<br>HSPA8 激活 Wnt/β-Catenin 信号传导，通过 CMA 介导的 CAV1 降解促进 BRAF V600E 结直肠癌进展,Advanced Science

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HSPA8 激活 Wnt/β-Catenin 信号传导，通过 CMA 介导的 CAV1 降解促进 BRAF V600E 结直肠癌进展
Advanced Science ( IF 14.3 ) Pub Date : 2023-11-16 , DOI: 10.1002/advs.202306535
Bowen Li ₁ , Hui Ming ₁ , Siyuan Qin ₁ , Li Zhou ₁ , Zhao Huang ₁ , Ping Jin ₁ , Liyuan Peng ₁ , Maochao Luo ₁ , Tingting Zhang ₁ , Kui Wang ₁ , Rui Liu ₂ , Yih-Cherng Liou _{3,

4} , Edouard C Nice ₅ , Jingwen Jiang ₆ , Canhua Huang ₁

Affiliation

BRAF V600E 由于对 CRC 的难治性分类进行分层和预测，在结直肠癌 (CRC) 的治疗中引起了广泛关注。最近的证据表明 Wnt/β-catenin 信号传导广泛激活并参与 BRAF V600E CRC 的难治性，但潜在的分子机制需要阐明。在此，热休克 70 kDa 蛋白 8 (HSPA8) 是分子伴侣介导的自噬 (CMA) 的重要调节因子，被确定为晚期 BRAF V600E CRC 的潜在治疗靶点。这些结果表明，HSPA8 在 BRAF V600E CRC 中转录上调，促进 Caveolin-1 (CAV1) 的 CMA 依赖性降解，将 β-catenin 释放到细胞核中，从而激活 Wnt/β-catenin 通路，有助于转移和进展BRAF V600E CRC。值得注意的是，HSPA8 直接与 CAV1 上的 KIFSN 基序相互作用，这种相互作用可以通过 p38 MAPK 介导的 CAV1 S168 磷酸化来增强。此外，VER155008 靶向 HSPA8 的药理学作用与 BRAF 抑制剂在 CRC 小鼠模型上表现出协同作用。总之，这些发现发现了 HSPA8/CAV1/β-连环蛋白轴在难治性 BRAF V600E CRC 发展中的重要作用，并强调 HSPA8 作为临床实践中的预测生物标志物和治疗靶点。

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HSPA8 Activates Wnt/β-Catenin Signaling to Facilitate BRAF V600E Colorectal Cancer Progression by CMA-Mediated CAV1 Degradation

BRAF V600E attracts wide attention in the treatment of colorectal cancer (CRC) as stratifying and predicting a refractory classification of CRC. Recent evidence indicates that Wnt/β-catenin signaling is broadly activated and participates in the refractoriness of BRAF V600E CRC, but the underlying molecular mechanism needs to be elucidated. Here, heat shock 70 kDa protein 8 (HSPA8), an essential regulator in chaperone-mediated autophagy (CMA), is identified as a potential therapeutic target for advanced BRAF V600E CRC. These results show that HSPA8 is transcriptionally upregulated in BRAF V600E CRC, which promotes CMA-dependent degradation of caveolin-1 (CAV1) to release β-catenin into the nucleus and thus activates the Wnt/β-catenin pathway, contributing to metastasis and progression of BRAF V600E CRC. Of note, HSPA8 directly interacts with the KIFSN motif on CAV1, the interaction can be enhanced by p38 MAPK-mediated CAV1 S168 phosphorylation. Furthermore, pharmacological targeting HSPA8 by VER155008 exhibits synergistic effects with BRAF inhibitors on CRC mouse models. In summary, these findings discover the important role of the HSPA8/CAV1/β-catenin axis in the development of refractory BRAF V600E CRC and highlight HSPA8 as a predictive biomarker and therapeutic target in clinical practice.

更新日期：2023-11-16

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