Loss of TDP43 inhibits progression of triple-negative breast cancer in coordination with SRSF3

Hao, Ke; Zhao, Limin; Zhang, Honglei; Feng, Xu; Xu, Haibo; Hao, Jiejie; Wang, Shaowei; Yang, Qin; Zou, Li; Su, Xiaohong; Wang, Liqiong; Wu, Chen; Wang, Yan; Nie, Jianyun; Jiao, Baowei

doi:10.1073/pnas.1714573115

Cited by 82 publications

(73 citation statements)

References 71 publications

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“…Encoded by the Tardbp gene, TDP-43 is well recognized as an essential factor in amyotrophic lateral sclerosis and frontotemporal lobar degeneration 55,56 . Previous studies have shown that TDP-43 is involved in the progression of breast and other cancers 29,57,58 . In our study, TDP-43 loss resulted in large lipid droplets, consistent with the phenotypes observed in Btn1a1 −/− mice 13 .…”

Section: Discussionmentioning

confidence: 99%

“…As milk secretion is one of the most characteristic features of mammalian species, and TDP-43 (encoded by the TARDBP gene) is involved in breast cancer progression 29 , we hypothesized that TDP-43 may play an important role in milk secretion, while the other candidate, SRSF9, was excluded for further investigation because of its negatively regulatory roles on milk secretion-related genes (BTN and XOR) ( Supplementary Fig. 4A, B).…”

Section: Tdp-43 Loss In Mammary Epithelium Induces Lactation Failurementioning

confidence: 99%

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TDP-43 facilitates milk lipid secretion by post-transcriptional regulation of Btn1a1 and Xdh

Zhao

Hao

et al. 2020

Nat Commun

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Milk lipid secretion is a critical process for the delivery of nutrition and energy from parent to offspring. However, the underlying molecular mechanism is less clear. Here we report that TDP-43, a RNA-binding protein, underwent positive selection in the mammalian lineage. Furthermore, TDP-43 gene (Tardbp) loss induces accumulation of large lipid droplets and severe lipid secretion deficiency in mammary epithelial cells to outside alveolar lumens, eventually resulting in lactation failure and pup starvation within three weeks postpartum. In human milk samples from lactating women, the expression levels of TDP-43 is positively correlated with higher milk output. Mechanistically, TDP-43 exerts post-transcriptional regulation of Btn1a1 and Xdh mRNA stability, which are required for the secretion of lipid droplets from epithelial cells to the lumen. Taken together, our results highlights the critical role of TDP-43 in milk lipid secretion, providing a potential strategy for the screening and intervention of clinical lactation insufficiency.

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Section: Discussionmentioning

confidence: 99%

Section: Tdp-43 Loss In Mammary Epithelium Induces Lactation Failurementioning

confidence: 99%

TDP-43 facilitates milk lipid secretion by post-transcriptional regulation of Btn1a1 and Xdh

Zhao

Hao

et al. 2020

Nat Commun

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“…However, the association of SRSF3 with the clinical outcomes of cancer patients remains poorly understood. It was previously found that SRSF3 is overexpressed in triple-negative breast cancer [16], and a higher expression of SRSF3 was associated with a shorter survival time and poorer prognosis [17]. However, Torres et al…”

Section: Discussionmentioning

confidence: 96%

Underexpression of SRSF3 and its target gene RBMX predicts good prognosis in patients with head and neck cancer

