Bip-Yorkie 相互作用决定了 Ire1/Xbp1s 激活的致癌和肿瘤抑制作用。,Proceedings of the National Academy of Sciences of the United States of America

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Bip-Yorkie 相互作用决定了 Ire1/Xbp1s 激活的致癌和肿瘤抑制作用。
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2022-10-10 , DOI: 10.1073/pnas.2202133119
Shuai Yang _{1,

2,

3,

4} , Hua Jiang _{3,

4,

5} , Weixiang Bian _{3,

4,

5} , Wenyan Xu _{2,

3,

4} , Yifan Guo _{2,

3,

4} , Sha Song _{2,

3,

4} , Jiadong Zheng _{2,

3,

4} , Xiaoyu Kuang _{2,

3,

4} , Chenxi Wu ₆ , Xiang Ding ₇ , Xiaowei Guo ₈ , Lei Xue ₇ , Zijing Yu _{3,

9} , Yongdeng Zhang _{3,

9} , Hyung Don Ryoo ₁₀ , Xu Li _{3,

4,

5} , Xianjue Ma _{2,

3,

4}

Affiliation

College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China.
Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China.
Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, China.
Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China.
College of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan 063210, China.
Shanghai Key Laboratory of Signaling and Diseases Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
School of Medicine, Hunan Normal University, Changsha 410013, China.
School of Life Sciences, Westlake University, Hangzhou 310024, China.
Department of Cell Biology, New York University Grossman School of Medicine, New York, NY 10016.

未折叠蛋白反应 (UPR) 是细胞控制内质网 (ER) 蛋白稳态的机制。ER 蛋白稳态对于适应发育和肿瘤发生过程中的细胞增殖和再生至关重要，但将 UPR、生长控制和癌症进展联系起来的机制仍不清楚。在这里，我们报告 Ire1/Xbp1s 通路以上下文相关的方式具有令人惊讶的致癌和肿瘤抑制作用。Ire1/Xbp1s 的激活上调其下游靶标 Bip，Bip 在细胞质中隔离 Yorkie (Yki)，一种 Hippo 通路传感器，以限制 Yki 转录输出。这种调节在器官大小控制、肠道稳态和再生方面提供了一种内源性防御机制。不料，Xbp1 消融促进肿瘤过度生长但抑制果蝇癌症模型中的侵袭性。从机制上讲，过度激活的 Ire1/Xbp1s 信号转而通过抑制 Yki 诱导 JNK 依赖性发育和致癌细胞迁移和上皮-间质转化 (EMT)。在人类中，XBP1 和 YAP (Yki ortholog) 靶基因表达之间的负相关特别存在于三阴性乳腺癌 (TNBC) 中，XBP1 或 HSPA5 (Bip ortholog) 高表达的患者具有更好的临床结果。在人类 TNBC 细胞系和异种移植模型中，异位 XBP1 或 HSPA5 表达可减轻肿瘤生长，但会加剧细胞迁移和侵袭。这些发现揭示了 Ire1/Xbp1s 和 Hippo 信号通路在生理环境下的保守串扰，

"点击查看英文标题和摘要"

Bip-Yorkie interaction determines oncogenic and tumor-suppressive roles of Ire1/Xbp1s activation.

Unfolded protein response (UPR) is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. ER proteostasis is essential to adapt to cell proliferation and regeneration in development and tumorigenesis, but mechanisms linking UPR, growth control, and cancer progression remain unclear. Here, we report that the Ire1/Xbp1s pathway has surprisingly oncogenic and tumor-suppressive roles in a context-dependent manner. Activation of Ire1/Xbp1s up-regulates their downstream target Bip, which sequesters Yorkie (Yki), a Hippo pathway transducer, in the cytoplasm to restrict Yki transcriptional output. This regulation provides an endogenous defensive mechanism in organ size control, intestinal homeostasis, and regeneration. Unexpectedly, Xbp1 ablation promotes tumor overgrowth but suppresses invasiveness in a Drosophila cancer model. Mechanistically, hyperactivated Ire1/Xbp1s signaling in turn induces JNK-dependent developmental and oncogenic cell migration and epithelial-mesenchymal transition (EMT) via repression of Yki. In humans, a negative correlation between XBP1 and YAP (Yki ortholog) target gene expression specifically exists in triple-negative breast cancers (TNBCs), and those with high XBP1 or HSPA5 (Bip ortholog) expression have better clinical outcomes. In human TNBC cell lines and xenograft models, ectopic XBP1s or HSPA5 expression alleviates tumor growth but aggravates cell migration and invasion. These findings uncover a conserved crosstalk between the Ire1/Xbp1s and Hippo signaling pathways under physiological settings, as well as a crucial role of Bip-Yki interaction in tumorigenesis that is shared from Drosophila to humans.

更新日期：2022-10-10

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