The Nuclear Pool of Tetraspanin CD9 Contributes to Mitotic Processes in Human Breast Carcinoma

Rappa, Germana; Green, Toni M.; Lorico, Aurelio

doi:10.1158/1541-7786.mcr-14-0242

Cited by 17 publications

(21 citation statements)

References 25 publications

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“…The intracellular pathway used by EV-derived biomaterials en route to the nucleus is also in line with studies showing new endosomal pathways that deliver surface proteins to the nucleus [44, 45]. Such mechanism might explain the presence of EV-associated proteins and nucleic acids in nuclei of target cells [17–19], and the atypical nuclear localization of CD9 and CD133 in cancer cells [46, 47]. …”

Section: Discussionsupporting

confidence: 55%

Nuclear transport of cancer extracellular vesicle-derived biomaterials through nuclear envelope invagination-associated late endosomes

et al. 2017

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Extracellular membrane vesicles (EVs) function as vehicles of intercellular communication, but how the biomaterials they carry reach the target site in recipient cells is an open question. We report that subdomains of Rab7+ late endosomes and nuclear envelope invaginations come together to create a sub-nuclear compartment, where biomaterials associated with CD9+ EVs are delivered. EV-derived biomaterials were also found in the nuclei of host cells. The inhibition of nuclear import and export pathways abrogated the nuclear localization of EV-derived biomaterials or led to their accumulation therein, respectively, suggesting that their translocation is dependent on nuclear pores. Nuclear envelope invagination-associated late endosomes were observed in ex vivo biopsies in both breast carcinoma and associated stromal cells. The transcriptome of stromal cells exposed to cancer cell-derived CD9+ EVs revealed that the regulation of eleven genes, notably those involved in inflammation, relies on the nuclear translocation of EV-derived biomaterials. Our findings uncover a new cellular pathway used by EVs to reach nuclear compartment.

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Section: Discussionsupporting

confidence: 55%

Nuclear transport of cancer extracellular vesicle-derived biomaterials through nuclear envelope invagination-associated late endosomes

et al. 2017

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“…Finally, other as yet unknown pathways could be involved in CD9 dependent regulation of AR activity due to the pleotropic effects of tetraspanins. The latter hypothesis is supported by recent results [ 88 ] showing nuclear localization of both CD9 and IGSF8 in breast carcinoma cells. That study showed that nuclear CD9 may be involved in regulation of mitosis, therefore IGSF8 inhibition may activate CD9 effects on both cell division and AR transcriptional regulation.…”

Section: Discussionsupporting

confidence: 76%

Identification of novel genes that regulate androgen receptor signaling and growth of androgen-deprived prostate cancer cells

et al. 2015

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Prostate cancer progression to castration refractory disease is associated with anomalous transcriptional activity of the androgen receptor (AR) in an androgen-depleted milieu. To identify novel gene products whose downregulation transactivates AR in prostate cancer cells, we performed a screen of enzymatically-generated shRNA lenti-libraries selecting for transduced LNCaP cells with elevated expression of a fluorescent reporter gene under the control of an AR-responsive promoter. The shRNAs present in selected populations were analyzed using high-throughput sequencing to identify target genes. Highly enriched gene targets were then validated with siRNAs against selected genes, testing first for increased expression of luciferase from an AR-responsive promoter and then for altered expression of endogenous androgen-regulated genes in LNCaP cells. We identified 20 human genes whose silencing affected the expression of exogenous and endogenous androgen-responsive genes in prostate cancer cells grown in androgen-depleted medium. Knockdown of four of these genes upregulated the expression of endogenous AR targets and siRNAs targeting two of these genes (IGSF8 and RTN1) enabled androgen-independent proliferation of androgen-dependent cells. The effects of IGSF8 appear to be mediated through its interaction with a tetraspanin protein, CD9, previously implicated in prostate cancer progression. Remarkably, homozygous deletions of IGSF8 are found almost exclusively in prostate cancers but not in other cancer types. Our study shows that androgen independence can be achieved through the inhibition of specific genes and reveals a novel set of genes that regulate AR signaling in prostate cancers.

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“…Therein, EV‐associated cargo molecules can modify the gene expression of the host cells. These surprising findings are in line with numerous studies showing the atypical nuclear localization of the EV‐associated proteins CD9 and CD133 as well as the shuttling of proteins and nucleic acids to nucleoplasm of recipient cells . Recently, we described that two proteins, ie vesicle‐associated membrane protein‐associated protein A (VAP‐A) and the cytoplasmic oxysterol‐binding protein‐related protein 3 (ORP3), are essential for the entry and the tethering of late endosomes to nuclear envelope invaginations of type II (Figure B).…”

Section: Introductionsupporting

confidence: 84%

Anti‐human CD9 antibody Fab fragment impairs the internalization of extracellular vesicles and the nuclear transfer of their cargo proteins

Santos

Rappa

Karbanová

et al. 2019

J Cellular Molecular Medi

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The intercellular communication mediated by extracellular vesicles ( EV s) has gained international interest during the last decade. Interfering with the mechanisms regulating this cellular process might find application particularly in oncology where cancer cell‐derived EV s play a role in tumour microenvironment transformation. Although several mechanisms were ascribed to explain the internalization of EV s, little is our knowledge about the fate of their cargos, which are crucial to mediate their function. We recently demonstrated a new intracellular pathway in which a fraction of endocytosed EV ‐associated proteins is transported into the nucleoplasm of the host cell via a subpopulation of late endosomes penetrating into the nucleoplasmic reticulum. Silencing tetraspanin CD 9 both in EV s and recipient cells strongly decreased the endocytosis of EV s and abolished the nuclear transfer of their cargos. Here, we investigated whether monovalent Fab fragments derived from 5H9 anti‐ CD 9 monoclonal antibody (referred hereafter as CD 9 Fab) interfered with these cellular processes. To monitor the intracellular transport of proteins, we used fluorescent EV s containing CD 9‐green fluorescent protein fusion protein and various melanoma cell lines and bone marrow‐derived mesenchymal stromal cells as recipient cells. Interestingly, CD 9 Fab considerably reduced EV uptake and the nuclear transfer of their proteins in all examined cells. In contrast, the divalent CD 9 antibody stimulated both events. By impeding intercellular communication in the tumour microenvironment, CD 9 Fab‐mediated inhibition of EV uptake, combined with direct targeting of cancerous cells could lead to the development of novel anti‐melanoma therapeutic strategies.

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The Nuclear Pool of Tetraspanin CD9 Contributes to Mitotic Processes in Human Breast Carcinoma

Cited by 17 publications

References 25 publications

Nuclear transport of cancer extracellular vesicle-derived biomaterials through nuclear envelope invagination-associated late endosomes

Nuclear transport of cancer extracellular vesicle-derived biomaterials through nuclear envelope invagination-associated late endosomes

Identification of novel genes that regulate androgen receptor signaling and growth of androgen-deprived prostate cancer cells

Anti‐human CD9 antibody Fab fragment impairs the internalization of extracellular vesicles and the nuclear transfer of their cargo proteins

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