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Updated: Jun 30, 2025
Generation and Expansion of Primary, Malignant Pleural Mesothelioma Tumor Lines
Published on: April 21, 2022
Characterization of KLHL14 anti-oncogenic action in malignant mesothelioma
Angelo Canciello1,2, Reyes Benot Domínguez1, Barbara Barboni2
1Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, 19122, USA.
Abstract:
Malignant mesothelioma (MM) is a very aggressive neoplasia with a short life expectancy and limited therapeutic options. Thus, the identification of novel molecular targets is a matter of great urgency. Kelch-like (KLHL) proteins play an important role in a number of physiological and pathological cell-regulatory processes. Among this family, the function of KLHL14 is still very poorly characterized. KLHL14 was originally identified as a gene involved in regulating the epithelial-mesenchymal transition (EMT) process. Here, we demonstrate that KLHL14 not only prevents EMT but also plays an anti-oncogenic role in MM. Indeed, KLHL14 depletion enhanced proliferation, motility, invasion and colony formation in MM cells. Importantly, we also demonstrated that KLHL14 mechanism of action is dependent on Transforming Growth Factor β (TGF-β). In fact, TGF-β promotes de novo synthesis, increases protein stability and induces nuclear-cytoplasmic shuttling of KLHL14. Collectively, this research is an important step further to decipher KLHLs mechanism of action and further contributes to the understanding of the molecular mechanisms regulating MM.
Insights
Kelch-like 14 (KLHL14) protein prevents malignant mesothelioma progression by inhibiting epithelial-mesenchymal transition. Transforming Growth Factor β (TGF-β) regulates KLHL14, offering potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Malignant mesothelioma (MM) is an aggressive cancer with poor prognosis.
- Limited therapeutic options necessitate identifying novel molecular targets.
- Kelch-like (KLHL) proteins regulate cellular processes, but KLHL14 function is poorly understood.
Purpose of the Study:
- To investigate the role of KLHL14 in malignant mesothelioma.
- To elucidate the mechanism of action of KLHL14 in MM.
- To explore the relationship between KLHL14 and Transforming Growth Factor β (TGF-β) signaling.
Main Methods:
- Cell culture and manipulation of KLHL14 expression in MM cells.
- Assessment of proliferation, motility, invasion, and colony formation.
- Analysis of KLHL14 regulation by TGF-β, including synthesis, stability, and localization.
Main Results:
- KLHL14 depletion enhanced MM cell proliferation, motility, invasion, and colony formation.
- KLHL14 acts as an anti-oncogenic factor by preventing epithelial-mesenchymal transition (EMT).
- TGF-β signaling positively regulates KLHL14 expression, stability, and nuclear-cytoplasmic shuttling.
Conclusions:
- KLHL14 plays a critical anti-oncogenic role in malignant mesothelioma.
- KLHL14's function is intrinsically linked to TGF-β signaling pathways.
- Targeting KLHL14 or its interaction with TGF-β may offer novel therapeutic strategies for MM.
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