Liver cancer-derived exosomal PTK6 induces the secretion of pulmonary CHI3L1 to facilitate lung metastatic niche formation

IF 11.8 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2026-04-10 Epub Date: 2026-02-09 DOI:10.1016/j.canlet.2026.218312

Jinxian Yang , Han Yu , Caiming Zhong , Lingyan Xu , Yuting Song , Yushan Miao , Qiqi Cao , Wen Wen , Hao Tang , Shuzhen Chen , Hongyang Wang

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Abstract

Pulmonary metastasis represents the most frequent site of distant dissemination in hepatocellular carcinoma (HCC). Elevated levels of Chitinase-3-like protein 1 (CHI3L1) in HCC patients are specifically associated with pulmonary metastasis, compared to metastasis to other sites or the absence of metastasis. HCC-derived exosomes, enriched in protein tyrosine kinase 6 (PTK6), induced CHI3L1 secretion in pulmonary epithelial cells via PTK6-mediated STAT3 phosphorylation (p-STAT3), thereby promoting angiogenesis and facilitating the establishment of a lung pre-metastatic niche. Elevated CHI3L1 enhanced HCC cell migration and angiogenesis, facilitating pulmonary metastatic niche formation. Targeting CHI3L1 with neutralizing antibodies or AAV2-shChi3l1 knockdown in pulmonary cells significantly reduced lung metastasis in vivo. Furthermore, Bortezomib suppressed CHI3L1 secretion in vitro and in vivo, inhibiting HCC lung metastasis. This study establishes CHI3L1 as a specific biomarker and a therapeutic target for HCC pulmonary metastasis.

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肝癌来源的外泌体PTK6诱导肺CHI3L1的分泌，促进肺转移生态位的形成。

肺转移是肝细胞癌（HCC）中最常见的远处播散部位。与转移到其他部位或无转移相比，HCC患者几丁质酶-3样蛋白1 （CHI3L1）水平升高与肺转移特异性相关。hcc来源的外泌体富含蛋白酪氨酸激酶6 (PTK6)，通过PTK6介导的STAT3磷酸化（p-STAT3）诱导肺上皮细胞分泌CHI3L1，从而促进血管生成并促进肺转移前生态位的建立。升高的CHI3L1增强了HCC细胞的迁移和血管生成，促进肺转移生态位的形成。在体内用中和抗体或AAV2-shChi3l1敲低肺细胞靶向CHI3L1可显著减少肺转移。此外，硼替佐米在体外和体内抑制CHI3L1分泌，抑制HCC肺转移。本研究确定了CHI3L1作为HCC肺转移的特异性生物标志物和治疗靶点。

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

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.