Background Understanding the molecular alterations associated with breast cancer (BC) progression may lead to more effective strategies for both prevention and management. The current model of BC progression suggests a linear, multistep process from normal epithelial to atypical ductal hyperplasia (ADH), to ductal carcinoma in situ (DCIS), and then invasive ductal carcinoma (IDC). Up to 20% ADH and 40% DCIS lesions progress to invasive BC if left untreated. Deciphering the molecular mechanisms during BC progression is therefore crucial to prevent over- or under-treatment. Our previous work demonstrated that miR-671-5p serves as a tumor suppressor by targeting Forkhead box protein M1 (FOXM1)-mediated epithelial-to-mesenchymal transition (EMT) in BC. Here, we aim to explore the role of miR-671-5p in the progression of BC oncogenic transformation and treatment. Methods The 21T series cell lines, which were originally derived from the same patient with metastatic BC, including normal epithelia (H16N2), ADH (21PT), primary DCIS (21NT), and cells derived from pleural effusion of lung metastasis (21MT), and human BC specimens were used. Microdissection, miRNA transfection, dual-luciferase, radio- and chemosensitivity, and host-cell reactivation (HCR) assays were performed. Results Expression of miR-671-5p displays a gradual dynamic decrease from ADH, to DCIS, and to IDC. Interestingly, the decreased expression of miR-671-5p detected in ADH coexisted with advanced lesions, such as DCIS and/or IDC (cADH), but not in simple ADH (sADH). Ectopic transfection of miR-671-5p significantly inhibited cell proliferation in 21NT (DCIS) and 21MT (IDC), but not in H16N2 (normal) and 21PT (ADH) cell lines. At the same time, the effect exhibited in time- and dose-dependent manner. Interestingly, miR-671-5p significantly suppressed invasion in 21PT, 21NT, and 21MT cell lines. Furthermore, miR-671-5p suppressed FOXM1-mediated EMT in all 21T cell lines. In addition, miR-671-5p sensitizes these cell lines to UV and chemotherapeutic exposure by reducing the DNA repair capability. Conclusions miR-671-5p displays a dynamic decrease expression during the oncogenic transition of BC by suppressing FOXM1-mediated EMT and DNA repair. Therefore, miR-671-5p may serve as a novel biomarker for early BC detection as well as a therapeutic target for BC management. Electronic supplementary material The online version of this article (10.1186/s13058-019-1173-5) contains supplementary material, which is available to authorized users.
Esophageal cancer (EC) is a lethal cancer with an extremely aggressive nature and poor survival rate. However, the molecular mechanisms driving the occurrence and progression of EC are not well understood. MicroRNAs (miRNAs) are small RNA molecules that regulate the expression of protein-coding genes. miRNA-mediated gene regulation plays an important role in EC. By cross-referencing studies from NCBI, we found that microRNA-375 (miR-375) is one of the most frequently downregulated miRNAs in EC. We assessed expression of miR-375 in EC cell lines and primary EC tissues and their matched normal tissues. We found significant downregulation of miR-375 in both cell lines and EC tissues. Forced expression of miR-375 attenuated EC cell proliferation and invasion. Human epidermal growth factor receptor 2 (HER2, ERBB2), a known proto-oncogene, was identified here as one of the potential target genes of miR-375. Ectopic expression of miR-375 significantly suppressed the expression of ERBB2 and subsequently downregulated one of its target genes, vascular endothelial growth factor A (VEGFA), which is related to cancer invasion and metastasis. These findings suggest that miR-375 acts as a tumor suppressor by blocking the ERBB2/VEGFA pathway with the potential to modulate the occurrence and/ or progression of EC.
