BACKGROUND: Liver kinase B1 (LKB1) loss by gene mutation, loss of heterozygosity, and promoter methylation rarely occurs in colorectal cancer. We wondered whether LKB1 loss could be deregulated at the transcriptional level to promote tumor progression and poor outcome in colorectal cancer. METHODS: Mechanistic studies were performed in two each of p53 wild-type (HCT116, LoVo) and p53-mutated (SW480, HT29) colon cancer cells to explore whether LKB1 loss could be deregulated by NKX2-1-mediated p53 pathway. LKB1 and NK2 homeobox 1 (NKX2-1) expressions in colorectal tumors were determined by immunohistochemistry, and the prognostic value of both molecules was assessed by Kaplan-Meier test and Cox regression model. RESULTS: Mechanistically, LKB1 loss at the transcriptional level due to alteration of the NKX2-1-mediated p53 pathway promotes invasiveness in colon cancer cells. The cell invasiveness induced by LKB1 loss was nearly suppressed by mammalian target of rapamycin (mTOR) inhibitor (rapamycin and everolimus) and mTOR/AKT dual inhibitor Palomid 529 (P529). Among patients, low LKB1 tumors exhibited shorter overall survival (OS) and relapse-free survival periods than high LKB1 tumors. The highest hazard ratio value for OS and relapse-free survival was observed in wild-type p53 with low LKB1/low NKX2-1 tumors and in mutated p53 with low LKB1/high NKX2-1 tumors when wild-type p53 with high LKB1/high NKX2-1 and mutated p53 with high LKB1/low NKX2-1 tumors were used as references. CONCLUSIONS: LKB1 loss at the transcriptional level via alteration of the NKX2-1/p53 axis promotes cell invasion, consequently resulting in poor outcome in colorectal cancer patients.
BACKGROUND:Liver kinase B1 (LKB1) loss by gene mutation, loss of heterozygosity, and promoter methylation rarely occurs in colorectal cancer. We wondered whether LKB1 loss could be deregulated at the transcriptional level to promote tumor progression and poor outcome in colorectal cancer. METHODS: Mechanistic studies were performed in two each of p53 wild-type (HCT116, LoVo) and p53-mutated (SW480, HT29) colon cancer cells to explore whether LKB1 loss could be deregulated by NKX2-1-mediated p53 pathway. LKB1 and NK2 homeobox 1 (NKX2-1) expressions in colorectal tumors were determined by immunohistochemistry, and the prognostic value of both molecules was assessed by Kaplan-Meier test and Cox regression model. RESULTS: Mechanistically, LKB1 loss at the transcriptional level due to alteration of the NKX2-1-mediated p53 pathway promotes invasiveness in colon cancer cells. The cell invasiveness induced by LKB1 loss was nearly suppressed by mammalian target of rapamycin (mTOR) inhibitor (rapamycin and everolimus) and mTOR/AKT dual inhibitor Palomid 529 (P529). Among patients, low LKB1 tumors exhibited shorter overall survival (OS) and relapse-free survival periods than high LKB1tumors. The highest hazard ratio value for OS and relapse-free survival was observed in wild-type p53 with low LKB1/low NKX2-1tumors and in mutated p53 with low LKB1/high NKX2-1tumors when wild-type p53 with high LKB1/high NKX2-1 and mutated p53 with high LKB1/low NKX2-1tumors were used as references. CONCLUSIONS:LKB1 loss at the transcriptional level via alteration of the NKX2-1/p53 axis promotes cell invasion, consequently resulting in poor outcome in colorectal cancerpatients.
Authors: Kyle G Mitchell; Edwin R Parra; Jiexin Zhang; David B Nelson; Erin M Corsini; Pamela Villalobos; Cesar A Moran; Ferdinandos Skoulidis; Ignacio I Wistuba; Junya Fujimoto; Jack A Roth; Mara B Antonoff Journal: Ann Thorac Surg Date: 2020-05-19 Impact factor: 4.330
Authors: Christopher G Peña; Yuji Nakada; Hatice D Saatcioglu; Gina M Aloisio; Ileana Cuevas; Song Zhang; David S Miller; Jayanthi S Lea; Kwok-Kin Wong; Ralph J DeBerardinis; Antonio L Amelio; Rolf A Brekken; Diego H Castrillon Journal: J Clin Invest Date: 2015-09-28 Impact factor: 14.808