Hai-Yan Piao1,2, Jing-Lei Qu3, Yun-Peng Liu4. 1. Department of Medical Oncology, The First Hospital of China Medical University, No. 155 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China. 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. 3. Department of Medical Oncology, The First Hospital of China Medical University, No. 155 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China. qujinglei@hotmail.com. 4. Department of Medical Oncology, The First Hospital of China Medical University, No. 155 Nanjing North Road, Heping District, Shenyang, 110000, Liaoning, China. cmuliuyunpeng@hotmail.com.
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.
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.
Authors: Timothy J Price; Monica Tang; Peter Gibbs; Daniel G Haller; Marc Peeters; Dirk Arnold; Eva Segelov; Amitesh Roy; Niall Tebbutt; Nick Pavlakis; Chris Karapetis; Matthew Burge; Jeremy Shapiro Journal: Expert Rev Anticancer Ther Date: 2018-08-03 Impact factor: 4.512
Authors: Ran Weissman; Eli L Diamond; Julien Haroche; Nir Pillar; Guy Shapira; Benjamin H Durham; Justin Buthorn; Fleur Cohen; Michelle Ki; Galia Stemer; Gary A Ulaner; Zahir Amoura; Jean-François Emile; Roei D Mazor; Noam Shomron; Omar I Abdel-Wahab; Ofer Shpilberg; Oshrat Hershkovitz-Rokah Journal: Cancers (Basel) Date: 2020-11-03 Impact factor: 6.639