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Proteomic Analysis and NIR-II Imaging of MCM2 Protein in Hepatocellular Carcinoma
Jing Yang1,2, Qi Xie1,2,3, Hui Zhou1
1State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Zhongnan Hospital of Wuhan University , Wuhan University School of Pharmaceutical Sciences , Wuhan 430071 , China.
Abstract:
Targeted therapy of hepatocellular carcinoma (HCC) is essential for improved therapies. Therefore, identification of key targets specifically to HCC is an urgent requirement. Herein, an iTRAQ quantitative proteomic approach was employed to identify differentially expressed proteins in HCC tumor tissues. Of the upregulated tumor-related proteins, minichromosome maintenance 2 (MCM2), a DNA replication licensing factor, was one of the most significantly altered proteins, and its overexpression was confirmed using tissue microarray. Clinicopathological analysis of multiple cohorts of HCC patients indicated that overexpression of MCM2 was validated in 89.8% tumor tissues and strongly correlated with clinical stage. Furthermore, siRNA-mediated repression of MCM2 expression resulted in significant suppression of the HepG2 cell cycle and proliferation through the cyclin D-dependent kinases (CDKs) 2/7 pathway. Finally, the first small molecule-based MCM2-targeted NIR-II probe CH1055-MCM2 was concisely generated and subsequently evaluated in mice bearing HepG2 xenografts. The excellent imaging properties such as good tumor uptake and high tumor contrast and specificity were achieved in the small animal models. This analytical strategy can determine novel accessible targets of HCC useful for imaging and therapy.
Insights
Minichromosome maintenance 2 (MCM2) is overexpressed in hepatocellular carcinoma (HCC) and drives cancer cell proliferation. Targeting MCM2 with a novel probe shows promise for HCC imaging and therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) requires novel therapeutic targets for improved treatment outcomes.
- Identifying proteins specifically overexpressed in HCC is crucial for developing targeted therapies.
Purpose of the Study:
- To identify and validate key protein targets in HCC using quantitative proteomics.
- To investigate the role of minichromosome maintenance 2 (MCM2) in HCC progression and explore its potential as a therapeutic target.
- To develop and evaluate a novel near-infrared II (NIR-II) imaging probe targeting MCM2 for HCC detection.
Main Methods:
- iTRAQ quantitative proteomic analysis of HCC tumor tissues.
- Tissue microarray and immunohistochemistry for MCM2 validation.
- siRNA-mediated MCM2 knockdown in HepG2 cells.
- Generation and in vivo evaluation of an MCM2-targeted NIR-II probe (CH1055-MCM2) in mouse xenograft models.
Main Results:
- MCM2 was identified as a significantly upregulated protein in HCC tumor tissues.
- MCM2 overexpression was confirmed in 89.8% of HCC tissues and correlated with advanced clinical stage.
- MCM2 repression suppressed HepG2 cell cycle and proliferation via the cyclin D-dependent kinases (CDKs) 2/7 pathway.
- The CH1055-MCM2 probe demonstrated excellent tumor uptake, contrast, and specificity in small animal models.
Conclusions:
- MCM2 is a promising therapeutic target and biomarker for HCC.
- Targeted inhibition of MCM2 can impede HCC cell proliferation.
- The MCM2-targeted NIR-II probe offers a novel strategy for HCC imaging and potentially therapy.
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