Knockdown of ITGA2 Promotes Pyroptosis in Thyroid Cancer by Regulating the DNA Damage Response.

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.