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Exosome-transmitted FOSL1 from cancer-associated fibroblasts drives colorectal cancer stemness and chemo-resistance through transcriptionally activating ITGB4

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Abstract

Cancer-associated fibroblasts (CAFs) have been proved to facilitate colorectal cancer (CRC) development, either with boosting chemo-resistance by communicating with CRC cells in the tumor microenvironment. However, the underlying molecular mechanisms remain largely unclear. Relative expressions of FOSL1 and ITGB4, either with their correlations in CRC tissues, were assessed using qRT-PCR analysis. Also, Kaplan–Meier survival analysis was employed for evaluating the prognosis. Identification of CAFs was determined by the detection of specific makers (α-SMA, FAP, and FSP1) using western blot and immunofluorescence staining. Cell proliferation, self-renewal capacity, and cell apoptosis were estimated by CCK-8, sphere-formation, and flow cytometry assays. Transcriptional regulation of FOSL1 on integrin β4 (ITGB4) was confirmed using ChIP and dual-luciferase reporter assays. Increased FOSL1 and ITGB4 in CRC tissues were both positively correlated with the poor prognosis of CRC patients. Interestingly, FOSL1 was enriched in the CAFs isolated from CRC stroma, instead of ITGB4. CRC cells under a co-culture system with CAFs-conditioned medium (CAFs-CM) exhibited increased FOSL1, promotive cell proliferation, and reduced apoptosis, while these effects could be blocked by exosome inhibitor (GW4869). Moreover, CAFs-derived exosomal FOSL1 was validated to enhance proliferative ability and oxaliplatin resistance of CRC cells. Our results uncovered that CAFs-derived exosomes could transfer FOSL1 to CRC cells, thereby promoting CRC cell proliferation, stemness, and oxaliplatin resistance by transcriptionally activating ITGB4.

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The data underlying this article will be shared on reasonable request to the corresponding author.

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Acknowledgements

The authors thanked the participants for their contribution to the study. We also thanked Prof. Hu for her assistance during data analysis and manuscript revision.

Funding

This work was supported by the Medical Research Foundation of Guangdong Province (No.B2022159); Research Project of Jiangmen Central Hospital (No.J202104) and Medical and Health Science and Technology Project of Jiangmen (No.2022YL01065, No.2022YL01089).

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Authors and Affiliations

  1. Department of Rehabilitation Medicine, Jiangmen Central Hospital, Jiangmen, 529099, Guangdong Province, China

    Shanshan Lin

  2. Department of Surgical Oncology, Zhongshan City People’s Hospital, No. 2 Sunwen East Road, Zhongshan City, Guangdong Province, China

    Bo Zhu

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  1. Shanshan Lin
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  2. Bo Zhu
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Contributions

SSL—acquisition of data; analysis and interpretation of data; drafting the manuscript. BZ—conception and design of study; acquisition of data; revising the manuscript critically for important intellectual content.

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Correspondence to Bo Zhu.

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This study has obtained approval of the Ethics Committee of Zhongshan City People’s Hospital.

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Lin, S., Zhu, B. Exosome-transmitted FOSL1 from cancer-associated fibroblasts drives colorectal cancer stemness and chemo-resistance through transcriptionally activating ITGB4. Mol Cell Biochem 479, 665–677 (2024). https://doi.org/10.1007/s11010-023-04737-9

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  • DOI: https://doi.org/10.1007/s11010-023-04737-9

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