Zhanwei Wang1, Dionyssios Katsaros2, Nicoletta Biglia3, Yi Shen1, Lenora Loo1, Xiao Yu4, Hongyan Lin4, Yuanyuan Fu1,5, Wen-Ming Chu1, Peiwen Fei1, Yan Ni1, Wei Jia1, Xiaobei Deng4, Biyun Qian6, Herbert Yu7. 1. University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA. 2. Department of Surgical Sciences, Gynecology, AOU Città della Salute, University of Torino, Turin, Italy. 3. Division of Obstetrics and Gynecology, Department of Surgical Sciences, University of Torino School of Medicine, Mauriziano Hospital, Turin, Italy. 4. Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai, 200025, China. 5. Department of Molecular Biosciences & Bioengineering, University of Hawaii at Manoa, Honolulu, HI, USA. 6. Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai, 200025, China. qianbiyun@shsmu.edu.cn. 7. University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA. hyu@cc.hawaii.edu.
Abstract
PURPOSE: Low expression of long intergenic non-coding RNA LINC00472 in breast cancer is associated with aggressive tumors and unfavorable disease outcomes in multiple clinical datasets, but the reasons for these associations were unknown. METHODS: To study the mechanisms underlying the lncRNA's connection to breast cancer, we investigated the molecular targets and regulation of LINC00472 in breast cancer cells, and analyzed relevant molecular features in relation to patient survival. Gene expression profiles of breast cancer cells overexpressing LINC00472 were analyzed for its regulatory pathways and downstream targets. Effects of LINC00472 overexpression on cell behaviors were evaluated in vitro and in vivo. Meta-analysis was performed using online datasets and our own study. RESULTS: Analysis of LINC00472 transcriptome revealed ERα upregulation of LINC00472 expression, and an ERα-binding site in the LINC00472 promoter was identified. Evaluation of LINC00472 overexpression also indicated a possible link between LINC00472 and NF-κB. Cell experiments confirmed that LINC00472 suppressed the phosphorylation of p65 and IκBα through binding to IKKβ, inhibiting its phosphorylation. High LINC00472 expression inhibited tumor growth both in vitro and in vivo and suppressed aggressive tumor cell behaviors in vitro. Suppressing LINC00472 expression in ER-positive tumor cells increased cell aggressive behaviors. Tamoxifen treatment of ER-positive cells inhibited ERα and LINC00472 expression and increased p65 and IκBα phosphorylation. Meta-analysis showed that LINC00472 expression were higher in ER-positive than ER-negative tumors and that high expression was associated with better disease outcomes in ER-positive patients. CONCLUSIONS: The study demonstrates that ERα upregulates LINC00472 which suppresses the phosphorylation of NF-κB, and suggests that endocrine treatment may lower LINC00472 and increase NF-κB activities, leading to tumor progression and disease recurrence.
PURPOSE: Low expression of long intergenic non-coding RNA LINC00472 in breast cancer is associated with aggressive tumors and unfavorable disease outcomes in multiple clinical datasets, but the reasons for these associations were unknown. METHODS: To study the mechanisms underlying the lncRNA's connection to breast cancer, we investigated the molecular targets and regulation of LINC00472 in breast cancer cells, and analyzed relevant molecular features in relation to patient survival. Gene expression profiles of breast cancer cells overexpressing LINC00472 were analyzed for its regulatory pathways and downstream targets. Effects of LINC00472 overexpression on cell behaviors were evaluated in vitro and in vivo. Meta-analysis was performed using online datasets and our own study. RESULTS: Analysis of LINC00472 transcriptome revealed ERα upregulation of LINC00472 expression, and an ERα-binding site in the LINC00472 promoter was identified. Evaluation of LINC00472 overexpression also indicated a possible link between LINC00472 and NF-κB. Cell experiments confirmed that LINC00472 suppressed the phosphorylation of p65 and IκBα through binding to IKKβ, inhibiting its phosphorylation. High LINC00472 expression inhibited tumor growth both in vitro and in vivo and suppressed aggressive tumor cell behaviors in vitro. Suppressing LINC00472 expression in ER-positive tumor cells increased cell aggressive behaviors. Tamoxifen treatment of ER-positive cells inhibited ERα and LINC00472 expression and increased p65 and IκBα phosphorylation. Meta-analysis showed that LINC00472 expression were higher in ER-positive than ER-negative tumors and that high expression was associated with better disease outcomes in ER-positive patients. CONCLUSIONS: The study demonstrates that ERα upregulates LINC00472 which suppresses the phosphorylation of NF-κB, and suggests that endocrine treatment may lower LINC00472 and increase NF-κB activities, leading to tumor progression and disease recurrence.
Entities:
Keywords:
Breast cancer; ERα; Endocrine resistance; LINC00472; LncRNA; NF-κB; Prognosis
Authors: Steven J Van Laere; Ilse Van der Auwera; Gert G Van den Eynden; Hilde J Elst; Joost Weyler; Adrian L Harris; Peter van Dam; Eric A Van Marck; Peter B Vermeulen; Luc Y Dirix Journal: Clin Cancer Res Date: 2006-06-01 Impact factor: 12.531
Authors: Demetrius M Kokkinakis; Xiaoyan Liu; Sunil Chada; Mansoor M Ahmed; Mohammed M Shareef; Ujjal K Singha; Sutin Yang; Jianhua Luo Journal: Cancer Res Date: 2004-10-15 Impact factor: 12.701
Authors: Yamei Zhou; Serenella Eppenberger-Castori; Corina Marx; Christina Yau; Gary K Scott; Urs Eppenberger; Christopher C Benz Journal: Int J Biochem Cell Biol Date: 2005-05 Impact factor: 5.085
Authors: L A deGraffenried; B Chandrasekar; W E Friedrichs; E Donzis; J Silva; M Hidalgo; J W Freeman; G R Weiss Journal: Ann Oncol Date: 2004-06 Impact factor: 32.976