Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype with the worst prognosis and the highest metastatic and recurrence potential, which represents 15–20% of all breast cancers in Chinese females, and the 5-year overall survival rate is about 80% in Chinese women. Recently, emerging evidence suggested that aberrant alternative splicing (AS) plays a crucial role in tumorigenesis and progression. AS is generally controlled by AS-associated RNA binding proteins (RBPs). Monocyte chemotactic protein induced protein 1 (MCPIP1), a zinc finger RBP, functions as a tumor suppressor in many cancers. Here, we showed that MCPIP1 was downregulated in 80 TNBC tissues and five TNBC cell lines compared to adjacent paracancerous tissues and one human immortalized breast epithelial cell line, while its high expression levels were associated with increased overall survival in TNBC patients. We demonstrated that MCPIP1 overexpression dramatically suppressed cell cycle progression and proliferation of TNBC cells in vitro and repressed tumor growth in vivo. Mechanistically, MCPIP1 was first demonstrated to act as a splicing factor to regulate AS in TNBC cells. Furthermore, we demonstrated that MCPIP1 modulated NFIC AS to promote CTF5 synthesis, which acted as a negative regulator in TNBC cells. Subsequently, we showed that CTF5 participated in MCPIP1-mediated antiproliferative effect by transcriptionally repressing cyclin D1 expression, as well as downregulating its downstream signaling targets p-Rb and E2F1. Conclusively, our findings provided novel insights into the anti-oncogenic mechanism of MCPIP1, suggesting that MCPIP1 could serve as an alternative treatment target in TNBC.
Highlights
Breast cancer is the most common malignancy and the fourth leading cause of cancer-related deaths among women in China, accounting for 19.9% of all cancer diagnosed and 9.9% of all cancer-associated deaths in females in 20201
We first analyzed Monocyte chemotactic protein induced protein 1 (MCPIP1) expression levels using the data available from the Cancer Genome Atlas (TCGA) database, which revealed that MCPIP1 expression was markedly downregulated in Triple-negative breast cancer (TNBC) tissues compared to the corresponding normal samples (Fig. 1A)
Our findings revealed that MCPIP1 was downregulated in TNBC tissues and cell lines, which exhibited an antiproliferative role through inducing cell cycle arrest at the G0/ G1 stage
Summary
Breast cancer is the most common malignancy and the fourth leading cause of cancer-related deaths among women in China, accounting for 19.9% of all cancer diagnosed and 9.9% of all cancer-associated deaths in females in 20201. Triple-negative breast cancer (TNBC), defined by a lack of expression of estrogen receptor (ER), Official journal of the Cell Death Differentiation Association. Accumulating evidence has demonstrated that dysregulated AS contributed to malignant diseases, including cancer, especially breast cancer[13,14,15]. Cancer cells often display aberrant AS profiles, which are associated with apoptosis[16], angiogenesis[17], migration[18], and drug resistance[19]. Nowadays, growing evidence indicates that aberrations in AS are considered a molecular hallmark of cancer[20]. These findings highlighted the possibility that manipulation of AS might provide a potential target for cancer treatment
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