KLF7-regulated ITGA2 as a therapeutic target for inhibiting oral cancer stem cells
Xin Qi1, Jiang Zhou2,3, Pan Wang4
1Zhejiang University, School of Medicine, First Affiliated Hospital, Hangzhou, Zhejiang, P. R. China.
Abstract:
Cancer stem cells (CSCs) play crucial roles in tumor metastasis, therapy resistance, and immune evasion. Identifying and understanding the factors that regulate the stemness of tumor cells presents promising opportunities for developing effective therapeutic strategies. In this study on oral squamous cell carcinoma (OSCC), we confirmed the key role of KLF7 in maintaining the stemness of OSCC. Using chromatin immunoprecipitation sequencing and dual-luciferase assays, we identified ITGA2, a membrane receptor, as a key downstream gene regulated by KLF7 in the maintenance of stemness. Tumor sphere formation assays, flow cytometry analyses, and in vivo limiting dilution tumorigenicity evaluations demonstrated that knocking down ITGA2 significantly impaired stemness. Upon binding to its extracellular matrix (ECM) ligand, type I collagen, ITGA2 activates stemness-associated signaling pathways, including PI3K-AKT, MAPK, and Hippo. TC-I 15, a small-molecule inhibitor of the ITGA2-collagen interaction, significantly sensitizes oral squamous cell carcinoma (OSCC) to cisplatin in xenograft models. In summary, we reveal that the KLF7/ITGA2 axis is a crucial modulator of stemness in OSCC. Our findings suggest that ITGA2 is a promising therapeutic target, offering a novel anti-CSC strategy.
Insights
This study identifies the KLF7/ITGA2 pathway as critical for maintaining cancer stem cell (CSC) stemness in oral squamous cell carcinoma (OSCC). Inhibiting the ITGA2-collagen interaction offers a new strategy against CSCs.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Cancer stem cells (CSCs) drive tumor metastasis, therapy resistance, and immune evasion.
- Targeting CSC stemness is crucial for effective cancer therapeutics.
- Oral squamous cell carcinoma (OSCC) stemness regulation requires further elucidation.
Purpose of the Study:
- To identify key regulators of stemness in oral squamous cell carcinoma (OSCC).
- To investigate the role of KLF7 and its downstream targets in maintaining OSCC stemness.
- To evaluate ITGA2 as a potential therapeutic target for OSCC.
Main Methods:
- Chromatin immunoprecipitation sequencing (ChIP-seq) and dual-luciferase assays to identify KLF7 targets.
- Tumor sphere formation, flow cytometry, and in vivo limiting dilution assays to assess stemness.
- Xenograft models treated with ITGA2 inhibitor (TC-I 15) to evaluate therapeutic efficacy.
Main Results:
- KLF7 was confirmed as a key regulator of stemness in OSCC.
- ITGA2 was identified as a direct downstream target of KLF7 involved in maintaining stemness.
- Knockdown of ITGA2 significantly reduced stemness properties in OSCC cells.
- ITGA2 activation by collagen triggers PI3K-AKT, MAPK, and Hippo signaling pathways.
- TC-I 15 sensitized OSCC to cisplatin in vivo.
Conclusions:
- The KLF7/ITGA2 axis is a critical regulator of stemness in oral squamous cell carcinoma.
- ITGA2 plays a significant role in OSCC stemness maintenance through ECM interactions and signaling pathways.
- Targeting the ITGA2-collagen interaction with inhibitors like TC-I 15 presents a promising anti-CSC strategy for OSCC.
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