<br>ARID1A 缺失诱导 P4HB 激活成纤维细胞以支持肺癌细胞生长、侵袭和化疗耐药,Cancer Science

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ARID1A 缺失诱导 P4HB 激活成纤维细胞以支持肺癌细胞生长、侵袭和化疗耐药
Cancer Science ( IF 4.5 ) Pub Date : 2023-12-15 , DOI: 10.1111/cas.16052
Risheng Huang ₁ , Danni Wu ₁ , Kangliang Zhang ₂ , Guanqiong Hu ₃ , Yu Liu ₄ , Yi Jiang ₅ , Chichao Wang ₁ , Yuanliang Zheng ₁

Affiliation

富含 AT 相互作用结构域的蛋白 1A ( ARID1A ) 的丢失经常发生在包括肺癌在内的人类恶性肿瘤中。 ARID1A突变在肺癌中的生物学后果尚不完全清楚。本研究旨在确定ARID1A耗尽的肺癌细胞对成纤维细胞活化的影响。从ARID1A耗尽的肺癌细胞中收集条件培养基并用于治疗肺成纤维细胞。研究肺成纤维细胞的增殖和迁移。在ARID1A敲低后，我们对肺癌细胞中的分泌基因进行了分析。利用基于抗体的中和来确认它们在介导肺癌细胞和成纤维细胞之间的串扰中的作用。 NOD-SCID-IL2RgammaC-null (NSG) 小鼠接受 ARID1A 突变肺癌患者的肿瘤组织，建立患者来源的异种移植 (PDX) 模型。值得注意的是， ARID1A耗尽的肺癌细胞促进了肺成纤维细胞的增殖和迁移。从机制上讲， ARID1A耗竭增强了肺癌细胞中脯氨酰4-羟化酶β（P4HB）的表达和分泌，从而通过β-连环蛋白信号通路诱导肺成纤维细胞的激活。 P4HB激活的肺成纤维细胞促进肺癌细胞的增殖、侵袭和化疗耐药。在两个 PDX 模型中，中和 P4HB 可抑制肿瘤生长并增加顺铂细胞毒性功效。 ARID1A突变肺癌患者的血清 P4HB 水平高于健康对照。此外，P4HB血清水平升高与肺癌转移显着相关。总之，我们的工作表明 P4HB 在肺癌进展过程中协调ARID1A突变的癌细胞和癌症相关成纤维细胞之间的串扰方面发挥着关键作用。 P4HB 可能是改善肺癌治疗的一个有希望的靶点。

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ARID1A loss induces P4HB to activate fibroblasts to support lung cancer cell growth, invasion, and chemoresistance

Loss of AT-interacting domain-rich protein 1A (ARID1A) frequently occurs in human malignancies including lung cancer. The biological consequence of ARID1A mutation in lung cancer is not fully understood. This study was designed to determine the effect of ARID1A-depleted lung cancer cells on fibroblast activation. Conditioned media was collected from ARID1A-depleted lung cancer cells and employed to treat lung fibroblasts. The proliferation and migration of lung fibroblasts were investigated. The secretory genes were profiled in lung cancer cells upon ARID1A knockdown. Antibody-based neutralization was utilized to confirm their role in mediating the cross-talk between lung cancer cells and fibroblasts. NOD-SCID-IL2RgammaC-null (NSG) mice received tumor tissues from patients with ARID1A-mutated lung cancer to establish patient-derived xenograft (PDX) models. Notably, ARID1A-depleted lung cancer cells promoted the proliferation and migration of lung fibroblasts. Mechanistically, ARID1A depletion augmented the expression and secretion of prolyl 4-hydroxylase beta (P4HB) in lung cancer cells, which induced the activation of lung fibroblasts through the β-catenin signaling pathway. P4HB-activated lung fibroblasts promoted the proliferation, invasion, and chemoresistance in lung cancer cells. Neutralizing P4HB hampered the tumor growth and increased cisplatin cytotoxic efficacy in two PDX models. Serum P4HB levels were higher in ARID1A-mutated lung cancer patients than in healthy controls. Moreover, increased serum levels of P4HB were significantly associated with lung cancer metastasis. Together, our work indicates a pivotal role for P4HB in orchestrating the cross-talk between ARID1A-mutated cancer cells and cancer-associated fibroblasts during lung cancer progression. P4HB may represent a promising target for improving lung cancer treatment.

更新日期：2023-12-15

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