KSRP suppresses cell invasion and metastasis through miR-23a-mediated EGR3 mRNA degradation in non-small cell lung cancer

Chien, Ming Hsien; Lee, Wei Jiunn; Yang, Yi; Li, Yin Lin; Chen, Bo Rong; Cheng, Tsu‐Yao; Yang, Ping-Shih; Wang, Ming Yang; Jan, Yi-Hua; Lin, Yen Kuang; Lee, Jang-Ming; Hsiao, Michael; Chen, Jin‐Shing; Hua, Kuo Tai

doi:10.1016/j.bbagrm.2017.08.005

Cited by 31 publications

(40 citation statements)

References 51 publications

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“…In the case of MSI2a dysregulation in TNBC, TP53INP1 mRNA becomes unstable, resulting in decreased TP53INP1, inevitably causing increased p-ERK and TNBC metastasis Overall, further studies are needed to identify whether the role of MSI2a is organ-site dependent. Indeed, previous studies have shown that RBPs, such as MSI2, possess the dual capacity to stimulate and repress the translation of specific mRNAs, depending on the cellular context [7,28,29]. In our study, we demonstrated that MSI2a was able to bind to and upregulate TP53INP1 and a panel of p53 signaling genes that can regulate p53 phosphorylation, including TP53INP1, ATM, EP300, HIPK2, and DNA-PKcs [30].…”

Section: Discussionsupporting

confidence: 56%

RNA-binding protein MSI2 isoforms expression and regulation in progression of triple-negative breast cancer

Zhou

et al. 2020

J Exp Clin Cancer Res

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Background: The RNA-binding protein Musashi-2 (MSI2) has been implicated in the tumorigenesis and tumor progression of some human cancers. MSI2 has also been reported to suppress tumor epithelial-to-mesenchymal transition (EMT) progression in breast cancer, and low MSI2 expression is associated with poor outcomes for breast cancer patients; however, the underlying mechanisms have not been fully investigated. This study investigated the expression and phenotypic functions of two major alternatively spliced MSI2 isoforms (MSI2a and MSI2b) and the potential molecular mechanisms involved in triple-negative breast cancer (TNBC) progression. Methods: The Illumina sequencing platform was used to analyze the mRNA transcriptomes of TNBC and normal tissues, while quantitative reverse transcription-polymerase chain reaction and immunohistochemistry validated MSI2 isoform expression in breast cancer tissues. The effects of MSI2a and MSI2b on TNBC cells were assayed in vitro and in vivo. RNA immunoprecipitation (RIP) and RNA sequencing were performed to identify the potential mRNA targets of MSI2a, and RIP and luciferase analyses were used to confirm the mRNA targets of MSI2. Results: MSI2 expression in TNBC tissues was significantly downregulated compared to that in normal tissues. In TNBC, MSI2a expression was associated with poor overall survival of patients. MSI2a overexpression in vitro and in vivo inhibited TNBC cell invasion as well as extracellular signal-regulated kinase 1/2 (ERK1/2) activity. However, MSI2b overexpression had no significant effects on TNBC cell migration. Mechanistically, MSI2a expression promoted TP53INP1 mRNA stability by its interaction with the 3′-untranslated region of TP53INP1 mRNA. Furthermore, TP53INP1 knockdown reversed MSI2a-induced suppression of TNBC cell invasion, whereas ectopic expression of TP53INP1 and inhibition of ERK1/2 activity blocked MSI2 knockdown-induced TNBC cell invasion. Conclusions: The current study demonstrated that MSI2a is the predominant functional isoform of MSI2 proteins in TNBC, that its downregulation is associated with TNBC progression and poor prognosis and that MSI2a expression inhibited TNBC invasion by stabilizing TP53INP1 mRNA and inhibiting ERK1/2 activity. Overall, our study provides new insights into the isoform-specific roles of MSI2a and MSI2b in the tumor progression of TNBC, allowing for novel therapeutic strategies to be developed for TNBC.

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Section: Discussionsupporting

confidence: 56%

RNA-binding protein MSI2 isoforms expression and regulation in progression of triple-negative breast cancer

Zhou

et al. 2020

J Exp Clin Cancer Res

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“…To further characterize the in vivo effect of DABIL-4 upon the metastatic potential, we analyzed total RNA isolated from the primary tumors using the NanoString PanCancer Immune Profiling Panel Assay. We noted significant declines in the level of several transcripts associated with metastasis (Cd36 (15), Egr3 (16)(17)(18) and Maf (19)) and tumorigenesis (Ccr2 (20), Ccr6 (21)) in many solid tumors including breast cancer (Fig 4 and Table 1). We also observed an increased levels of the C200r1 transcript which is associated with inhibition of metastasis and tumorigenesis (22,23) (Fig 4 and Table 1).…”

Section: Dabil-4 Inhibits Tumor Growth and Prevents Lung Metastases Imentioning

confidence: 90%

IL-4 receptor targeting as an effective immunotherapy against triple-negative breast cancer

