These findings highlighted the possibility that manipulation of AS might provide a potential target for cancer treatment. Nowadays, growing evidence indicates that aberrations in AS are considered a molecular hallmark of cancer 20. Cancer cells often display aberrant AS profiles, which are associated with apoptosis 16, angiogenesis 17, migration 18, and drug resistance 19. Accumulating evidence has demonstrated that dysregulated AS contributed to malignant diseases, including cancer, especially breast cancer 13, 14, 15. Therefore, effective therapeutic targets are urgently identified.Īlternative splicing (AS) is a major mechanism for generating multiple structurally and functionally different proteins from a single gene, greatly expanding proteome diversity 12. However, the efficacy of second-line chemotherapy is limited by low response rates and short progression-free survival (PFS), leading to unchanged OS among TNBC patients over the past two decades 10, 11. Owing to the absence of effective targets, systematic chemotherapy remains the mainstay of TNBC patients 9. The 5-year overall survival (OS) rate is about 80% in Chinese women 7, 8. TNBC patients often have poor clinical outcomes due to the high risk of early relapse and visceral metastases within 5 years 6. This subtype represents 15–20% of all breast cancers in Chinese women 4 and is more common in patients with younger age, African-American race, and BRCA1 germline mutations 5. Triple-negative breast cancer (TNBC), defined by a lack of expression of estrogen receptor (ER), progesterone receptor (PR) expression, and human epidermal growth factor receptor 2 (HER2), is the most aggressive subtype among breast cancers 2, 3. 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.īreast 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 2020 1. 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. Furthermore, we demonstrated that MCPIP1 modulated NFIC AS to promote CTF5 synthesis, which acted as a negative regulator in TNBC cells.
Mechanistically, MCPIP1 was first demonstrated to act as a splicing factor to regulate AS in TNBC cells.
We demonstrated that MCPIP1 overexpression dramatically suppressed cell cycle progression and proliferation of TNBC cells in vitro and repressed tumor growth in vivo. 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. Monocyte chemotactic protein induced protein 1 (MCPIP1), a zinc finger RBP, functions as a tumor suppressor in many cancers. AS is generally controlled by AS-associated RNA binding proteins (RBPs). Recently, emerging evidence suggested that aberrant alternative splicing (AS) plays a crucial role in tumorigenesis and progression. 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.
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