Comprehensive Genetic Search to Clarify the Molecular Mechanism of Drug Resistance Identifies ASCL2-LEF1/TSPAN8 Axis in Colorectal Cancer
- 31 Downloads
Treatment-resistance genes limiting anticancer therapy have not been well clarified in colorectal cancer (CRC). We explored gene expression profiles to identify biomarkers for predicting treatment resistance to an anticancer drug in CRC.
Six CRC cell lines were treated with phenylbutyrate (PB). The gene expression profiles were then compared using microarrays (harboring 54,675 genes), and genes associated with PB resistance were identified. Candidate genes were functionally examined in cell lines and clinically validated for treatment resistance in clinical samples.
Both DLD1 and HCT15 cells were PB resistant, while HCT116 cells were identified as PB sensitive. On microarray analysis, among the PB resistance-related genes, the expression of the genes ASCL2, LEF1, and TSPAN8 was clearly associated with PB resistance. PB-sensitive cells transfected with one of these three genes exhibited significant (P < 0.001) augmentation of PB resistance; ASCL2 induced expression of both LEF1 and TSPAN8, while neither LEF1 nor TSPAN8 induced ASCL2. RNA interference via ASCL2 knockdown made PB-resistant cells sensitive to PB and inhibited both genes. ASCL2 knockdown also played a critical role in sensitivity to treatment by 5-fluorouracil and radiotherapy in addition to PB. Finally, ASCL2 expression was significantly correlated with histological grade of rectal cancer with preoperative chemoradiation therapy.
ASCL2 was identified as a causative gene involved in therapeutic resistance against anticancer treatments in CRC.
- 5.Yamada Y, Takahari D, Matsumoto H, et al. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2013 14:1278–86CrossRefGoogle Scholar
- 10.Gilbert J, Baker SD, Bowling MK, et al. A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies. Clin Cancer Res. 2001 7:2292–300Google Scholar
- 17.Li L, Yang D, Cui D, et al. Quantitative proteomics analysis of the role of tetraspanin-8 in the drug resistance of gastric cancer. Int J Oncol. 2018 52:473–484Google Scholar
- 19.Stange DE, Engel F, Longerich T, et al. Expression of an ASCL2 related stem cell signature and IGF2 in colorectal cancer liver metastases with 11p15.5 gain. Gut. 2010 59:1236–44Google Scholar
- 24.Wang L, Xue M, Chung DC. c-Myc is regulated by HIF-2alpha in chronic hypoxia and influences sensitivity to 5-FU in colon cancer. Oncotarget. 2016 7:78910–78917Google Scholar
- 26.Ishii S, Yamashita K, Harada H, et al. The H19-PEG10/IGF2BP3 axis promotes gastric cancer progression in patients with high lymph node ratios. Oncotarget. 2017 8:74567–74581Google Scholar
- 28.Yue S, Mu W, Erb U, et al. The tetraspanins CD151 and Tspan8 are essential exosome components for the crosstalk between cancer initiating cells and their surrounding. Oncotarget. 2015 6:2366–84Google Scholar
- 30.Cajigas-Du Ross CK, Martinez SR, Woods-Burnham L, et al. RNA sequencing reveals upregulation of a transcriptomic program associated with stemness in metastatic prostate cancer cells selected for taxane resistance. Oncotarget. 2018 9:30363–30384Google Scholar
- 32.Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012 487:330–7Google Scholar
- 35.Arcy ND, Gabrielli B. Topoisomerase II inhibitors and poisons, and the influence of cell cycle checkpoints. Curr Med Chem. 2017 24:1504–1519Google Scholar