Activation of LncRNA TINCR by H3K27 acetylation promotes Trastuzumab resistance and epithelial-mesenchymal transition by targeting MicroRNA-125b in breast Cancer
Authors: Yuanwen Chen
Xin Chen
Kejian Zou
Huaying Dong
Mulin Ye
Mingli Han
Jianguo Hu
Chengyi Wu
Journal: Molecular Cancer (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Breast cancer; H3K27 acetylation; HER-2; Snail-1; TINCR
Affiliations: Department of General Surgery, Hainan General Hospital, Hainan Medical University, No.19 Xiu Hua Road, Xiuying District, Haikou City, 570311, Hainan Province, China. ., Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China., Department of General Surgery, Hainan General Hospital, Hainan Medical University, No.19 Xiu Hua Road, Xiuying District, Haikou City, 570311, Hainan Province, China., Department of General Surgery, Chongqing Renji Hospital, University of Chinese Academy of Science, Chongqing, 400062, China., Department of General Surgery, The Frist Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China., Department of General Surgery, The Frist Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China. ., Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. .

Abstract:  Background: Trastuzumab resistance followed by metastasis is a major obstacle for improving the clinical outcome of patients with advanced human epidermal growth factor receptor 2-positive (HER-2+) breast cancer. While long non-coding RNAs (lncRNAs) can modulate cell behavior, the contribution of these RNAs in trastuzumab resistance and metastasis of HER-2+ breast cancer is not well known. In this study, we sought to identify the regulatory role of lncRNA in trastuzumab resistance and accompanied Epithelial-mesenchymal Transition (EMT) process in advanced HER-2+ breast cancer. Methods: Trastuzumab-resistant SKBR-3-TR and BT474-TR cell lines were established by grafting SKBR-3 and BT474 cells into mouse models and subjected to trastuzumab treatment. LncRNA microarray followed by quantitative reverse transcription PCR (qRT-PCR) was carried out to verify the differentially expressed lncRNAs. Western blotting, bioinformatics analysis, immunofluorescence assay and immunoprecipitation assays (ChIP and RIP) were performed to identify the involvement and functional interactions between H3K27 acetylation and terminal differentiation-induced non-coding RNA (TINCR) or between TINCR and its downstream genes including miR-125b, HER-2 and Snail-1. In addition, a series of in vitro and in vivo assays were performed to assess the functions of TINCR. Results: An increase in both, IC50 value of trastuzumab and EMT was observed in the established trastuzumab-resistant cell lines. The expression level of TINCR was significantly increased in trastuzumab-resistant cells when compared with sensitive cells. Knockdown of TINCR reversed the trastuzumab resistance and the acquired EMT in these cells. TINCR was detected in the cytoplasm of breast cancer cells and could sponge miR-125b, thereby releasing HER-2 and inducing trastuzumab resistance. In addition, Snail-1 was found to be the target gene of miR-125b and overexpression of Snail-1 could reverse the suppressed migration, invasion, and EMT caused by TINCR silencing. The upregulation of TINCR in breast cancer was attributed to the CREB-binding protein (CBP)-mediated H3K27 acetylation at the promoter region of TINCR. Clinically, HER-2+ breast cancer patients with high TINCR expression levels were associated with poor response to trastuzumab therapy and shorter survival time. Conclusion: TINCR could promote trastuzumab resistance and the accompanied EMT process in breast cancer. Therefore, TINCR might be a potential indicator for prognosis and a therapeutic target to enhance the clinical efficacy of trastuzumab treatment. 

Retracted: No

PubPeer comments:
 This paper was criticised as part of a self-reflection posted on Twitter on 2nd-3rd April, 2021 (twitter TheHandLab status 1377760796130869248) Criticism: Along with another paper (10.1016 j.concog.2009.04.009), this paper made a relatively small point about two papers which used a method of analysing their data that broke some statistical assumptions (inverse effectiveness as regression-to-the-mean or double-dipping ). Eventually I wrote a much larger, more detailed paper (10.1007 s10548-009-0097-2), and in retrospect, these three papers should have been merged into a single, larger, comprehensive paper with a systematic review meta-analysis. ,