Mass Spectrometry-Based Proteomics Identifies Serpin B9 as a Key Protein in Promoting Bone Metastases in Lung Cancer.

IF 4.1 2区医学 Q2 CELL BIOLOGY Molecular Cancer Research Pub Date : 2024-04-02 DOI:10.1158/1541-7786.MCR-23-0310

Yufeng Huang, Ming Gong, Hongmin Chen, Chuangzhong Deng, Xiaojun Zhu, Jiaming Lin, Anfei Huang, Yanyang Xu, Yi Tai, Guohui Song, Huaiyuan Xu, Jinxin Hu, Huixiong Feng, Qinglian Tang, Jinchang Lu, Jin Wang

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Abstract

Bone metastasis (BM) is one of the most common complications of advanced cancer. Immunotherapy for bone metastasis of lung cancer (LCBM) is not so promising and the immune mechanisms are still unknown. Here, we utilized a model of BM by injecting cancer cells through caudal artery (CA) to screen out a highly bone metastatic derivative (LLC1-BM3) from a murine lung cancer cell line LLC1. Mass spectrometry-based proteomics was performed in LLC1-parental and LLC1-BM3 cells. Combining with prognostic survival information from patients with lung cancer, we identified serpin B9 (SB9) as a key factor in BM. Molecular characterization showed that SB9 overexpression was associated with poor prognosis and high bone metastatic burden in lung cancer. Moreover, SB9 could increase the ability of lung cancer cells to metastasize to the bone. The mechanistic studies revealed that tumor-derived SB9 promoted BM through an immune cell-dependent way by inactivating granzyme B, manifesting with the decreased infiltration of cytotoxic T cells and increased expression level of exhausted markers. A specific SB9-targeting inhibitor [1,3-benzoxazole-6-carboxylic acid (BTCA)] significantly suppressed LCBM in the CA mouse model. This study reveals that SB9 may serve as a therapeutic target and potential prognostic marker for patients with LCBM.

Implications: SB9 as a therapeutic target for LCBM.

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基于质谱的蛋白质组学发现 Serpin B9 是促进肺癌骨转移的关键蛋白。

骨转移（BM）是晚期癌症最常见的并发症之一。肺癌骨转移（LCBM）的免疫治疗前景并不乐观，其免疫机制仍不清楚。在这里，我们利用通过尾动脉（CA）注射癌细胞的骨转移模型，从鼠肺癌细胞系LLC1中筛选出了一种高度骨转移的衍生物（LLC1-BM3）。在LLC1亲代细胞和LLC1-BM3细胞中进行了基于质谱的蛋白质组学研究。结合肺癌患者的预后生存信息，我们发现 Serpin B9（SB9）是影响 BM 的关键因素。分子特征显示，SB9 的过表达与肺癌的不良预后和高骨转移负荷有关。此外，SB9 还能增强肺癌细胞向骨转移的能力。机理研究发现，肿瘤衍生的SB9通过使颗粒酶B（GrB）失活，以免疫细胞依赖的方式促进骨转移，表现为细胞毒性T细胞（CTL）浸润减少和衰竭标志物表达水平升高。一种特异性 SB9 靶向抑制剂（BTCA）能显著抑制 CA 小鼠模型中的 LCBM。本研究揭示了 SB9 可作为 LCBM 患者的治疗靶点和潜在预后标志物。意义丝裂蛋白 B9 可作为肺癌骨转移的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer Research 医学-细胞生物学

CiteScore

9.90

自引率

0.00%

发文量

280

审稿时长

4-8 weeks

期刊介绍： Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.