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Knockdown of ITGA2 Promotes Pyroptosis in Thyroid Cancer by Regulating the DNA Damage Response
Liang Yan1, Dongming Hua2, Rong Ying2
1Thyroid Surgery, Shanghai University of Traditional Chinese Medicine Affiliated Shuguang Hospital, 201203 Shanghai, China.
Background:
The most common endocrine cancer, thyroid carcinoma (TC), has a dismal prognosis when it reaches an advanced stage. Integrin α-2 (ITGA2) has been implicated in cancer progression, influencing both DNA damage and repair mechanisms. However, it is unknown how ITGA2 influences these processes in TC.
Methods:
ITGA2 was identified as a key prognostic gene for TC from the Cancer Genome Atlas-thyroid carcinoma (THCA), GSE3678, GSE29265, and GSE33630 datasets. Functional assays were used to evaluate the impact of ITGA2 knockdown on cell viability, migration, apoptosis, invasion, pyroptosis (N-terminal fragment of GSDME, GSDME-N), and cytotoxicity (Lactate dehydrogenase, LDH). DNA damage markers (phosphorylated histone H2AX on serine 139 (γ-H2AX), phosphorylated ataxia telangiectasia mutated (p-ATM), phosphorylated checkpoint kinase 2 (p-CHK2)) and the level of Reactive Oxygen Species (ROS) were used to assess oxidative stress. The impact of ITGA2 inhibition on Wnt/β-catenin signaling was evaluated, and a mouse xenograft model assessed tumor growth in vivo.
Results:
ITGA2 was significantly overexpressed in TC. Knockdown of ITGA2 significantly reduced cell viability, migration, and invasion, while promoting pyroptosis by upregulating cleaved-poly(ADP-ribose) polymerase (PARP) and GSDME-N. ITGA2 silencing also increased LDH activity, enhanced the expression of DNA damage markers (p-ATM, γ-H2AX, p-CHK2), and increased ROS levels. Furthermore, suppression of ITGA2 activity attenuated the Wnt/β-catenin pathway by reducing the levels of MYC proto-oncogene, bHLH transcription factor (C-myc), CD44 molecule (CD44), slug, snail, β-catenin, and wingless-type MMTV integration site family, member 1 (Wnt-1). ITGA2 silencing significantly inhibited tumor growth in a mouse model.
Conclusion:
ITGA2 promotes TC progression by regulating the DNA damage response and inhibiting pyroptosis. Knockdown of ITGA2 increases oxidative stress, exacerbates DNA damage, and inhibits the Wnt/β-catenin pathway, indicating it may have potential as a treatment target in TC.
Insights
Integrin α-2 (ITGA2) drives thyroid cancer progression by hindering DNA damage responses and pyroptosis. Inhibiting ITGA2 shows promise for treating advanced thyroid carcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Thyroid carcinoma (TC) has a poor prognosis in advanced stages.
- Integrin α-2 (ITGA2) is linked to cancer progression and DNA repair.
- The role of ITGA2 in TC progression and DNA damage is not well understood.
Purpose of the Study:
- To investigate the role of ITGA2 in thyroid carcinoma (TC) progression.
- To evaluate the impact of ITGA2 on DNA damage, pyroptosis, and Wnt/β-catenin signaling in TC.
- To assess ITGA2 as a potential therapeutic target for TC.
Main Methods:
- ITGA2 identified as a key prognostic gene in TC datasets.
- Functional assays assessed ITGA2 knockdown effects on cell viability, migration, invasion, pyroptosis, and cytotoxicity.
- DNA damage markers, ROS levels, and Wnt/β-catenin pathway components were analyzed.
- A mouse xenograft model evaluated tumor growth inhibition.
Main Results:
- ITGA2 is overexpressed in TC and promotes cell viability, migration, and invasion.
- ITGA2 knockdown induced pyroptosis, increased DNA damage markers (γ-H2AX, p-ATM, p-CHK2), and elevated ROS levels.
- ITGA2 inhibition suppressed Wnt/β-catenin signaling and significantly reduced tumor growth in vivo.
Conclusions:
- ITGA2 promotes TC progression by regulating DNA damage response and inhibiting pyroptosis.
- ITGA2 knockdown increases oxidative stress, DNA damage, and inhibits the Wnt/β-catenin pathway.
- ITGA2 represents a potential therapeutic target for advanced thyroid carcinoma.
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