approaches to gastric cancer. Curr Treat Options Oncol 23:1247–1268CrossRefPubMed

Gallardo A, Lerma E, Escuin D, Tibau A, Muñoz J, Ojeda B, Barnadas A, Adrover E, Sánchez-Tejada L, Giner D et al (2012) Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas. Br J Cancer 106:1367–1373CrossRefPubMedPubMedCentral

Ishaq S, Nunn L (2015) Helicobacter pylori and gastric cancer: a state of the art review. Gastroenterol Hepatol Bed Bench 8:S6–S14PubMedPubMedCentral

Kim J, Cho YA, Choi WJ, Jeong SH (2014) Gene-diet interactions in gastric cancer risk: a systematic review. World J Gastroenterol 20:9600–9610CrossRefPubMedPubMedCentral

Kircher DA, Trombetti KA, Silvis MR, Parkman GL, Fischer GM, Angel SN, Stehn CM, Strain SC, Grossmann AH, Duffy KL et al (2019) AKT1(E17K) activates focal adhesion kinase and promotes melanoma brain metastasis. Mol Cancer Res 17:1787–1800CrossRefPubMedPubMedCentral

Koblinski JE, Ahram M, Sloane BF (2000) Unraveling the role of proteases in cancer. Clin Chim Acta 291:113–135CrossRefPubMed

Lah TT, Babnik J, Schiffmann E, Turk V, Skaleric U (1993) Cysteine proteinases and inhibitors in inflammation: their role in periodontal disease. J Periodontol 64:485–491PubMed

Li P, Zhang X, Wang H, Wang L, Liu T, Du L, Yang Y, Wang C (2017) MALAT1 is associated with poor response to oxaliplatin-based chemotherapy in colorectal cancer patients and promotes chemoresistance through EZH2. Mol Cancer Ther 16:739–751CrossRefPubMed

Li Q, Zheng ZC, Ni CJ, Jin WX, Jin YX, Chen Y, Zhang XH, Chen ED, Cai YF (2018) Correlation of cystatin E/M with clinicopathological features and prognosis in triple-negative breast cancer. Ann Clin Lab Sci 48:40–44PubMed

Liu X, Wu J, Zhang D, Bing Z, Tian J, Ni M, Zhang X, Meng Z, Liu S (2018) Identification of potential key genes associated with the pathogenesis and prognosis of gastric cancer based on integrated bioinformatics analysis. Front Genet 9:265CrossRefPubMedPubMedCentral

Lordick F, Carneiro F, Cascinu S, Fleitas T, Haustermans K, Piessen G, Vogel A, Smyth EC (2022) Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 33:1005–1020CrossRefPubMed

Qin Y, Yang G, Li M, Liu HJ, Zhong WL, Yan XQ, Qiao KL, Yang JH, Zhai DH, Yang W et al (2017) Dihydroartemisinin inhibits EMT induced by platinum-based drugs via Akt-Snail pathway. Oncotarget 8:103815–103827CrossRefPubMedPubMedCentral

Qu X, Liu B, Wang L, Liu L, Zhao W, Liu C, Ding J, Zhao S, Xu B, Yu H et al (2023) Loss of cancer-associated fibroblast-derived exosomal DACT3-AS1 promotes malignant transformation and ferroptosis-mediated oxaliplatin resistance in gastric cancer. Drug Resist Updates 68:100936CrossRef

Ren J, Hu Z, Niu G, Xia J, Wang X, Hong R, Gu J, Wang D, Ke C (2023) Annexin A1 induces oxaliplatin resistance of gastric cancer through autophagy by targeting PI3K/AKT/mTOR. FASEB J 37:e22790CrossRefPubMed

Revathidevi S, Munirajan AK (2019) Akt in cancer: Mediator and more. Semin Cancer Biol 59:80–91CrossRefPubMed

Rottenberg S, Disler C, Perego P (2021) The rediscovery of platinum-based cancer therapy. Nat Rev Cancer 21:37–50CrossRefPubMed

Sun R, Wu J, Chen Y, Lu M, Zhang S, Lu D, Li Y (2014) Down regulation of Thrombospondin2 predicts poor prognosis in patients with gastric cancer. Mol Cancer 13:225CrossRefPubMedPubMedCentral

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249CrossRefPubMed

Xie Q, Liu L, Chen X, Cheng Y, Li J, Zhang X, Xu N, Han Y, Liu H, Wei L et al (2021) Identification of cysteine protease inhibitor CST2 as a potential biomarker for colorectal cancer. J Cancer 12:5144–5152CrossRefPubMedPubMedCentral

Yu X, Li S, Pang M, Du Y, Xu T, Bai T, Yang K, Hu J, Zhu S, Wang L et al (2020) TSPAN7 exerts anti-tumor effects in bladder cancer through the PTEN/PI3K/AKT pathway. Front Oncol 10:613869CrossRefPubMed

Title: Cystatin SA attenuates gastric cancer cells growth and increases sensitivity to oxaliplatin via PI3K/AKT signaling pathway
Authors: Yida Lu
Huizhen Wang
Sihan Chen
Bo Yang
Yaxian Li
Yongxiang Li
Publication date: 01-05-2024
Publisher: Springer Berlin Heidelberg
Keywords: Gastric Cancer
Gastric Cancer
Published in: Journal of Cancer Research and Clinical Oncology / Issue 5/2024
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-024-05780-9

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