Nianxue Wang1, Jing Wen2, Wei Ren1, Yuting Wu3, Chaonan Deng4. 1. Department of Immunology, Guizhou Medical University, Guiyang City, 550025, Guizhou Province, China. 2. Department of Ultrasonic Center, Affiliated Hospital of Guizhou Medical University, Guiyang City, 550004, Guizhou Province, China. 3. Department of Pathology, Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Guiyang City, 550004, Guizhou Province, China. 4. Department of Pathology, Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Guiyang City, 550004, Guizhou Province, China. dcn_gy1011@163.com.
Abstract
PURPOSE: The BRAFV600E mutation is an oncogenic driver associated with aggressive tumor behaviors and increased mortality among patients with papillary thyroid cancer (PTC). Although the BRAF inhibitor vemurafenib gave promising results in BRAFV600E-mutant PTC, resistance development remains a major clinical challenge. This study aimed to explore the mechanisms underlying drug resistance in PTC. METHODS: Two vemurafenib-resistant PTC cell lines (KTC1 and BCPAP) were established by continuous treatment with vemurafenib for 5 months. The knockdown and upregulation of Tribbles homolog 2 (TRIB2) in PTC cells were achieved by the transfection with short hairpin RNA against TRIB2 or recombinant lentiviral vector carrying TRIB2, respectively. The β-catenin inhibitor, ICG-001, was used for the inhibition of the Wnt/β-catenin signaling in PTC cells. RESULTS: Vemurafenib-resistant PTC cells showed higher TRIB2 expression, upregulated ERK and AKT activation, enhanced invasive capacity, and increased epithelial-mesenchymal transition compared to the drug-sensitive groups. TRIB2 knockdown repressed the activation of ERK and AKT, inhibited invasion and EMT, and induced apoptosis of PTC cells. TRIB2 deficiency also enhanced the sensitivity of both PTC cells to vemurafenib. Vemurafenib-resistant PTC cells showed elevated expression of β-catenin in both cytoplasm and nucleus. The pre-incubation of cells with β-catenin inhibitor significantly inhibited TRIB2 expression, suppressed EMT, and repressed the activation of ERK and AKT in vemurafenib-resistant cells. CONCLUSION: Our study showed that the upregulation of TRIB2 by the Wnt/β-catenin activation confers resistance to vemurafenib in PTC with BRAFV600 mutation. These findings support the potential use of TRIB2 as a therapeutic target for resistant PTC.
PURPOSE: The BRAFV600E mutation is an oncogenic driver associated with aggressive tumor behaviors and increased mortality among patients with papillary thyroid cancer (PTC). Although the BRAF inhibitor vemurafenib gave promising results in BRAFV600E-mutant PTC, resistance development remains a major clinical challenge. This study aimed to explore the mechanisms underlying drug resistance in PTC. METHODS: Two vemurafenib-resistant PTC cell lines (KTC1 and BCPAP) were established by continuous treatment with vemurafenib for 5 months. The knockdown and upregulation of Tribbles homolog 2 (TRIB2) in PTC cells were achieved by the transfection with short hairpin RNA against TRIB2 or recombinant lentiviral vector carrying TRIB2, respectively. The β-catenin inhibitor, ICG-001, was used for the inhibition of the Wnt/β-catenin signaling in PTC cells. RESULTS:Vemurafenib-resistant PTC cells showed higher TRIB2 expression, upregulated ERK and AKT activation, enhanced invasive capacity, and increased epithelial-mesenchymal transition compared to the drug-sensitive groups. TRIB2 knockdown repressed the activation of ERK and AKT, inhibited invasion and EMT, and induced apoptosis of PTC cells. TRIB2 deficiency also enhanced the sensitivity of both PTC cells to vemurafenib. Vemurafenib-resistant PTC cells showed elevated expression of β-catenin in both cytoplasm and nucleus. The pre-incubation of cells with β-catenin inhibitor significantly inhibited TRIB2 expression, suppressed EMT, and repressed the activation of ERK and AKT in vemurafenib-resistant cells. CONCLUSION: Our study showed that the upregulation of TRIB2 by the Wnt/β-catenin activation confers resistance to vemurafenib in PTC with BRAFV600 mutation. These findings support the potential use of TRIB2 as a therapeutic target for resistant PTC.
Authors: Guangming Chen; Chenxi Gao; Xuan Gao; Dennis Han Zhang; Shih-Fan Kuan; Timothy F Burns; Jing Hu Journal: Mol Cancer Ther Date: 2017-11-22 Impact factor: 6.261
Authors: Mingzhao Xing; Ali S Alzahrani; Kathryn A Carson; David Viola; Rossella Elisei; Bela Bendlova; Linwah Yip; Caterina Mian; Federica Vianello; R Michael Tuttle; Eyal Robenshtok; James A Fagin; Efisio Puxeddu; Laura Fugazzola; Agnieszka Czarniecka; Barbara Jarzab; Christine J O'Neill; Mark S Sywak; Alfred K Lam; Garcilaso Riesco-Eizaguirre; Pilar Santisteban; Hirotaka Nakayama; Ralph P Tufano; Sara I Pai; Martha A Zeiger; William H Westra; Douglas P Clark; Roderick Clifton-Bligh; David Sidransky; Paul W Ladenson; Vlasta Sykorova Journal: JAMA Date: 2013-04-10 Impact factor: 56.272