et al. 2020

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Head and neck cancer collectively is one of the most common cancer types in the world. Oral squamous cell carcinoma (OSCC) is the most common subtype of head and neck cancer. SRSF3 is a protooncogene and is overexpressed in patients with OSCC. However, the relationship between SRSF3 expression and the clinical outcomes of patients with head and neck cancer remains unclear. By using the cBio-Portal for Cancer Genomics, a public online tool originally developed at Memorial Sloan Kettering Cancer Center (New York, NY, USA), it was revealed that patients with head and neck cancer with an underexpression of SRSF3 showed better overall and disease-/progression-free survival rates. Moreover, 227 genes were found to be significantly coexpressed with SRSF3 in head and neck cancer. Then, in combination with the analysis of a previous splice-array dataset that included significantly changed genes after the silencing of SRSF3, four potential target genes of SRSF3 were identified. RBMX and HNRNPL were further confirmed to be target genes of SRSF3. Moreover, the underexpression of RBMX was determined to be significantly associated with a favorable overall survival rate among patients, while patients with an underexpression of both SRSF3 and RBMX is a subgroup of individuals with better prognoses than all other patients. These results suggest that the underexpression of SRSF3 and that of its target RBMX can be used as potential biomarkers to predict favorable overall survival among head and neck cancer patients. Keywords; head and neck cancer, RBMX, SRSF3 Materials and Methods Cell culture and RNA interference CAL 27 cells were grown in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS; Gibco Laboratories, Gaithersburg, MD, USA) and 1% antibiotic-antimycotic solution (Invitrogen, Carlsbad, CA, USA). Separately, SCC-9 cells were cultured in a mixed medium of DMEM and Ham's F12 medium (1:1) supplemented with 10% FBS and 1% antibiotic-antimycotic solution and 400 ng/mL of hydrocortisone. Human SRSF3 small interfering RNA (siRNA) was synthesized by GenePharma (Shanghai, China). Cells were transfected with 20 nM of siRNA using lipofectamine 3,000 reagent (Invitrogen) according to the manufacturer's instructions. Forty-eight h later, cells underwent a second transfection and, 96 h after that, total protein and RNA samples were collected. The sequences of siRNAs used in this study are as follows: 5' AGAGCUAGAUGGAAGAACA 3' (SRSF3) and 5' ACUCUAUCUG-CACGCUGAC 3' (nonspecific; NS). Plasmid and transfection The T7-tagged SRSF3 expression plasmid (T7-SRSF3) was kindly provided by Dr. Zheng Zhi-Ming (National Cancer Institute, Bethesda, MD, USA). CAL 27 or SCC-9 cells were transfected with plasmid using lipofectamine 3,000 reagent according to the manufacturer's instructions. Western blot Total protein samples were loaded onto 10% sodium dodecyl sulfatepolyacrylamide gel electrophoresis gel and transferred to a nitrocellulose membrane. The membrane was blocked by 5% nonfat milk and analyzed by the followi...

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“…However, whether the splicing factors function as oncogenes or tumor-suppressors is dependent on cancer types. For example, it was shown that serine/arginine-rich splicing factor 3 (SRSF3) promotes the progression of breast cancer but suppresses hepatic carcinogenesis [60,61]. Moreover, it has been implicated that the post-translational modification of splicing factors regulates cancer-specific splicing events.…”

Section: Deregulated Gene Expression Of Splicing Factors In Cancermentioning

confidence: 99%

“…It was reported that SRSF3, in cooperation with another splicing factor TAR DNA-binding protein 43 (TDP43), plays an important role in the growth and metastasis of TNBC tumors. SRSF3 and TDP43 enhance the skipping of exon 12 of partitioning defective 3 (PAR3) and the inclusion of exon 12 of NUMB, and these splicing alterations promote the growth and metastasis of TNBC tumors, respectively [60]. In addition, SRSF3 is indicated to regulate alternative splicing of HER2 [86].…”

Section: Sr Proteinsmentioning

confidence: 99%

Roles of Splicing Factors in Hormone-Related Cancer Progression

Takeiwa

Mitobe

Ikeda

et al. 2020

IJMS

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Splicing of mRNA precursor (pre-mRNA) is a mechanism to generate multiple mRNA isoforms from a single pre-mRNA, and it plays an essential role in a variety of biological phenomena and diseases such as cancers. Previous studies have demonstrated that cancer-specific splicing events are involved in various aspects of cancers such as proliferation, migration and response to hormones, suggesting that splicing-targeting therapy can be promising as a new strategy for cancer treatment. In this review, we focus on the splicing regulation by RNA-binding proteins including Drosophila behavior/human splicing (DBHS) family proteins, serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) in hormone-related cancers, such as breast and prostate cancers.

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Loss of TDP43 inhibits progression of triple-negative breast cancer in coordination with SRSF3

Cited by 82 publications

References 71 publications

TDP-43 facilitates milk lipid secretion by post-transcriptional regulation of Btn1a1 and Xdh

TDP-43 facilitates milk lipid secretion by post-transcriptional regulation of Btn1a1 and Xdh

Underexpression of SRSF3 and its target gene RBMX predicts good prognosis in patients with head and neck cancer

Roles of Splicing Factors in Hormone-Related Cancer Progression

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