Parveen

Siddharth

Kumar

et al. 2020

Preprint

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In many solid tumors including triple-negative breast cancer (TNBC), IL-4 receptor (IL-4R) upregulation has been shown to promote cancer cell proliferation, apoptotic resistance, metastatic potential and a Th2 response in the tumor microenvironment (TME). Immunosuppressive cells in the TME including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) also express the IL4-R. We hypothesized that selective depletion of IL4-R bearing cells in TNBC may have dual cytotoxic and immunotherapeutic benefit. To selectively target IL-4R+ cells, we genetically constructed, expressed and purified DABIL-4, a fusion protein toxin consisting of the catalytic and translocation domains of diphtheria toxin fused to murine IL-4. We found that DABIL-4 has potent and specific cytotoxic activity against TNBC cells in vitro. In murine TNBC models, DABIL-4 significantly reduced tumor growth, splenomegaly and lung metastases, and this was associated with reductions in MDSC, TAM and regulatory T-cells (Tregs) populations with a concomitant increase in the proportion of IFNγ+ CD8 T-cells. The anti-tumor activity of DABIL-4 was absent in IL-4R KO mice directly implicating IL-4R directed killing as the mechanism of anti-tumor activity. Moreover, NanoString analysis of DABIL-4 treated TNBC tumors revealed marked decline in mRNA transcripts that promote tumorigenesis and metastasis. Our findings demonstrate that DABIL-4 is a potent targeted antitumor agent which depletes both IL-4R bearing tumor cells as well as immunosuppressive cell populations in the TME.STATEMENT OF SIGNIFICANCEIn solid tumors like breast cancer, Interleukin-4 receptor (IL-4R) expression in the tumor microenvironment aids tumor growth and metastasis. IL-4R expression upon host immune cells further dampens antitumor immunity. In this study, we have genetically constructed a fusion protein toxin, DABIL-4, composed of the catalytic and translocation domains of diphtheria toxin and murine IL-4. DABIL-4 showed specific cytotoxicity against triple-negative breast cancer (TNBC) cells in vitro. DABIL-4 also markedly inhibited TNBC tumor growth and metastasis in vivo. The primary activity of DABIL-4 was found to be depletion of IL-4R+ immune cells in combination with direct elimination of tumor cells. In conclusion, DABIL-4 targeting of both tumor and immunosuppressive host cells is a versatile and effective treatment strategy for TNBC.

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“…EGR3 played a role in cell growth and migration. It had been reported that EGR3 depletion resulted in a significant decrease of migratory and invasive abilities of CL1-5 cells 25 .…”

Section: Fibroblasts Derived From Ggn-adc Expressed Low Levels Of Sommentioning

confidence: 93%

Single-cell transcriptome atlas of lung adenocarcinoma featured with ground glass nodules

Yang

Shi

et al. 2020

Cell Discov

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As an early type of lung adenocarcinoma, ground glass nodule (GGN) has been detected increasingly and now accounts for most lung cancer outpatients. GGN has a satisfactory prognosis and its characteristics are quite different from solid adenocarcinoma (SADC). We compared the GGN adenocarcinoma (GGN-ADC) with SADC using the single-cell RNA sequencing (scRNA-seq) to fully understand GGNs. The tumor samples of five patients with lung GGN-ADCs and five with SADCs underwent surgery were digested to a single-cell suspension and analyzed using 10× Genomic scRNA-seq techniques. We obtained 60,459 cells and then classified them as eight cell types, including cancer cells, endothelial cells, fibroblasts, T cells, B cells, Nature killer cells, mast cells, and myeloid cells. We provided a comprehensive description of the cancer cells and stromal cells. We found that the signaling pathways related to cell proliferation were downregulated in GGN-ADC cancer cells, and stromal cells had different effects in GGN-ADC and SADC based on the analyses of scRNA-seq results. In GGN-ADC, the signaling pathways of angiogenesis were downregulated, fibroblasts expressed low levels of some collagens, and immune cells were more activated. Furthermore, we used flow cytometry to isolate the cancer cells and T cells in 12 GGN-ADC samples and in an equal number of SADC samples, including CD4+ T and CD8+ T cells, and validated the expression of key molecules by quantitative real-time polymerase chain reaction analyses. Through comprehensive analyses of cell phenotypes in GGNs, we provide deep insights into lung carcinogenesis that will be beneficial in lung cancer prevention and therapy.

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KSRP suppresses cell invasion and metastasis through miR-23a-mediated EGR3 mRNA degradation in non-small cell lung cancer

Cited by 31 publications

References 51 publications

RNA-binding protein MSI2 isoforms expression and regulation in progression of triple-negative breast cancer

RNA-binding protein MSI2 isoforms expression and regulation in progression of triple-negative breast cancer

IL-4 receptor targeting as an effective immunotherapy against triple-negative breast cancer

Single-cell transcriptome atlas of lung adenocarcinoma featured with ground glass nodules

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