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The functional DIAPH3-FOXM1 interaction modulates the aggressive transformation of anaplastic thyroid carcinoma cells
1Department of Otorhinolaryngology; Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumour Hospital, Shijiazhuang, Hebei, China.
Abstract:
Anaplastic thyroid carcinoma (ATC) is reckoned as an infrequent but extremely advanced neoplasm of the endocrine system. Diaphanous-related formin 3 (DIAPH3) has been extensively implicated in carcinogenic events, but it has not been introduced in ATC. Herein, the role of DAPIH3 and the interrelated functional mechanism are characterised in ATC. The Gene Expression Omnibus (GEO) database was checked for differential DIAPH3 expression in ATC samples and noncancerous samples. Western blotting examined DIAPH3 and forkhead box M1 (FOXM1) expression in ATC cells. In vitro cell counting kit 8 (CCK-8) method, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, Scratch, Matrigel invasion, and terminal-deoxynucleotidyl transferase mediated nick end labelling (TUNEL) assays were used to assess the potential of cells to proliferate, migrate, and invade as well as the cellular apoptotic rate. Co-IP was applied to access DIAPH3-FOXM1 protein interaction. Western blotting also disclosed the expression of proteins associated with apoptosis and Wnt/β-catenin signalling. DIAPH3 was hyper-expressed in papillary cell carcinoma (PTC) tissues and cells. Depleting DIAPH3 strongly eliminated the proliferative, migratory, as well as invasive capabilities of PTC cells while intensifying the apoptotic ability. FOXM1 also harboured elevated expression in PTC cells. FOXM1 was the binding partner with DIAPH3, and the 2 were positively correlated. FOXM1 upregulation again exacerbated the potentials to proliferate, migrate, and invade but it repressed the apoptotic rate of DIAPH3-depleted cells. Furthermore, loss of DIAPH3 downregulated FOXM1 to block Wnt/b-catenin signalling in PTC cells. Combined with these findings, DIAPH3 might favour the aggressive advancement of ATC and motivate the Wnt/β-catenin signalling via binding with FOXM1.
Insights
Diaphanous-related formin 3 (DIAPH3) promotes aggressive anaplastic thyroid carcinoma (ATC) by interacting with FOXM1, activating Wnt/β-catenin signaling, and driving proliferation and invasion while inhibiting apoptosis.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Anaplastic thyroid carcinoma (ATC) is a rare but aggressive endocrine neoplasm.
- The role of Diaphanous-related formin 3 (DIAPH3) in ATC pathogenesis is not well understood.
- Understanding DIAPH3's function is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role and mechanism of DIAPH3 in anaplastic thyroid carcinoma.
- To explore the relationship between DIAPH3, FOXM1, and Wnt/β-catenin signaling in ATC.
- To assess DIAPH3's impact on tumor cell proliferation, migration, invasion, and apoptosis.
Main Methods:
- Differential DIAPH3 expression analysis using GEO database.
- Western blotting for DIAPH3 and FOXM1 expression.
- In vitro assays (CCK-8, EdU, Scratch, Matrigel invasion, TUNEL) to evaluate cell behavior.
- Co-immunoprecipitation (Co-IP) to confirm protein interactions.
Main Results:
- DIAPH3 was significantly upregulated in ATC tissues and cells.
- DIAPH3 depletion reduced proliferation, migration, and invasion, while increasing apoptosis.
- DIAPH3 directly interacted with and upregulated FOXM1, a known oncogene.
- FOXM1 overexpression reversed the effects of DIAPH3 depletion on cell behavior and apoptosis.
- DIAPH3 loss downregulated FOXM1, inhibiting Wnt/β-catenin signaling.
Conclusions:
- DIAPH3 promotes aggressive ATC progression by upregulating FOXM1 and activating Wnt/β-catenin signaling.
- DIAPH3 is a potential therapeutic target for anaplastic thyroid carcinoma.
- Targeting DIAPH3 may offer a novel strategy to inhibit ATC growth and metastasis.
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