β-田野病毒B2蛋白可以靶向線粒體並發揮死亡因子的作用，但其對人肺癌的作用尚不清楚。根據我們的數據，β-田野病毒B2蛋白可以通過 p53 調控的依賴或獨立途徑誘導人肺癌細胞死亡，這與誘導活性氧信號和 p53 調控相關。此外，β-田野病毒B2 蛋白增加 p53 和 p21 的表達在p53 有表達細胞 (A549) 中，但並沒有在 p53 無表達細胞 (H1299) 中的有調控。 β-田野病毒B2 蛋白調控 A549 細胞系中的 Bax 表達，而在 H1299 細胞系中的 則是RIP3 表達增加。此外，我們發現 B2 可以殺死 NOD/SCID 小鼠中 A549 細胞誘導的固態腫瘤。然而，突變體 ΔB2 不能。在 NOD/SCID 小鼠中，在 NOD/SCID 小鼠中，B2 誘導 p53/Bax 介導的細胞凋亡和 RIPK3 介導的壞死性凋亡。然後，B2 誘導的壓力訊息可以通過調控 ATG5、BECN1 和 Bcl-2 來抑制自噬。最後，免疫化學分析表明，ROS/p38/Nrf2 壓力訊息可明顯降低與癌細胞遷移和侵襲相關的腫瘤標誌物如 CD133、Thy1 和 Napsin 的表達。因此，B2 觸發的 ROS/Nrf2 的壓力訊號可以協調多個信號之間的相互作用進而殺死腫瘤以及抑制 A549 肺癌細胞自噬的途徑。 β-田野病毒B2 蛋白作為壞死誘導劑，可通過 調控 p53 和 RIP3 表達引發肺癌死亡。我們提出了肺癌治療的新觀點。

The betanodavirus B2 protein targets mitochondria and triggers mitochondrion-mediated cell death signaling in lung cancer cells. but its molecular mechanism remains unknown. According to our data, B2 induces human lung cancer cell death through p53-mediated dependent and independent pathways, which correlate with stimulated reactive oxygen species signaling and p53 up-regulation. Additionally, B2 protein of betanodavirus upregulates p53 and p21 expression in p53-expressing cells (A549), but not in p53 non-expressing cells (H1299). Betanodavirus B2 protein upregulated both Bax expression in A549 cell lines and upregulated RIP3 expression in H1299 cell lines. Furthermore, we found that B2 could kill an A549 cell-induced solid tumor in NOD/SCID mice; however, mutant ΔB2 could not. In NOD/SCID mice, B2 induces both p53/Bax-mediated apoptosis and RIPK3-mediated necroptosis. B2 then induces stress signals that can suppress autophagy by downregulating ATG5, BECN1, and Bcl-2. Finally, immunochemistry analysis showed that ROS/p38/Nrf2 stress could strongly reduce the expression of tumor markers such as CD133, Thy1, and Napsin, which correlate to migration and invasion in cancer cells. Thus, B2-triggered-ROS/Nrf2-mediated stress signals can orchestrate crosstalk between multiple signals via pathways that kill tumors and suppress autophagy in A549 lung cancer cells in vivo. The betanodavirus B2 protein, as a necrotic inducer, can trigger lung cancer death via p53 upregulation and RIP3 expression, suggesting a new perspective on lung cancer therapy.

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