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胶原 I 诱导的 VCAN/ERK 信号和 PARP1/ZEB1 介导的转移促进 OSBPL2 缺陷促进结直肠癌进展。

Collagen I-induced VCAN/ERK signaling and PARP1/ZEB1-mediated metastasis facilitate OSBPL2 defect to promote colorectal cancer progression.

机构信息

Center for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China.

Institute of Gastrointestinal Surgery and Translational Medicine, School of Medicine, Tongji University, Shanghai, China.

出版信息

Cell Death Dis. 2024 Jan 24;15(1):85. doi: 10.1038/s41419-024-06468-1.

DOI:10.1038/s41419-024-06468-1
PMID:38267463
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10808547/
Abstract

The global burden of colorectal cancer (CRC) has rapidly increased in recent years. Dysregulated cholesterol homeostasis facilitated by extracellular matrix (ECM) remodeling transforms the tumor microenvironment. Collagen I, a major with ECM component is highly expressed in colorectal tumors with infiltrative growth. Although oxysterol binding protein (OSBP)-related proteins accommodate tumorigenesis, OSBPL2, which is usually involved in deafness, is not associated with CRC progression. Therefore, we aimed to investigate the pathological function of OSBPL2 and identify the molecular link between ECM-Collagen I and OSBPL2 in CRC to facilitate the development of new treatments for CRC. OSBPL2 predicted a favorable prognosis in stage IV CRC and substantially repressed Collagen I-induced focal adhesion, migration, and invasion. The reduction of OSBPL2 activated ERK signaling through the VCAN/AREG/EREG axis during CRC growth, while relying on PARP1 via ZEB1 in CRC metastasis. OSBPL2 defect supported colorectal tumor growth and metastasis, which were suppressed by the ERK and PARP1 inhibitors SCH772984 and AG14361, respectively. Overall, our findings revealed that the Collagen I-induced loss of OSBPL2 aggravates CRC progression through VCAN-mediated ERK signaling and the PARP1/ZEB1 axis. This demonstrates that SCH772984 and AG14361 are reciprocally connective therapies for OSBPL2 CRC, which could contribute to further development of targeted CRC treatment.

摘要

近年来，结直肠癌（CRC）的全球负担迅速增加。细胞外基质（ECM）重塑促进的胆固醇稳态失调改变了肿瘤微环境。胶原蛋白 I 是 ECM 的主要成分，在浸润性生长的结直肠肿瘤中高度表达。虽然氧化固醇结合蛋白（OSBP）相关蛋白促进肿瘤发生，但通常与耳聋有关的 OSBPL2 与 CRC 进展无关。因此，我们旨在研究 OSBPL2 的病理功能，并确定 CRC 中 ECM-胶原蛋白 I 与 OSBPL2 之间的分子联系，以促进 CRC 新疗法的开发。OSBPL2 预测 IV 期 CRC 的预后良好，并显著抑制胶原蛋白 I 诱导的黏附、迁移和侵袭。在 CRC 生长过程中，OSBPL2 的减少通过 VCAN/AREG/EREG 轴激活 ERK 信号，而在 CRC 转移过程中则依赖 PARP1 通过 ZEB1。OSBPL2 缺陷支持结直肠肿瘤的生长和转移，ERK 和 PARP1 抑制剂 SCH772984 和 AG14361 分别抑制了这些过程。总的来说，我们的研究结果表明，胶原蛋白 I 诱导的 OSBPL2 缺失通过 VCAN 介导的 ERK 信号和 PARP1/ZEB1 轴加重 CRC 进展。这表明 SCH772984 和 AG14361 是针对 OSBPL2 CRC 的互补治疗方法，这可能有助于进一步开发靶向 CRC 治疗方法。

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