Effect of miR-146a-5p on proliferation and metastasis of triple-negative breast cancer via regulation of SOX5

Abstract

Abstract. MicroRNA (miR)-146a-5p functions as a tumor suppressor in various types of cancer. However, the role of miR-146a-5p in the development of triple-negative breast cancer (TNBC) is unclear. The present study aimed to investigate the role of miR-146a-5p in TNBC. The expression level of miR-146a-5p in TNBC tissues and cell lines was initially detected using reverse transcription-quantitative polymerase chain reaction. To predict the target gene of miR-146a-5p, TargetScan software was used and a dual luciferase assay was performed to verify the prediction. Furthermore, in order to explore the role of miR-146a-5p in TNBC, miR-146a-5p was overexpressed in TNBC cells using miR-146a-5p mimics. An MTT assay was performed to detect cell proliferation, and a Transwell assay was conducted to determine cell migration and invasion. Furthermore, western blotting was performed to measure associated protein expression. It was revealed that miR-146a-5p was downregulated in TNBC tissues and cell lines. SOX5 was indicated to be a target gene of miR-146a-5p and was upregulated in TNBC cells. Additionally, miR-146a-5p could inhibit TNBC cell proliferation, migration and invasion, repress the expression of mesenchymal markers (N-cadherin, vimentin and fibronectin) and increase epithelial marker (E-cadherin) expression. Furthermore, SOX5 overexpression eliminated the effects of miR-146a-5p mimics on TNBC cells. In conclusion, the data of the present study indicated that miR-146a-5p inhibits the proliferation and metastasis of TNBC cells by regulating SOX5.

MicroRNA-based potential diagnostic, prognostic and therapeutic applications in triple-negative breast cancer

“…The miR-199a-5p expression is significantly reduced in TNBC patients in comparison with other patients with non-TNBC breast cancer and a healthy group [42]. Also, other studies demonstrated that miR-199a-5p was associated with early stages of TNBC and miR-199a-5p may be a diagnostically valuable TNBC-specific marker in a large number of patients [43,89]. Savad et al showed that miR-205 and miR-342 expressions were significantly down-regulated in the TNBC group compared to other BC groups in 59 patients with breast cancer.…”

“…Metastasis is a process in which tumor cell breaks away from the original site and travels through the blood or lymphatic system to the other parts of the body and form new tumors. Some miRNAs such as miR-146a-5p, miR-26a, miR-136 and miR-136 have been proved to inhibit the expression of numerous cancer-related genes that subsequently suppress metastasis in TNBC [43][44][45].…”

MicroRNAs Involved in Carcinogenesis, Prognosis, Therapeutic Resistance, and Applications in Human Triple-Negative Breast Cancer

“…Furthermore, the miR-181a was involved in TNBC metastasis via elevated expression of Bim [72]. [115,116] miR-373 TXNIP Induces cancer cell EMT and metastasis [117,118] miR-10b HOXD10 Promotes invasion and metastasis [119] miR-21 PTEN Lymph node metastasis [120] miR-17/92 cluster COL4A3, LAMA3, TIMP2/3 Lymph node metastases, promote metastasis [121,122] miR-629-3p LIFR Lung metastases [123] miR-455-3p EI24 Promotes proliferation, invasion, and migration [124] miR-125b APC Promotes proliferation, metastasis, and EMT [125] miR-181a Bim Promotes EMT, migratory, and invasive [72] Oncosuppressor miRNAs miR-200a/b/c PKCα, UBASH3B, XIAP Suppress proliferation, migration, invasion, and metastasis, promote apoptosis [77,126,127] miR-205 Unknown Lymph node metastasis [128] let-7 RAS, c-Myc Block growth and reduce metastasis [129] miR-145 MUC1, Arf6, JAM-A, Fascin Reduce cell motility, invasiveness, and metastasis [130][131][132] miR-206 CORO1C Regulates metastasis [133] miR-30a ROR1 Associates with high histological grade and more lymph node metastasis [134] miR-190a/940 Unknown Prevents metastasis and cell invasion [19,135] miR-33b HMGA2, SALL4, Twist1 Inhibit metastasis [114] miR-146a-5p SOX5 Inhibits proliferation and metastasis [136] miR-150 HMGA2 Inhibits metastasis [137] miR-124 ZEB2 Inhibits invasion and metastasis [138] miR-148a WNT1, NRP1 Suppress metastasis [139] miR-126-3p RGS3 Inhibits proliferation, migration, invasion, and angiogenesis [140] miR-508-3p ZEB1 Inhibits cell invasion and EMT [141] miR-613 Daam1 Inhibits cell migration and invasion [142] miR-519d-3p LIMK1 Suppresses growth and mot...…”

“…MiR-190a and miR-940 were also significantly reduced in TNBC tissues to prevent metastasis and cell invasion [19,135]. Additionally, several miRNAs function as oncosuppressor miRNAs involved in metastasis of TNBC, such as miR-33b [114], miR-146a-5p [136], miR-150 [137], miR-124 [138] and miR-148a [139], miR-126-3p [140], miR-508-3p [141], miR-613 [142], miR-519d-3p [143], miR-26a [144], and miR-130a [145], by targeting HMGA2, SALL4 and Twist1, SRY-box transcription factor 5 (SOX5), HMGA2, ZEB2, wnt family member 1 (WNT1) and neuropilin 1 (NRP1), the regulator of G-protein signaling 3 (RGS3), ZEB1, disheveled-associated activator of morphogenesis 1 (Daam1), LIM domain kinase 1 (LIMK1), metadherin (MTDH), FOSL1, and zonula occludens 1 (ZO-1, also called TJP1), respectively.…”

“…Overexpression of miR-1301 suppresses TNBC cell proliferation, migration, and colony formation in vivo and in vitro by binding to the 3 -UTR of enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) [159]. Additionally, some other miRNAs with tumor suppressor properties include miR-146a-5p [136], miR-26a [144], miR-490-3p [160], miR-143-3p [161], miR-17-5p [162], miR-539 [163], miR-125b [164], miR-217 [165], and miR-589 [166], which are downregulated and involved in suppressing tumor cell proliferation in TNBC by targeting different oncogenes. [152,153] miR-200c XIAP Inhibits proliferation, induces apoptosis [126] miR-34a Notch-1, ErbB2, c-SRC Inhibit cell growth and invasion, activate senescence, sensitize to dasatinib [154][155][156] miR-940 ZNF24 Inhibits cell proliferation and migration [157] miR-211-5p SETBP1 Inhibits cell proliferation and migration [158] miR-1301 EZH2 Suppresses proliferation, migration, and colony formation [159] miR-146a-5p SOX5 Inhibits the proliferation and metastasis [136] miR-26a MTDH Suppresses tumor proliferation and metastasis [144] miR-490-3p TNKS2 Inhibits the growth and invasiveness [160] miR-143-3p LIMK1 Suppresses the growth [161] miR-17-5p ETV1 Suppresses cell proliferation and invasion [162] miR-539 LAMA4 Inhibits proliferation and migration [163] miR-125b MAP2K7 Inhibits proliferation [164] miR-217 KLF5 Inhibits cell growth, migration [165] miR-589 MTA2 Decreases cell proliferation, migration, and invasion [166]…”