TDP43 promotes stemness of breast cancer stem cells through CD44 variant splicing isoforms. 2022

Lu Guo, and Hao Ke, and Honglei Zhang, and Li Zou, and Qin Yang, and Xuemei Lu, and Limin Zhao, and Baowei Jiao
State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.

Alternative splicing (AS) is a promising clinical target for cancer treatment at the post-transcriptional level. We previously identified a unique AS profile in triple-negative breast cancer (TNBC), which is regulated by the splicing regulator TAR DNA-binding protein-43 (TDP43), thus indicating the crucial role of TDP43 in heterogeneous TNBC. Cluster of differentiation 44 (CD44), a widely recognized marker for breast cancer stem cells (BCSCs), is extensively spliced into CD44 variant AS isoforms (CD44v) during the development of breast cancer. At present, however, the regulatory mechanism of CD44v is not fully understood. In the current study, we found that loss of TDP43 inhibits BCSC stemness by reducing the abundance of CD44v. In addition, serine-arginine-rich splicing factor 3 (SRSF3), another splicing factor and partner of TDP43, acts as an upstream regulator of TDP43 to maintain CD44v isoforms and thereafter BCSC stemness. Mechanistically, SRSF3 stabilizes the mRNA of TDP43 by inhibiting nonsense-mediated decay (NMD). These findings illustrate the important role of complicated regulatory networks formed by splicing factors in TNBC progression, thus providing potential therapeutic targets from an AS perspective.

UI MeSH Term Description Entries
D004268 DNA-Binding Proteins Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases. DNA Helix Destabilizing Proteins,DNA-Binding Protein,Single-Stranded DNA Binding Proteins,DNA Binding Protein,DNA Single-Stranded Binding Protein,SS DNA BP,Single-Stranded DNA-Binding Protein,Binding Protein, DNA,DNA Binding Proteins,DNA Single Stranded Binding Protein,DNA-Binding Protein, Single-Stranded,Protein, DNA-Binding,Single Stranded DNA Binding Protein,Single Stranded DNA Binding Proteins
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000068103 Serine-Arginine Splicing Factors A family of regulatory factors essential for constitutive and alternative splicing in RNA metabolism. SR-Rich Splicing Proteins,Serine-Arginine-Rich Splicing Proteins,Factors, Serine-Arginine Splicing,Proteins, SR-Rich Splicing,Proteins, Serine-Arginine-Rich Splicing,SR Rich Splicing Proteins,Serine Arginine Rich Splicing Proteins,Serine Arginine Splicing Factors,Splicing Factors, Serine-Arginine,Splicing Proteins, SR-Rich,Splicing Proteins, Serine-Arginine-Rich
D012326 RNA Splicing The ultimate exclusion of nonsense sequences or intervening sequences (introns) before the final RNA transcript is sent to the cytoplasm. RNA, Messenger, Splicing,Splicing, RNA,RNA Splicings,Splicings, RNA
D014411 Neoplastic Stem Cells Highly proliferative, self-renewing, and colony-forming stem cells which give rise to NEOPLASMS. Cancer Stem Cells,Colony-Forming Units, Neoplastic,Stem Cells, Neoplastic,Tumor Stem Cells,Neoplastic Colony-Forming Units,Tumor Initiating Cells,Cancer Stem Cell,Cell, Cancer Stem,Cell, Neoplastic Stem,Cell, Tumor Initiating,Cell, Tumor Stem,Cells, Cancer Stem,Cells, Neoplastic Stem,Cells, Tumor Initiating,Cells, Tumor Stem,Colony Forming Units, Neoplastic,Colony-Forming Unit, Neoplastic,Initiating Cell, Tumor,Initiating Cells, Tumor,Neoplastic Colony Forming Units,Neoplastic Colony-Forming Unit,Neoplastic Stem Cell,Stem Cell, Cancer,Stem Cell, Neoplastic,Stem Cell, Tumor,Stem Cells, Cancer,Stem Cells, Tumor,Tumor Initiating Cell,Tumor Stem Cell,Unit, Neoplastic Colony-Forming,Units, Neoplastic Colony-Forming
D017398 Alternative Splicing A process whereby multiple RNA transcripts are generated from a single gene. Alternative splicing involves the splicing together of other possible sets of EXONS during the processing of some, but not all, transcripts of the gene. Thus a particular exon may be connected to any one of several alternative exons to form a mature RNA. The alternative forms of mature MESSENGER RNA produce PROTEIN ISOFORMS in which one part of the isoforms is common while the other parts are different. RNA Splicing, Alternative,Splicing, Alternative,Alternate Splicing,Nested Transcripts,Alternate Splicings,Alternative RNA Splicing,Alternative RNA Splicings,Alternative Splicings,Nested Transcript,RNA Splicings, Alternative,Splicing, Alternate,Splicing, Alternative RNA,Splicings, Alternate,Splicings, Alternative,Splicings, Alternative RNA,Transcript, Nested,Transcripts, Nested
D018960 Hyaluronan Receptors Acidic sulfated integral membrane glycoproteins expressed in several alternatively spliced and variable glycosylated forms on a wide variety of cell types including mature T-cells, B-cells, medullary THYMOCYTES; GRANULOCYTES; MACROPHAGES; erythrocytes, and fibroblasts. Their interaction with HYALURONIC ACID mediates binding of lymphocytes to high endothelial VENULES. Antigens, CD44,CD44 Antigens,Hyaluronan-Binding Protein,Receptors, Hyaluronan,CD44 Antigen,Chondroitin Sulfate Proteoglycan 8,Hyaluronan Receptor,Hyaluronic Acid Binding Protein,Antigen, CD44,Hyaluronan Binding Protein,Receptor, Hyaluronan
D020033 Protein Isoforms Different forms of a protein that may be produced from different GENES, or from the same gene by ALTERNATIVE SPLICING. Isoform,Isoforms,Protein Isoform,Protein Splice Variant,Splice Variants, Protein,Protein Splice Variants,Isoform, Protein,Isoforms, Protein,Splice Variant, Protein,Variant, Protein Splice,Variants, Protein Splice
D064726 Triple Negative Breast Neoplasms Breast neoplasms that do not express ESTROGEN RECEPTORS; PROGESTERONE RECEPTORS; and do not overexpress the NEU RECEPTOR/HER-2 PROTO-ONCOGENE PROTEIN. ER-Negative PR-Negative HER2-Negative Breast Cancer,ER-Negative PR-Negative HER2-Negative Breast Neoplasms,Triple Negative Breast Cancer,Triple-Negative Breast Cancer,Triple-Negative Breast Neoplasm,Breast Cancer, Triple-Negative,Breast Cancers, Triple-Negative,Breast Neoplasm, Triple-Negative,Breast Neoplasms, Triple-Negative,ER Negative PR Negative HER2 Negative Breast Cancer,ER Negative PR Negative HER2 Negative Breast Neoplasms,Triple Negative Breast Neoplasm,Triple-Negative Breast Cancers,Triple-Negative Breast Neoplasms

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