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Long Non‑Coding RNA TMPO‑AS1 Facilitates Chemoresistance and Invasion in Breast Cancer by Modulating the Mir‑1179/TRIM37 Axis

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Long Non‑Coding RNA TMPO‑AS1 Facilitates Chemoresistance and Invasion in Breast Cancer by Modulating the Mir‑1179/TRIM37 Axis ONCOLOGY LETTERS 22: 500, 2021 Long non‑coding RNA TMPO‑AS1 facilitates chemoresistance and invasion in breast cancer by modulating the miR‑1179/TRIM37 axis XIAOJIE NING, JIANGUO ZHAO, FAN HE, YUAN YUAN, BIN LI and JIAN RUAN Department of Thyroid and Breast Surgery, Wuhan Number 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China Received December 3, 2019; Accepted March 8, 2021 DOI: 10.3892/ol.2021.12761 Abstract. Breast cancer has become the most common Introduction female tumor in the world. Although great progress has been made in the past decade, the treatment of advanced Breast cancer is one of the most commonly diagnosed cancer breast cancer remains unsatisfactory. An increasing number among women and the fifth cause of cancer‑associated of reports have indicated that long non‑coding RNAs death worldwide (1). Although systemic therapies, including (lncRNAs) have a pivotal role in chemoresistance as poten‑ surgery, chemo/radiotherapy and targeted therapy, lead to tial oncogenes in numerous types of cancer. However, the marked improvements in clinical outcome, the survival rates precise mechanisms underlying the action of lncRNAs in of patients with breast cancer remain unsatisfactory in devel‑ breast cancer resistance to chemotherapy have yet to be fully oping countries, considering that breast cancer in developing elucidated. In the present study, the function and molecular countries accounts for 50% of all breast cancer cases and mechanisms of the lncRNA TMPO‑antisense RNA 1 (AS1) 62% of cancer‑associated deaths (2). Docetaxel (DOC), an in terms of its resistance to docetaxel (DOC) were explored effective chemotherapeutic drug, is indispensable for standard in the MDA‑MB‑231 and MCF7 breast cancer cell lines. treatment in breast cancer, according to the latest National The results obtained suggested that TMPO‑AS1 was mark‑ Comprehensive Cancer Network guidelines (3). However, edly upregulated in DOC‑resistant breast cancer cells the presence of chemoresistance is considered as one of the compared with the sensitive breast cancer cells. Functionally, barriers that leads to poor efficacy (4). Therefore, it is impera‑ TMPO‑AS1‑knockdown sensitized MDA‑231/DOC and tive to gain a deeper understanding of the key molecular MCF‑7/DOC cells to DOC and suppressed cell invasion, with mechanisms associated with chemoresistance in breast cancer. increased rates of DOC‑induced apoptosis. Mechanistically, Long non‑coding RNAs (lncRNAs) are a class of TMPO‑AS1‑downregulation induced DOC‑sensitivity in non‑coding RNAs >200 nucleotides in length (5). Evidence has breast cancer cells via depleting tripartite motif‑containing indicated that lncRNAs have a critical role in tumorigenesis, protein 37 (TRIM37) by sponging microRNA (miR)‑1179. serving either as oncogenes or tumor suppressors in different Taken together, the present study has revealed the existence types of cancer, such as gastric, liver and colon cancer (6,7). In of a novel TMPO‑AS1/miR‑1179/TRIM37 molecular axis addition, lncRNAs are also associated with chemoresistance conferring DOC resistance of breast cancer cells, thereby of tumors (8). For example, the lncRNA Colorectal Neoplasia suggesting a promising novel therapeutic target for breast Differentially Expressed has been shown to facilitate colorectal cancer. cancer chemoresistance through the Wnt/β‑catenin signaling pathway (9). Metastasis‑associated lung adenocarcinoma transcript 1 modulates autophagy‑associated chemoresistance in gastric cancer (10), whereas the lncRNA Urothelial Cancer Associated 1 promotes cisplatin resistance in oral squamous cell carcinoma by inhibiting miR‑184 (11). There are numerous different forms of lncRNAs that are Correspondence to: Dr Jian Ruan, Department of Thyroid and Breast Surgery, Wuhan Number 1 Hospital, Tongji Medical College, involved in the processes of biological regulation, including Huazhong University of Science and Technology, 215 Zhongshan cell proliferation, apoptosis and cell cycle regulation, among Avenue, Wuhan, Hubei 430022, P.R. China which antisense (AS) lncRNA is usually reverse‑transcribed E‑mail: [email protected] from the corresponding gene (7). TMPO‑AS1, located on chromosome 12, was previously identified in human lung Key words: TMPO‑AS1, tripartite motif‑containing protein 37, cancer (12). Emerging evidence has indicated that TMPO‑AS1 chemoresistance, miR‑1179 could act as an indicator of the prognosis of patients with lung cancer through regulation of the cell cycle and cell adhe‑ sion (13). Another study demonstrated that TMPO‑AS1 served 2 NING et al: TMPO‑AS1 PROMOTES CHEMORESISTANCE AND INVASION IN BREAST CANCER an oncogenic role and may be a potentially novel prognostic machine (Applied Biosystems; Thermo Fisher Scientific, Inc.) biomarker as well as a therapeutic target in prostate cancer (14). with the SYBR Green reaction mix (Applied Biosystems; However, the function and mechanism of TMPO‑AS1 in DOC Thermo Fisher Scientific, Inc.).