Comprehensive Genetic Search to Clarify the Molecular Mechanism of Drug Resistance Identifies ASCL2-LEF1/TSPAN8 Axis in Colorectal Cancer

• Published in: Annals of surgical oncology Vol. 26; no. 5; pp. 1401 - 1411
• Main Authors: Tanaka, Toshimichi, Kojima, Keita, Yokota, Kazuko, Tanaka, Yoko, Ooizumi, Yosuke, Ishii, Satoru, Nishizawa, Nobuyuki, Yokoi, Keigo, Ushiku, Hideki, Kikuchi, Mariko, Kojo, Ken, Minatani, Naoko, Katoh, Hiroshi, Sato, Takeo, Nakamura, Takatoshi, Sawanobori, Masakazu, Watanabe, Masahiko, Yamashita, Keishi
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.05.2019; Springer Nature B.V
• Subjects: 5-Fluorouracil; Antineoplastic Agents - pharmacology; ANTINEOPLASTIC DRUGS; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; BIOLOGICAL MARKERS; Biomarkers, Tumor; Cancer therapies; Chemoradiotherapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; DNA microarrays; Drug resistance; Drug Resistance, Neoplasm - genetics; FLUOROURACILS; Gastrointestinal Oncology; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; GENES; GENETICS; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Lymphoid Enhancer-Binding Factor 1 - genetics; Lymphoid Enhancer-Binding Factor 1 - metabolism; Medicine; Medicine & Public Health; NEOPLASMS; Oncology; Phenylbutyrates - pharmacology; Phenylbutyric acid; Prognosis; Radiation therapy; RADIOLOGY AND NUCLEAR MEDICINE; RADIOTHERAPY; RECTUM; RNA; RNA-mediated interference; Signal Transduction; Surgery; Surgical Oncology; Survival Rate; Tetraspanins - genetics; Tetraspanins - metabolism; Tumor Cells, Cultured
• ISSN: 1068-9265; 1534-4681; 1534-4681
• DOI: 10.1245/s10434-019-07172-7

Background 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. Methods 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. Results 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. Conclusions ASCL2 was identified as a causative gene involved in therapeutic resistance against anticancer treatments in CRC.