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SOX8 promotes cetuximab resistance via HGF/MET bypass pathway activation in colorectal cancer

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Abstract

Aim

Cetuximab is an essential drug for the treatment of wild-type K-RAS colorectal cancer (CRC). It improves the overall survival of patients. However, acquired resistance prevents its clinical efficacy. Tumor heterogeneity may be a nonnegligible reason for cetuximab resistance. We attempted to explore the corresponding molecular mechanism.

Methods

Cetuximab-resistant CRC cell RKO and cetuximab-sensitive CRC cell Caco-2 were applied in this study. Cells were centrifuged to determine the concentration in the culture supernatant (CS). MTT, EdU, and colony formation assays were utilized to evaluate cell survival and proliferation. Chromatin immunoprecipitation (ChIP) and promoter-luciferase reporter assays were employed to confirm the direct binding of transcription factors. Western blot and reverse transcription-polymerase chain reaction (RT-PCR) assays were used to detect the expression of molecular markers in the pathway.

Results

Hepatocyte growth factor (HGF) was up-regulated in RKO cell culture supernatant and induced cetuximab resistance in Caco-2 cells. SRY-Box Transcription Factor 8 (SOX8) bound to the promoter sequence of HGF. HGF activated the HGF/MET bypass pathway and induced cetuximab resistance in Caco-2 cells.

Conclusion

The SOX8/HGF/MET axis played a crucial role in the communication between cetuximab-resistant cells and cetuximab-sensitive cells, inducing treatment resistance.

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Availability of data and material

The data used to support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

Liaoning S&T Project (2020-ZLLH-46, 2021-MS-068).

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Authors and Affiliations

  1. Department of Medical Oncology, The First Hospital of China Medical University, No. 155 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China

    Hai-yan Piao, Jing-Lei Qu & Yun-Peng Liu

  2. Medical Oncology Department of Gastrointestinal Cancer, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning, China

    Hai-yan Piao

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  1. Hai-yan Piao
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Contributions

PHY performed the majority of experiments and analyzed the data, and drafted the manuscript; LYP designed the research; QJL collected and analyzed the data.

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Correspondence to Jing-Lei Qu or Yun-Peng Liu.

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The authors declare no conflicts of interest.

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The study was reviewed and approved by the Faculty of Science Ethics Committee at Liaoning Cancer Hospital & Institute (Cancer Hospital of China Medical University, 20201144K).

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Piao, Hy., Qu, JL. & Liu, YP. SOX8 promotes cetuximab resistance via HGF/MET bypass pathway activation in colorectal cancer. Cancer Chemother Pharmacol 89, 441–449 (2022). https://doi.org/10.1007/s00280-021-04378-z

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  • DOI: https://doi.org/10.1007/s00280-021-04378-z

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