β ‑actin was used as the internal resistance and invasion in breast cancer cells has yet to be fully reference of lncRNA and mRNA qPCR, while U6 as the elucidated. In addition, tripartite motif‑containing protein 37 internal reference of miRNA. Primers for TMPO‑AS1 were (TRIM37) has been shown to be involved in the development as follows: Forward, 5'‑AGC CCA CAC ACT ACA GGC A‑3' of breast cancer (15), but the role of TRIM37 in breast cancer and reverse, 5'‑GCA CAA AAG CAG TAC GAC CT‑3'. Primers chemotherapy is unclear. for miR‑1179 as follows: Forward, 5'‑AAG CAT TCT TTC ATT The purpose of the present study was to investigate the GGT TGG A‑3' and reverse CTC TAC AGC TAT ATT GCC AGC association between TMPO‑AS1 and breast cancer drug CAC. Primers for U6 were: Forward, 5'‑TGC GGG TGC TCG resistance, and to identify the key targets and molecular axes CTT CGG CAG C‑3' and reverse 5'‑GTG CAG GGT CCG AGG of TMPO‑AS1 affecting breast chemotherapy resistance. T‑3'. Primers for β‑actin were: Forward, 5'‑CCT CTC CCA AGT The current findings may provide novel insights into the CCA CAC AG‑3' and reverse, 5'‑GGG CAC GAA GGC TCA TCA mechanism in which breast cancer acquires chemoresistance, TT‑3'. Primers for TRIM37 were: Forward, 5'‑TGG ACT TAC facilitating the development of novel therapeutical drugs for TCG CAA ATG‑3' and reverse: 5'‑ATC TGG TGG TGA CAA breast cancer. ATC‑3'. The following thermocycling conditions were used for PCR: Pre‑denaturation at 93˚C for 15 sec, then denaturation at Materials and methods 90˚C for 25 sec, annealing at 58˚C for 25 sec and extension at 72˚C for 30 sec for 35 cycles. The 2‑ΔΔCq method was used to Cell lines and cell culture. Breast cancer cell lines analyze gene expression levels (16). (MDA‑MB‑231 and MCF7 cell lines) were acquired from The Cell Bank of Type Culture Collection of The Chinese Academy DOC‑resistance analysis. In vitro cancer cell proliferation of Sciences. Cells were treated with increasing concentrations was detected using a Cell Counting Kit‑8 (CCK‑8) assay. of DOC (20‑1,000 nM) for 48 h. The surviving DOC‑resistant Briefly, the proliferation of non‑DOC‑treated cancer cells sublines, MDA‑231/DOC and MCF‑7/DOC, were established was regarded as the 100% standard. MDA‑231/DOC and successfully. The cells cultured in DMEM medium (Nanjing MCF‑7/DOC cells were processed with various concen‑ KeyGen Biotech. Co., Ltd.) were supplemented with 10% fetal trations of DOC in order to determine the half‑maximal bovine serum (FBS) (Gibco; Thermo Fisher Scientific, Inc.) at inhibitory concentration (the IC50 value). Subsequently, 37˚C in a humidified atmosphere of 5% CO2. following incubation at room temperature for 48 h, cell viability was detected with CCK‑8 (Dojindo Molecular Cell transfection. pcDNA3.1‑TMPO‑AS1, pcDNA3.1‑TRIM37 Technologies, Inc.), following the manufacturer's instruc‑ and empty vector plasmids (2 µg used for transfection) were tions. The absorbance of the breast cancer cells was acquired from GeneCopoeia, Inc. In total, three siRNAs measured at 450 nm using a microplate reader (Bio‑Rad specifically targeting TMPO‑AS1 (10 nM; si‑TMPO‑AS1 #1, Laboratories, Inc.). 5'‑CCG CCA AAC GCC CGC CTT T‑3'; si‑TMPO‑AS1 #2, 5 ' ‑ A G G TAG AAA CGC AGT TTA A‑3'; and si‑TMPO‑AS1 # 3 , Western blot analysis. The cancer cells were first lysed in 5'‑GAG CCG AAC UAC GAA CCA ATT‑3') or TRIM37 (10 nM; RIPA buffer incubated with cocktail protease inhibitors si‑TRIM37, 5'‑GGA GAA GAT TCA GAA TGA A‑3') and scram‑ (both from Beyotime Institute of Biotechnology) in order to bled siRNA negative control (10 nM; si‑NC, 5'‑UUC UCC extract the total protein. Subsequently, proteins (30 µg/lane) GAA CGU GUC ACG U‑3'), miR‑1179 mimic (10 nM; 5'‑AAG were separated via 10% SDS‑PAGE and then blotted onto a CAU UCU UUC AUU GGU UGG‑3'), scrambled miRNA PVDF membrane (EMD Millipore). Subsequently, the PVDF control (10 nM; miR‑NC, 5'‑AGG TAG AAA CGC AGT TTA membrane was probed with primary antibodies (anti‑TRIM37, A‑3'), miR‑1179 inhibitor (10 nM; miR‑inhibitor, 5'‑CAG dilution 1:1,000; Abcam) was incubated at 4˚C overnight. The UAC UUU UGU GUA GUA CAA‑3') and scrambled inhibitor membrane was then incubated with the HRP‑conjugated goat control (10 nM; inhibitor‑NC, 5'‑CAG UAC UUU UGU GUA anti‑rabbit IgG secondary antibody (1:1,000; cat. no. ab205718; GUA CAA‑3') were acquired from Shanghai GenePharma Abcam) at room temperature for 2 h. Finally, blots were Co., Ltd. All transfection processes were performed with detected and visualized with an ECL detection kit (Santa Cruz Lipofectamine® 2000 (Invitrogen; Thermo Fisher Scientific, Biotechnology, Inc.). Inc.) at 37˚C for 48 h according to the manufacturer's instruc‑ tions.
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