Lichen sclerosus (LS) is a chronic inflammatory skin disorder with unknown pathogenesis. The aberrant expression of microRNAs (miRNAs) is considered to exert a crucial role in LS. We used the next-generation sequencing technology (RNASeq) for miRNA profiling and Ingenuity Pathway Analysis (IPA) for molecular network analysis. We performed qRT-PCR, miRNA transfection and Matrigel assays for functional studies. We identified a total of 170 differentially expressed miRNAs between female LS and matched adjacent normal tissue using RNASeq, with 119 upregulated and 51 downregulated. Bioinformatics analysis revealed molecular networks that may shed light on the pathogenesis of LS. We verified the expression of a set of miRNAs that are related to autoimmunity, such as upregulated miR-326, miR-142-5p, miR-155 and downregulated miR-664a-3p and miR-181a-3p in LS tissue compared to the matched adjacent normal tissue. The differentially expressed miRNAs were also verified in blood samples from LS patients compared to healthy female volunteers. Functional studies demonstrated that a forced expression of miR-142-5p in human dermal fibroblast PCS-201-010 cells resulted in decreased cell proliferation and migration. These findings suggest that differentially expressed miRNAs may play an important role in LS pathogenesis; therefore, they could serve as biomarkers for LS management.
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is negative for estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2). It is typically associated with high rate of metastasis and limited targeted treatment options. Chemotherapy is the standard treatment for metastatic TNBC. However, the development of chemoresistance limits its clinical application. Elevated expression of immune-related genes in TNBC suggests that immunotherapy strategies may provide new therapeutic options for TNBC. Programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors have been approved by the FDA for TNBC treatment. However, tumor immune evasion is considered an important obstacle. BRCA1 is a nuclear-cytoplasmic shuttling protein that plays a key role in preventing the development of a malignant phenotype. BRCA1 dysregulation and nuclear export are an important mechanism in cancer development and chemoresistance, especially in TNBC. Blocking BRCA1 nuclear export could be used as a strategy to prevent resistance. BRCA1 nuclear export has been reported to be mediated by several proteins such as BRCA1-binding protein 2 (BRAP2) and chromosomal maintenance 1 (CRM1, also known as exportin 1, XPO1). CRM1-mediated events have been implicated in breast cancer and involved in chemoimmunotherapy. microRNA-200b (miR-200b) is a cell-autonomous suppressor of EMT (epithelial-mesenchymal transition) and involved in tumor metastasis. In our present work, we discovered that miR-200b overexpression resulted in significant BRCA1 nuclear retention accompanied by downregulated expression of CRM1 and STAT1 (signal transducer and activator of transcription 1). Bioinformatics analysis indicated that miR-200b directly targets STAT1, which was confirmed by luciferase assay. We demonstrated that STAT1 is a transcription factor (TF) of CRM1, by both Transfac analysis and chromatin immunoprecipitation (ChIP)-qPCR assay. In patient tissue samples, we found that miR-200b expression was relatively lower in TNBC compared to non-TNBCs. Furthermore, we demonstrated that miR-200b-mediated BRCA1 nuclear retention is associated with significant PD-L1 downregulation, and sensitizes the TNBC cells to chemotherapeutic agents. In addition, high level PD-L1 expression is associated with not only chemoimmunoresistance but also tumor metastasis. These data provide strong evidence that miR-200b-mediated regulation of BRCA1 nucleus retention is through transcriptional regulation of CRM1 by STAT1, and miR-200b regulates PD-L1 expression in TNBC. In conclusion, this novel dual role of miR-200b may serve as a strategy in metastatic TNBC therapy by repressing STAT1-mediated CRM1 transcription regulation, and reversing the chemoimmunoresistance via PD-L1 inhibition. Citation Format: Xiaohui Tan, Shuchang Ren, Woojin Lee, Xiaoling Wu, Katayoon Rezaei, Yan-gao Man, Patricia Latham, Robert S. Siegel1, Rachel F. Brem, Zhongwu Li, Xiaofeng Chang, Sidney W. Fu. Dual functions of miR-200b in triple-negative breast cancer metastasis and chemoimmuno-resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 498.
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