Abstract
Circular RNAs (circRNAs) are increasingly gaining importance and attention due to their diverse potential functions and their value as diagnostic biomarkers (disease specific). This study aims to explore the novel mechanisms by which exosome-contained circRNAs promote tumor development and metastasis in TNBC. We identified increased circRNA circPSMA1 in TNBC cells, their exosomes, and serum exosomes samples from TNBC patients. The overexpression of circPSMA1 promoted TNBC cell proliferation, migration, and metastasis both in vitro and in vivo. Moreover, we investigated the tumor-infiltrating immune cells (TICs) or stromal components in immune microenvironment (IME), and identified the significant differences in the immune cells between TNBC and non-TNBC samples. Mechanistically, circPSMA1 acted as a “miRNAs sponge” to absorb miR-637; miR-637 inhibited TNBC cell migration and metastasis by directly targeted Akt1, which recognized as a key immune-related gene and affected downstream genes β-catenin and cyclin D1. Subsequent co-culture experiments also demonstrated that exosomes from TNBC carrying large amounts of circPSMA1 could transmit migration and proliferation capacity to recipient cells. Kaplan–Meier plots showed that high expression of Akt1 and low expression of mir-637 are highly correlated with poor prognosis in patients with lymph node metastasis of TNBC. Collectively, all these results reveal that circPSMA1 functions as a tumor promoter through the circPSMA1/miR-637/Akt1-β-catenin (cyclin D1) regulatory axis, which can facilitate the tumorigenesis, metastasis, and immunosuppression of TNBC. Our research proposes a fresh perspective on novel potential biomarkers and immune treatment strategies for TNBC.
Highlights
Aside from skin cancer, breast cancer is the most common cancer among women, and it is the second leading cause of cancer-related death among women in Official journal of the Cell Death Differentiation AssociationYang et al Cell Death and Disease (2021)12:420Exosomes are small membrane-bound vesicles with sizes ranging from 30 to 100 nm[3] that contain informational molecules such as proteins, mRNA, and lipids
CircPSMA1 is upregulated in triple-negative breast cancer (TNBC) cells and their exosomes and in TNBC patients To understand the expression profiles of circRNAs in TNBC, we profiled the circRNAs in MDA-MB-231 cells (TNBC cell line) and their exosomes and compared them with the profiles in MCF-7 cells and their exosomes[17]
We found that the expression of circPSMA1 was significantly upregulated in MDA-MB-231 cells and their exosomes compared with MCF/7 cells and their exosomes
Summary
Aside from skin cancer, breast cancer is the most common cancer among women, and it is the second leading cause of cancer-related death among women in Official journal of the Cell Death Differentiation AssociationYang et al Cell Death and Disease (2021)12:420Exosomes are small membrane-bound vesicles with sizes ranging from 30 to 100 nm[3] that contain informational molecules such as proteins, mRNA, and lipids. Exosomes are well known by the “exosomal shuttle” that delivers oncogenic microRNAs (miRNAs), mRNAs, noncoding RNAs, and proteins to the recipient cells and tumor microenvironment[4,5]. With the development of biotechnology and high-throughput sequencing technology, circRNAs are regarded as abundant, diverse, and conserved molecules that act as pivotal regulators of many biological processes[11]. Some circRNAs were identified as tumor oncogenes in the progression of breast cancer[14,15,16], few studies have found a relationship between circRNA and TNBC. We profiled the circRNAs in breast cancer cell lines and their exosomes by RNA sequencing and showed that circPSMA1 might act as an oncogenic gene in TNBC progression. CircPSMA1 could be a valuable marker and an independent prognostic factor for TNBC diagnosis and therapy
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