ABSTRACT
AIMS: The RNA-binding protein LSM7 is essential for RNA splicing, acting as a key component of the spliceosome complex; however, its specific role in breast cancer (BC) has not been extensively investigated. MATERIALS AND METHODS: LSM7 expression in BC samples was evaluated through bioinformatics analysis and immunohistochemistry. The impact of LSM7 on promoting metastatic tumor characteristics was examined using transwell and wound healing assays, as well as an orthotopic xenograft model. Additionally, the involvement of LSM7 in alternative splicing of CD44 was explored via RNA immunoprecipitation and third-generation sequencing. The regulatory role of TCF3 in modulating LSM7 gene expression was further elucidated using luciferase reporter assays and chromatin immunoprecipitation. KEY FINDINGS: Our findings demonstrate that LSM7 was significantly overexpressed in metastatic BC tissues and was associated with poor prognostic outcomes in patients with BC. LSM7 overexpression markedly increased the migratory and invasive capabilities of BC cells in vitro and significantly promoted spontaneous lung metastasis in vivo. Furthermore, RIP-seq analysis revealed that LSM7 binded to CD44 RNA, enhancing the expression of its alternatively spliced isoform CD44s, thereby driving BC metastasis and invasion. Additionally, the transcription factor TCF3 was found to activate LSM7 transcription by directly binding to its promoter. SIGNIFICANCE: In summary, this study highlights the pivotal role of LSM7 in the production of the CD44s isoform and the promotion of breast cancer metastasis. Targeting the TCF3/LSM7/CD44s axis may offer a promising therapeutic strategy for breast cancer treatment.
Subject(s)
Alternative Splicing , Breast Neoplasms , Hyaluronan Receptors , RNA-Binding Proteins , Humans , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Female , Alternative Splicing/genetics , Hyaluronan Receptors/metabolism , Hyaluronan Receptors/genetics , Animals , Mice , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Gene Expression Regulation, Neoplastic , Cell Line, Tumor , Mice, Nude , Mice, Inbred BALB C , Neoplasm Metastasis , Cell Movement/genetics , PrognosisABSTRACT
TNF receptor superfamily member 11a (TNFRSF11a, RANK) and its ligand TNF superfamily member 11 (TNFRSF11, RANKL) are overexpressed in many malignancies. However, the clinical importance of RANKL/RANK in colorectal cancer (CRC) is mainly unknown. We examined CRC samples and found that RANKL/RANK was elevated in CRC tissues compared with nearby normal tissues. A higher RANKL/RANK expression was associated with a worse survival rate. Furthermore, RANKL was mostly produced by regulatory T cells (Tregs), which were able to promote CRC advancement. Overexpression of RANK or addition of RANKL significantly increased the stemness and migration of CRC cells. Furthermore, RANKL/RANK signaling stimulated C-C motif chemokine ligand 20 (CCL20) production by CRC cells, leading to Treg recruitment and boosting tumor stemness and malignant progression. This recruitment process was accomplished by CCL20-CCR6 interaction, demonstrating a connection between CRC cells and immune cells. These findings suggest an important role of RANKL/RANK in CRC progression, offering a potential target for CRC prevention and therapy.
Subject(s)
Chemokine CCL20 , Colorectal Neoplasms , Neoplastic Stem Cells , RANK Ligand , Receptor Activator of Nuclear Factor-kappa B , Receptors, CCR6 , Signal Transduction , T-Lymphocytes, Regulatory , Humans , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/genetics , Chemokine CCL20/metabolism , Chemokine CCL20/genetics , RANK Ligand/metabolism , Receptors, CCR6/metabolism , Receptors, CCR6/genetics , Receptor Activator of Nuclear Factor-kappa B/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Animals , Male , Mice , Female , Neoplasm Metastasis , Cell Line, Tumor , Middle Aged , Mice, Nude , Cell MovementABSTRACT
Lung cancer is one of the most prevalent human cancers with a high lethality rate worldwide. In this study, we demonstrated that GSE1 (genetic suppressor element 1) expression is aberrantly upregulated in lung adenocarcinoma and that GSE1 depletion inhibits the proliferation and migration of both A549 and H1299 cells. Immunoprecipitation assays demonstrated that GSE1 interacts with histone deacetylase 1 (HDAC1) and other BRAF-HDAC complex (BHC) components in cells. The transcriptome of GSE1-knockdown A549 cells indicated that 207 genes were upregulated and 159 were downregulated based on a p-value < .05 and fold change ≥ 1.5. Bioinformatics analysis suggested that 140 differentially expressed genes harbor binding sites for HDAC1, including the tumor suppressor gene KLF6 (Kruppel-like factor 6). Indeed, quantitative reverse-transcription polymerase chain reaction and western blot analysis revealed that GSE1 could inhibit the transcription of KLF6 in lung cancer cells. In conclusion, GSE1 cooperates with HDAC1 to promote the proliferation and metastasis of non-small cell lung cancer cells through the downregulation of KLF6 expression.