IL-6 induces tumor suppressor protein tyrosine phosphatase receptor type D by inhibiting miR-34a to prevent IL-6 signali
- PDF / 6,987,493 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 88 Downloads / 216 Views
IL‑6 induces tumor suppressor protein tyrosine phosphatase receptor type D by inhibiting miR‑34a to prevent IL‑6 signaling overactivation Fan Zhang1 · Bo Wang2 · Tao Qin2 · Lu Wang2 · Qingqing Zhang2 · Ying Lu2 · Bo Song2 · Xiaotang Yu2 · Lianhong Li2 Received: 16 December 2019 / Accepted: 18 June 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Protein tyrosine phosphatase receptor type D (PTPRD) is a tumor suppressor gene that is epigenetically silenced and mutated in several cancers, including breast cancer. Since IL-6/STAT3 signaling is often hyperactivated in breast cancer and STAT3 is a direct PTPRD substrate, we investigated the role of PTPRD in breast cancer and the association between PTPRD and IL-6/ STAT3 signaling. We found that PTPRD acts as a tumor suppressor in breast cancer tissues and that high PTPRD expression is positively associated with tumor size, lymph node metastasis, PCNA expression, and patient survival. Moreover, breast cancers with high PTPRD expression tend to exhibit high IL-6 and low phosphorylated-STAT3 expression. IL-6 was found to inhibit miR-34a transcription and induce PTPRD expression in breast cancer and breast epithelial cells, whereas PTPRD was shown to mediate activated STAT3 dephosphorylation and to be a conserved, direct target of miR-34a. IL-6-induced PTPRD upregulation was blocked by miR-34a mimics, whereas experimental PTPRD overexpression suppressed MDAMB-231 cell migration, invasion, and epithelial to mesenchymal transition, decreased STAT3 phosphorylation, and increased miR-34a transcription. Our findings suggest that PTPRD mediates activated STAT3 dephosphorylation and is induced by the IL-6/STAT3-mediated transcriptional inhibition of miR-34a, thereby establishing a negative feedback loop that inhibits IL-6/STAT3 signaling overactivation. Keywords Interleukin-6 · Signal transducer and activator of transcription 3 · Protein tyrosine phosphatase receptor type D · MicroRNA-34a
Introduction Genetic and biochemical studies have shown that oncogenic proteins and tumor suppressor genes provide critical balance in the regulation of key pathways that control cell number and behavior [1]. Breast cancer progression involves Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11010-020-03803-w) contains supplementary material, which is available to authorized users. * Xiaotang Yu [email protected] * Lianhong Li [email protected] 1
Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116032, China
Department of Pathology and Forensic Medicine, College of Basic Medical Science, Dalian Medical University, Lvshun South Road, Dalian 116044, China
2
multiple heterogeneous disorders and several genetic alterations, including oncogene activation and the functional disruption of specific tumor suppressor genes, which cause proliferative progression, increase cancer aggression, reduce differentiation and apoptosis, and increase cellular s
Data Loading...
