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Hsa Circ 0005273 Facilitates Breast Cancer Tumorigenesis by Regulating

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Hsa Circ 0005273 Facilitates Breast Cancer Tumorigenesis by Regulating Wang et al. Journal of Experimental & Clinical Cancer Research (2021) 40:29 https://doi.org/10.1186/s13046-021-01830-z RESEARCH Open Access Hsa_circ_0005273 facilitates breast cancer tumorigenesis by regulating YAP1-hippo signaling pathway Xuehui Wang1,2†, Changle Ji1†, Jiashu Hu1, Xiaochong Deng1, Wenfang Zheng1, Yunhe Yu1, Kaiyao Hua1, Xiqian Zhou1 and Lin Fang1* Abstract Background: Circular RNAs (circRNAs), a novel class of endogenous RNAs, have shown to participate in the development of breast cancer (BC). Hsa_circ_0005273 is a circRNA generated from several exons of PTK2. However, the potential functional role of hsa_circ_0005273 in BC remains largely unknown. Here we aim to evaluate the role of hsa_circ_0005273 in BC. Methods: The expression level of hsa_circ_0005273 and miR-200a-3p were examined by RT-qPCR in BC tissues and cell lines. The effect of knocking down hsa_circ_0005273 in BC cell lines were evaluated by examinations of cell proliferation, migration and cell cycle. In addition, xenografts experiment in nude mice were performed to evaluate the effect of hsa_circ_0005273 in BC. RNA immunoprecipitation assay, RNA probe pull-down assay, luciferase reporter assay and fluorescence in situ hybridization were conducted to confirm the relationship between hsa_circ_ 0005273, miR-200a-3p and YAP1. Results: Hsa_circ_0005273 is over-expressed in BC tissues and cell lines, whereas miR-200a-3p expression is repressed. Depletion of hsa_circ_0005273 inhibited the progression of BC cells in vitro and in vivo, while overexpression of hsa_circ_0005273 exhibited the opposite effect. Importantly, hsa_circ_0005273 upregulated YAP1 expression and inactivated Hippo pathway via sponging miR-200a-3p to promote BC progression. Conclusions: Hsa_circ_0005273 regulates the miR-200a-3p/YAP1 axis and inactivates Hippo signaling pathway to promote BC progression, which may become a potential biomarker and therapeutic target. Keywords: hsa_circ_0005273, miR-200a-3p, YAP1, Hippo signaling pathway, Breast cancer Background recurrence and drug resistance are the significant rea- Breast cancer (BC) is the most commonly diagnosed ma- sons of cancer-associated deaths among breast cancer lignancy and the leading cause of cancer-related deaths patients. Therefore, further investigating the molecular in women [1]. Despite robust advances in surgical and mechanism of BC remains an urgent and difficult task. medical management in BC, the morbidity and mortality Circular RNAs (circRNAs), a novel class of endogen- are not decreasing [2]. Higher rates of metastasis, ous non-coding RNAs (ncRNAs), are formed from exons or introns through special selective shearing [3]. Unlike linear RNAs that are terminated with 5’caps and 3’tails, * Correspondence: [email protected] † circRNAs are single-stranded covalently closed circular Xuehui Wang and Changle Ji contributed equally to this work. 1Department of Thyroid and Breast Surgery, Shanghai Tenth People’s transcripts [4, 5], providing them higher ability to resist Hospital, School of Medicine, Tongji University, Shanghai 200072, China to environmental degradation [6]. Recent years, Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. Journal of Experimental & Clinical Cancer Research (2021) 40:29 Page 2 of 17 circRNAs have been proved as diagnostic biomarkers of relatives. The methodology of this study adhered to the hepatoblastoma [7] and bladder cancer [8] in blood or standards outlined in the Declaration of Helsinki. plasma according to their stability and tissue specificity [9, 10]. Aberrant expression of circRNAs are correlated Cell culture and transfection with the progression and prognosis of various cancers The human BC cell lines MDA-MB-231, MCF-7, HCC- [11]. Emerging evidence illustrated that circRNAs play 1937, SKBR3 and normal breast epithelial cell line MCF- key oncogenic or anti-cancer roles in multiple cancers, 10A were purchased from Chinese Academy of Sciences including BC. For example, circRNA_0025202 regulates (Shanghai, China). MDA-MB-231, MCF-7, HCC-1937 tamoxifen sensitivity and tumor progression via regulat- and SKBR3 cells were cultured