The novel long noncoding RNA AU021063, induced by IL-6/Arid5a signaling, exacerbates breast cancer invasion and metastasis by stabilizing Trib3 and activating the Mek/Erk pathway

• Published in: Cancer letters Vol. 520; pp. 295 - 306
• Main Authors: Nyati, Kishan Kumar, Hashimoto, Shigeru, Singh, Shailendra Kumar, Tekguc, Murat, Metwally, Hozaifa, Liu, Yu-Chen, Okuzaki, Daisuke, Gemechu, Yohannes, Kang, Sujin, Kishimoto, Tadamitsu
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.11.2021; Elsevier Limited
• Subjects: Animals; Antigens; Arid5a; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Cycle Proteins - genetics; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation - genetics; Cervical cancer; Cloning; Cytokines; Disease Models, Animal; DNA-Binding Proteins - genetics; Extracellular signal-regulated kinase; Female; Humans; Interleukin 6; Interleukin-6 - genetics; Invasiveness; Kinases; LncRNA; Lung cancer; MAP Kinase Signaling System - genetics; Metabolic pathways; Metastases; Metastasis; Mice; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Neoplasm Metastasis; Proteins; RNA, Long Noncoding - genetics; Signal Transduction; Transcription; Transcription Factors - genetics; Tumor necrosis factor-TNF; United States > US; Japan; LncRNA; Breast cancer; Arid5a; Metastasis; Interleukin-6
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.08.004

Interleukin (IL-6) is a pleotropic cytokine with both tumor-promoting and -inhibitory effects on breast cancer growth. However, the mechanisms governing the outcome of IL-6 on cancer progression remain to be clarified. Our study unraveled a novel long noncoding RNA (lncRNA) AU021063 downstream of IL-6 signaling. We found that IL-6 induced the expression of AU021063 predominantly in breast cancer compared to other cancer types. Mechanistically, IL-6 induced AT-rich interactive domain 5a (Arid5a) expression, which promotes the transcription of AU021063. In turn, AU021063 promotes breast cancer metastasis through stabilizing tribbles homolog 3 (Trib3) and activating Mek/Erk signaling pathway. Genetic ablation of either Arid5a, AU021063 or Trib3 abolished breast cancer metastasis in vitro and in vivo. Overall, our study highlights the importance of IL-6-Arid5a-AU021063 axis in regulating breast cancer invasiveness and metastasis, which may provide potential novel therapeutics for breast cancer. •The IL-6/Arid5a axis upregulates AU021063 expression in breast cancer cells.•AU021063 stabilizes the Trib3 and activates Mek/Erk pathway in breast cancer cells.•AU021063 and Trib3 promote invasion and metastasis in vitro and in vivo.•Trib3 is required for AU021063-mediated invasion and metastasis of breast cancer cells.