Abstract
BackgroundTriple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with highly invasive ability and metastatic nature to the lymph nodes. Long non-coding RNAs (lncRNAs) have been widely explored in cancer tumorigenesis and progression. However, their roles in TNBC lymph node metastasis remains rarely studied.MethodsThe expression of lncRNA highly upregulated in metastatic TNBC (HUMT) in cell lines and tissues was detected by quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). RNA immunoprecipitation (RIP) and RNA pulldown were used to verify the interaction between lncRNA and protein. Chromatin immunoprecipitation (CHIP) and dCas9-gRNA-guided chromatin immunoprecipitation (dCas9-CHIP) were conducted to identify the specific binding site of HUMT-YBX1 complex. Western blot was used to detect the downstream of HUMT.ResultsHUMT was significantly upregulated in lymph node invasive cells and predicted poorer clinical prognosis. Functional study indicated that HUMT promoted lymphangiogenesis and lymph node metastasis. Bioinformatic analysis and qRT-PCR showed that the high expression of HUMT was correlated with the hypomethylation status of its promoter region. Further, HUMT recruited Y-box binding protein 1 (YBX1) to form a novel transcription complex and activated the expression of forkhead box k1 (FOXK1), thus enhancing the expression of vascular endothelial growth factor C (VEGFC). The therapeutic value was further validated in patient-derived xenograft (PDX) models, and a combined marker panel exhibited a better prognostic value for TNBC in receiver operating characteristic (ROC) analysis.ConclusionsOur study identified a novel TNBC lymph node metastasis-associated lncRNA, which promoted TNBC progression and indicated a novel biomarker and potential therapeutic target for TNBC lymph node metastasis.
Highlights
Breast cancer is the most common cancer among women worldwide with increasing incidence [1, 2]
highly upregulated in metastatic Triple-negative breast cancer (TNBC) (HUMT) expression is significantly upregulated in cancer cells with lymph node-invasive nature and predicted poor prognosis To investigate the biological mechanism of TNBC lymph node metastasis, we grafted MDA-MB-231 and BT549 cells into the fat pads of nude mice and performed passages to screen highly lymph node-invasive cells in vivo (Fig. 1a, b)
To identify which biological change exerted an impact on triple-negative breast cancer lymph node metastasis, highly lymph node-invasive cells and parental cells were applied to genome-wide microarray in replicates (Fig. 1c)
Summary
Breast cancer is the most common cancer among women worldwide with increasing incidence [1, 2]. Triple-negative breast cancer (TNBC) is associated with poorer clinical outcomes and fewer treatments than any other molecular subtype, surgery and chemotherapy still remain as the only first-line regimens [3]. Representing only about 10–20% of breast cancers, TNBC is more invasive and malignant with a higher rate of lymph node metastasis and exhibited shorter median survival [4, 5]. Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with highly invasive ability and metastatic nature to the lymph nodes. Long non-coding RNAs (lncRNAs) have been widely explored in cancer tumorigenesis and progression. Their roles in TNBC lymph node metastasis remains rarely studied
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