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

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 OSBPL2Low CRC, which could contribute to further development of targeted CRC treatment.

• Authors: Kang Lin, Yun Zhao, Yuqi Tang, Ying Chen, Moubin Lin, Luwei He
• Journal: Cell death & disease (Cell Death Dis) Vol. 15 Issue 1 Pg. 85 (01 24 2024) ISSN: 2041-4889 [Electronic] England
• PMID: 38267463 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2024. The Author(s).

Chemical References

• 1-(4-dimethylaminomethylphenyl)-8,9-dihydro-7H-2,7,9a-benzo(cd)azulen-6-one
• Benzodiazepines
• Azulenes
• Collagen Type I
• ZEB1 protein, human
• Zinc Finger E-box-Binding Homeobox 1
• OSBPL2 protein, human
• Receptors, Steroid
• VCAN protein, human
• Versicans
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1

Topics

• Humans
• Benzodiazepines
• Azulenes
• Collagen Type I
• Colorectal Neoplasms (genetics)
• Tumor Microenvironment
• Zinc Finger E-box-Binding Homeobox 1 (genetics)
• Receptors, Steroid
• Versicans
• Poly (ADP-Ribose) Polymerase-1