in Dulbecco’s Modified ing FOXO3a [12]. CircFBXW7 inhibits the progression Eagle’s Medium (DMEM) (Gibco, USA) with 10% Fetal of TNBC through encoding a 185-aa Protein [13]. Bovine Serum (FBS) (Gibco, USA), penicillin (100 units/ Therefore, the potential function and molecular mecha- ml) and streptomycin (100 μg/ml) (Enpromise, China). nisms of circRNAs in BC need further investigation. MCF-10A cells were cultured in Mammary Epithelial Hippo signaling pathway, a highly conserved pathway, Basal Medium (MEBM) (Cambrex, USA). All these cells performs an important role in governing cell prolifera- were cultured at 37 °C with 5% CO2. Small, interfering, tion and apoptosis of various cancer types, especially in specifically targeting human hsa_circ_0005273 (si-circ_ BC. The dysregulation and inactivation of Hippo path- 0005273), non-specific negative control oligos (si-NC) way always result in cancer initiation and progression and hsa_circ_0005273 lentiviral plasmid (lv-circ_ [14]. YAP1 (yes-associated protein), a downstream gene 0005273) were purchased from IBSBio (Shanghai, of Hippo signaling pathway, is a significant oncogene in China). Human miR-200a-3p-mimics, non-specific nega- BC [15, 16]. Inhibiting the activity of YAP1 could re- tive control (miR-200a-3p-NC) and miR-200a-3p inhibi- strain vascular invasiveness of BC cells [17]. Since the tor were purchased from RiboBio (Guangzhou, China). mutation, activation and overexpression of YAP1 are re- MDA-MB-231, MCF-7 and SKBR3 cells were cultured lated to the occurrence and progression of BC, finding a and transfected with reagents above using Lipofecta- new molecule that could suppress YAP1 is imperative. mine® 2000 (Invitrogen; Thermo Fisher Scientific, USA) In this research, we identified hsa_circ_0005273, a cir- according to the manufacturer’s instructions. We used cRNA of Protein Tyrosine Kinase 2 (PTK2), was signifi- DNA Midiprep Kits (Qiagen, Hilden, Germany) to pre- cantly high-expressed in BC tissues and cell lines. pare plasmid vectors. A lentivirus carrying si-circ_ Importantly, hsa_circ_0005273 exerted its oncogenic 0005273 was constructed by ZORIN (Shanghai, China) role in BC via acting as a sponge of tumor suppressor and transfection procedures were performed according miR-200a-3p to inactivate YAP1-Hippo signaling path- to the manufacturer’s instructions. way in vivo and in vitro. Our findings provided new in- sights into the diagnosis and treatment of BC. RNA extraction and RT-qPCR Total RNA was extracted from frozen tissues and cul- tured cells by Trizol reagent (Invitrogen, Carlsbad, CA, Materials and methods USA) and the concentration and purity of RNA samples CircRNA expression profiling analysis was assessed with a Nanodrop 2000 spectrophotometer CircRNAs expression dataset of BC were downloaded (Thermo Fisher Scientific, USA). cDNA was synthesized from NCBI GEO database (https://www.ncbi.nlm.nih. by a commercial cDNA synthesis kit (Takara Biotechnol- gov/geo/) and analyzed using the GEO2R (http://www. ogy, Dalian, China). We conducted quantitative real- ncbi.nlm.nih.gov/geo/geo2r/) to show different circRNAs time polymerase chain reaction (RT-qPCR) by using the expression. SYBR Green PCR Kit (Takara Biotechnology, Dalian, China) and primer sequences were designed and synthe- Tissue samples sized by RiboBio (Guangzhou, China). Expression of cir- Tumor tissues and their adjacent normal tissues of 120 cRNA, miRNA and mRNA were assessed by threshold ΔΔ BC patients were collected from the Department of cycle (CT) values and analyzed using the 2- Ct method. Breast and Thyroid Surgery of Shanghai Tenth People’s Primers and siRNAs designed in this study are shown in Hospital of Tongji University (Shanghai, China). None of supplemental Table S1. the patients received any local or systemic treatment be- fore surgery and all tissue specimens were immediately Confirming specificity for hsa_circ_0005273 snap-frozen in liquid nitrogen until further use. Our PCR products amplified by primers were separated on study protocols were approved by Institutional Ethics 1% agarose gel to verify the specificity of the hsa_circ_ Committees of Shanghai Tenth People’s Hospital and in- 0005273 PCR products. Sanger sequencing was per- formed consent was obtained from all patients or their formed to validate the sequence
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