Identification of Cysteine Protease Inhibitor CST2 as a Potential Biomarker for Colorectal Cancer

Xie, Qiurong; Liu, Liya; Chen, Xiaoping; Cheng, Ying; Li, Jiapeng; Zhang, Xiuli; Xu, Nanhui; Han, Yong Chol; Liu, Huixin; Wei, Lihui; Peng, Jun; Shen, Aling

doi:10.7150/jca.53983

Cited by 9 publications

(7 citation statements)

References 43 publications

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“…In our previous study, we confirmed and substantiated that CST2 RNA levels were inversely correlated with clinical data in the database. Unexpectedly, we discovered that CST2 was markedly expressed in tissues and exerted an anticancer effect (Xie et al 2021 ). Furthermore, the literature lacks information on CST2 protein expression in GC tissues and cells.…”

Section: Discussionmentioning

confidence: 99%

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

Lu,

Wang,

Chen

et al. 2024

J Cancer Res Clin Oncol

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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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Section: Discussionmentioning

confidence: 99%

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

Lu,

Wang,

Chen

et al. 2024

J Cancer Res Clin Oncol

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“…CSTB is a protease inhibitor of cathepsin that is increased in cancer and acts as an intracellular thiol protease inhibitor [ 73 , 74 ]. Evidence suggests the role of CSTB in various diseases [ 46 , 75 ].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of CSTB and DMBT1 expression in saliva of gastric cancer patients and controls

et al. 2022

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Background Gastric cancer (GC) is the fifth most common cancer and the third cause of cancer deaths globally, with late diagnosis, low survival rate, and poor prognosis. This case-control study aimed to evaluate the expression of cystatin B (CSTB) and deleted in malignant brain tumor 1 (DMBT1) in the saliva of GC patients with healthy individuals to construct diagnostic algorithms using statistical analysis and machine learning methods. Methods Demographic data, clinical characteristics, and food intake habits of the case and control group were gathered through a standard checklist. Unstimulated whole saliva samples were taken from 31 healthy individuals and 31 GC patients. Through ELISA test and statistical analysis, the expression of salivary CSTB and DMBT1 proteins was evaluated. To construct diagnostic algorithms, we used the machine learning method. Results The mean salivary expression of CSTB in GC patients was significantly lower (115.55 ± 7.06, p = 0.001), and the mean salivary expression of DMBT1 in GC patients was significantly higher (171.88 ± 39.67, p = 0.002) than the control. Multiple linear regression analysis demonstrated that GC was significantly correlated with high levels of DMBT1 after controlling the effects of age of participants (R2 = 0.20, p < 0.001). Considering salivary CSTB greater than 119.06 ng/mL as an optimal cut-off value, the sensitivity and specificity of CSTB in the diagnosis of GC were 83.87 and 70.97%, respectively. The area under the ROC curve was calculated as 0.728. The optimal cut-off value of DMBT1 for differentiating GC patients from controls was greater than 146.33 ng/mL (sensitivity = 80.65% and specificity = 64.52%). The area under the ROC curve was up to 0.741. As a result of the machine learning method, the area under the receiver-operating characteristic curve for the diagnostic ability of CSTB, DMBT1, demographic data, clinical characteristics, and food intake habits was 0.95. The machine learning model’s sensitivity, specificity, and accuracy were 100, 70.8, and 80.5%, respectively. Conclusion Salivary levels of DMBT1 and CSTB may be accurate in diagnosing GCs. Machine learning analyses using salivary biomarkers, demographic, clinical, and nutrition habits data simultaneously could provide affordability models with acceptable accuracy for differentiation of GC by a cost-effective and non-invasive method.

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“…In addition, the epithelial and mesenchymal transition (EMT) and TGF-β signaling can be induced by CST2 in gastric cancer, which can promote metastasis and tumor progression [41]. CSTs have also been suggested as a prognostic biomarker for various cancers [57][58][59]. CST4, known as cystatin SA, was also founded highly expressed in gastric and colorectal cancer to promote cell proliferation, invasion, and metastasis [42,60].…”

Section: Discussionmentioning

confidence: 99%

Recurrent triple-negative breast cancer from cysteine deprivation loses tumorigenicity via downregulation of the CST4 signaling

Tang

Alothaim

Charbonneau

2022

Preprint

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Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with a high risk of recurrence following therapeutic treatments. Targeted cysteine therapy via inhibition of cysteine uptake by erastin effectively induces mesenchymal TNBC cells to ferroptosis. However, a small residual population of cancer cells exhibited the erastin-resistance and survived after the erastin treatment. This phenomenon is likely analogous to the event of tumor recurrence in patients after therapy. To characterize this resistance, we established the erastin-resistant/recurrent TNBC cell models in vitro by multi-cycles of erastin challenge. By an epigenetic compound library screen, the erastin-resistance be abolished by adjuvant epigenetic compounds. Intriguingly, the erastin-recurrent TNBC cells failed to grow in anchorage-independent conditions, implying a loss of tumorigenicity. By transcriptomic profiling analysis, the recurrent cells displayed many gene expression alterations and attenuated signaling processes, including K-Ras signaling. Three members of the cystatin gene family, including CST4, were significantly downregulated in recurrent cells. Knocking out of CST4 by CRISPR/Cas9 significantly suppressed the tumorigenic potential and K-Ras signaling. Our findings suggested that targeted cysteine therapy could be a valid treatment for mesenchymal TNBC with a low probability of tumor recurrence.

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Identification of Cysteine Protease Inhibitor CST2 as a Potential Biomarker for Colorectal Cancer

Cited by 9 publications

References 43 publications

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

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

Evaluation of CSTB and DMBT1 expression in saliva of gastric cancer patients and controls

Recurrent triple-negative breast cancer from cysteine deprivation loses tumorigenicity via downregulation of the CST4 signaling

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