STAT3 是 Smo 依赖性信号传导所必需的，并在 Shh 髓母细胞瘤中介导 Smo 靶向治疗耐药性和肿瘤发生,Molecular Oncology

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STAT3 是 Smo 依赖性信号传导所必需的，并在 Shh 髓母细胞瘤中介导 Smo 靶向治疗耐药性和肿瘤发生
Molecular Oncology ( IF 5.0 ) Pub Date : 2021-09-05 , DOI: 10.1002/1878-0261.13097
Liangping Yuan ₁ , Hongying Zhang ₁ , Jingbo Liu ₁ , Anshu Malhotra ₁ , Abhinav Dey ₁ , Bing Yu ₁ , Kishore Kumar Jella ₁ , Leon F McSwain ₁ , Matthew J Schniederjan ₂ , Tobey J MacDonald _{1,

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Affiliation

声波刺猬 (Shh) 驱动的髓母细胞瘤 (Shh MB) 细胞依赖于组成型 Shh 信号传导，但由于耐药性，Shh MB 的靶向治疗一直无效。本研究的目的是探讨信号转导和转录激活因子 3 (STAT3) 在 Shh 信号传导和 Shh MB 细胞耐药性中的关键作用。在这里，我们表明 STAT3 是 Smoothened (Smo) 依赖的 Shh 信号传导所必需的，反过来，它又受到 Shh 信号传导的相互调节，并证明 STAT3 活性对于 HCK 原癌基因 Src 家族酪氨酸激酶 (Hck) 的表达至关重要。 ) 在嘘 MB。我们还证明了维持的 STAT3 活性抑制 p21 表达并促进 Shh MB 细胞的集落形成，Smo 拮抗剂抗性 Shh MB 细胞的体外研究。最后，STAT3 抑制剂治疗显着防止了基因工程 Shh MB 小鼠体内肿瘤的形成。总的来说，我们表明 STAT3 是维持 Shh 信号传导所必需的，因此是治疗 Shh MB 和克服抗 Smo 耐药性的潜在治疗靶点。

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STAT3 is required for Smo-dependent signaling and mediates Smo-targeted treatment resistance and tumorigenesis in Shh medulloblastoma

Sonic hedgehog (Shh)-driven medulloblastoma (Shh MB) cells are dependent on constitutive Shh signaling, but targeted treatment of Shh MB has been ineffective due to drug resistance. The purpose of this study was to address the critical role of signal transducer and activator of transcription 3 (STAT3) in Shh signaling and drug resistance in Shh MB cells. Herein, we show that STAT3 is required for Smoothened (Smo)-dependent Shh signaling and, in turn, is reciprocally regulated by Shh signaling, and demonstrate that STAT3 activity is critical for expression of HCK proto-oncogene, Src family tyrosine kinase (Hck) in Shh MB. We also demonstrate that maintained STAT3 activity suppresses p21 expression and promotes colony formation of Shh MB cells, whereas dual treatment with inhibitors of both Smo and STAT3 results in marked synergistic killing and overcomes drug resistance in vitro of Smo antagonist-resistant Shh MB cells. Finally, STAT3 inhibitor treatment significantly prevents in vivo tumor formation in genetically engineered Shh MB mice. Collectively, we show that STAT3 is necessary to maintain Shh signaling and thus is a potential therapeutic target to treat Shh MB and overcome anti-Smo drug resistance.

更新日期：2021-09-05

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