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Maryam Kianpour1, Ching-Wen Huang2, Pichpisith Pierre Vejvisithsakul3
1Institute of Biomedical Sciences, College of Medicine, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
Abstract:
The objectives were to identify the functional domains of a potential oncoprotein, cell migration inducing hyaluronidase 2 (CEMIP2), evaluate its expression levels and roles in colorectal cancer (CRC), and develop an aptamer-based nanoparticle for targeted therapy. Data mining on TCGA identified that CEMIP2 might play oncogenic roles in CRC. In a local cohort, CEMIP2 mRNA levels significantly stepwise increase in CRC patients with higher stages, and high CEMIP2 confers worse disease-free survival. In addition, CEMIP2 mRNA levels significantly correlated to hyaluronan levels in sera from CRC patients. Deletion mapping identified that CEMIP2 containing G8 and PANDER-like domains preserved hyaluronidase activity and oncogenic roles, including cell proliferation, anchorage-independent cell growth, cell migration and invasion, and human umbilical vein endothelial cell (HUVEC) tube formation in CRC-derived cells. A customized monoclonal mouse anti-human CEMIP2 antibody probing the PANDER-like domain (anti-289307) counteracted CEMIP2-mediated carcinogenesis in vitro. Cell-SELEX pinpointed an aptamer, aptCEMIP2(101), specifically interacted with the full-length CEMIP2, potentially involving its 3D structure. Treatments with aptCEMIP2(101) significantly reduced CEMIP2-mediated tumorigenesis in vitro. Mesoporous silica nanoparticles (MSN) carrying atpCEMIP2(101) and Dox were fabricated. Dox@MSN, MSN-aptCEMIP2(101), and Dox@MSN-aptCEMIP2(101) significantly suppressed tumorigenesis in vitro compared to the Mock, while Dox@MSN-aptCEMIP2(101) showed substantially higher effects compared to Dox@MSN and MSN-aptCEMIP2(101) in CRC-derived cells. Our study identified a novel oncogene and developed an effective aptamer-based targeted therapeutic strategy.
Insights
Cell migration inducing hyaluronidase 2 (CEMIP2) is a novel colorectal cancer (CRC) oncogene. Aptamer-based nanoparticles targeting CEMIP2 show promise for effective CRC therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Colorectal cancer (CRC) remains a significant health challenge with a need for novel therapeutic targets.
- The role of cell migration inducing hyaluronidase 2 (CEMIP2) in CRC pathogenesis is not fully understood.
- Identifying new oncogenes and developing targeted therapies are crucial for improving CRC patient outcomes.
Purpose of the Study:
- To identify functional domains of CEMIP2 and evaluate its expression and role in colorectal cancer.
- To develop an aptamer-based nanoparticle for targeted therapy against CEMIP2 in CRC.
- To investigate the therapeutic efficacy of CEMIP2-targeting aptamer-loaded nanoparticles.
Main Methods:
- Utilized TCGA data mining and a local CRC cohort for expression analysis.
- Employed deletion mapping to identify functional domains of CEMIP2 responsible for oncogenic activity.
- Developed a CEMIP2-specific aptamer (aptCEMIP2(101)) and fabricated aptamer-loaded mesoporous silica nanoparticles (MSN) with doxorubicin (Dox).
Main Results:
- CEMIP2 mRNA levels significantly increased with CRC stage and correlated with poorer disease-free survival and higher serum hyaluronan levels.
- CEMIP2's G8 and PANDER-like domains were essential for its hyaluronidase activity and oncogenic functions (proliferation, migration, invasion, HUVEC tube formation).
- Aptamer-based nanoparticles, particularly Dox@MSN-aptCEMIP2(101), demonstrated significant suppression of CRC cell tumorigenesis in vitro.
Conclusions:
- CEMIP2 is identified as a novel oncogene in colorectal cancer, with its expression correlating to disease progression and severity.
- The PANDER-like domain of CEMIP2 is critical for its oncogenic functions, suggesting it as a therapeutic target.
- Aptamer-conjugated nanoparticles offer a promising targeted therapeutic strategy for colorectal cancer, showing enhanced efficacy when combined with chemotherapy.
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