Inhibition of Tumor Growth and Metastasis by Depletion of Vesicular Sorting Protein Hrs: Its Regulatory Role on E-Cadherin and β-Catenin

Toyoshima, Masafumi; Tanaka, Nobuyuki; Aoki, Jun; Tanaka, Yoshinori; Murata, Kazuko; Kyuuma, Masanao; Katori, Hideyuki; Ishii, Naoto; Yaegashi, Nobuo; Sugamura, Kazuo

doi:10.1158/0008-5472.can-06-2756

Cited by 67 publications

(70 citation statements)

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“…Hgs, one of the master regulators that direct activated receptors toward lysosomes, has been shown to play an important role in the lysosomal targeting of E-cadherin (16). Hgs contains an ubiquitin-interacting motif and is involved in the endosomal sorting of ubiquitinated membrane proteins, such as growth factor receptors and E-cadherin (17)(18)(19)(20). Ubiquitinated Ecadherin is specifically trafficked to the lysosome for degradation (16).…”

Section: Discussionmentioning

confidence: 99%

“…Ubiquitinated Ecadherin is specifically trafficked to the lysosome for degradation (16). Toyoshima and colleagues (20) revealed that Hgs depletion was associated with the upregulation of Ecadherin and reduced b-catenin signaling. The increased accumulation of E-cadherin observed in MARY-X spheroids and lymphovascular tumor emboli most likely results from impaired E-cadherin degradation in lysosomes mediated, in part, by decreased Hgs.…”

Section: Discussionmentioning

confidence: 99%

“…Total RNA was eluted and dissolved in RNase-free water, and the concentration was determined using a NanoDrop spectrophotometer (NanoDrop Technologies). For the first-strand cDNA synthesis, the SuperScript III First-Strand Synthesis System (Invitrogen, Inc.), oligo (dT) 20 , and 2 mg of total RNA were used. The synthesized cDNA was used for real-time RT-PCR analysis of relative expression levels of target genes.…”

Section: Rna Isolation and Cdna Synthesismentioning

confidence: 99%

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Early to Intermediate Steps of Tumor Embolic Formation Involve Specific Proteolytic Processing of E-Cadherin Regulated by Rab7

Yin

Gao

Tian

et al. 2012

Molecular Cancer Research

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The lymphovascular embolus is an enigmatic entity adept at metastatic dissemination and chemotherapy resistance. Using MARY-X, a human breast cancer xenograft that exhibits florid lymphovascular emboli in mice and spheroids in vitro, we established a model where the in vitro transition stages from minced tumoral aggregates to well-formed spheroids served as a surrogate for in vivo emboli formation. MARY-X well-formed spheroids and emboli exhibited strong similarity of expression. The aggregate-to-spheroid transition stages were characterized by increased ExoC5, decreased Hgs and Rab7, increased calpains, increased full-length E-cadherin (E-cad/FL), and the transient appearance of E-cad/NTF2, a 95 kDa E-cadherin fragment and increased Notch3icd (N3icd), the latter two fragments produced by increased g-secretase. Both transient and permanent knockdowns of Rab7 in MCF-7 cells increased protein but not transcription of E-cad/FL and resulted in the de novo appearance of E-cad/NTF2, the presence of nuclear E-cad/CTF2, and increased Notch1icd (N1icd). Overexpression of Rab7 conversely decreased E-cad/FL, g-secretase (PS1/NTF), and E-cad/NTF2. Overexpression of calpains did not alter PS1/NTF but decreased E-cad/FL and E-cad/NTF2 and increased N1icd. Well-formed spheroids showed increased Rab7, absent E-cad/NTF2, decreased PS1/NTF, increased E-cad/NTF1, and increased N3icd, the latter two fragments being the direct and indirect consequences, respectively, of increased calpains (calpain 1 and calpain 2). Inhibition of calpains decreased E-cad/NTF1 but increased E-cad/NTF2 showing that calpains compete with g-secretase (PS1) for closely located cleavage/binding sites on E-cadherin and that increased calpains can shuttle even decreased

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Rna Isolation and Cdna Synthesismentioning

confidence: 99%

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Early to Intermediate Steps of Tumor Embolic Formation Involve Specific Proteolytic Processing of E-Cadherin Regulated by Rab7

Yin

Gao

Tian

et al. 2012

Molecular Cancer Research

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“…Therefore, experiments addressed to analyze the candidate target genes expression were carried out in parathyroid tissues. Recently, HGS, which has been found highly expressed in a number of human cancers (Rayala et al 2006, Toyoshima et al 2007, has been reported as a target gene of the miR-296 inhibitory action in primary brain tumor endothelial cells (Würdinger et al 2008). Accordingly, both PaCs and adenomas characterized by low miR-296 expression levels showed HGS mRNA levels higher than those observed in PaN tissue.…”

Section: Endocrine-related Cancermentioning

confidence: 99%

Differential expression of microRNAs in human parathyroid carcinomas compared with normal parathyroid tissue

Corbetta

Vaira

Guarnieri

et al. 2010

Endocrine-Related Cancer

136

117

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Parathyroid carcinoma (PaC) is a rare cause of primary hyperparathyroidism. Though the loss of the oncosuppressor CDC73/HRPT2 gene product, parafibromin, has been involved in the hyperparathyroidism-jaw tumor syndrome and in a consistent set of sporadic PaCs, parathyroid carcinogenesis remains obscure. MicroRNAs are a new class of small, non-coding RNAs implicated in development of cancer, since their deregulation can induce aberrant expression of several target genes. The aim of the present study was to identify differentially expressed microRNAs in parathyroid cancers compared with normal tissues. We performed a TaqMan low-density array profiling of four parathyroid cancers harboring CDC73 inactivating mutations and negative for parafibromin immunostaining. Their microRNA profiling was compared with that of two normal parathyroid biopsies. Out of 362 human microRNAs assayed, 279 (77%) were successfully amplified. Fourteen and three microRNAs were significantly down-and over-expressed in parathyroid cancers respectively. Of these, miR-296 and miR-139 were down-regulated, and miR-503 and miR-222 were over-expressed with a null false discovery rate. Carcinomas could be discriminated from parathyroid adenomas by a computed score based on the expression levels of miR-296, miR-222, and miR-503 as miR-139 was similarly down-regulated in both cancers and adenomas. Finally, miR-296 and miR-222 levels negatively correlated with mRNA levels of the hepatocyte growth factor receptor-regulated tyrosine kinase substrate and p27/kip1 levels respectively. These results suggest the existence of an altered microRNA expression pattern in PaCs together with a potential role of miR-296 as novel oncosuppressor gene in these neoplasia.

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“…MVB function has also been related to several kinds of cancer due to its role in the degradation of receptor tyrosine kinases and its involvement in cytokinesis. Accordingly, TSG101 has been found to be over-expressed in several cancers and Hrs over-expression is associated with malignancy (Toyoshima, et al 2007, Tu, et al 2011. Surprisingly, in other cases ESCRT loss-of-function, instead of overexpression, can lead to tumorigenesis.…”

Section: Endocytic Trafficking and Diseasementioning

confidence: 99%

Endocytic regulation of alkali metal transport proteins in mammals, yeast and plants

et al. 2013

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Mulet Salort, JM.; Llopis Torregrosa, V.; Primo Planta, C.; Marques Romero, MC.; Yenush, L. (2013) The relative concentrations of ions and solutes inside cells are actively maintained by several classes of transport proteins, in many cases against their concentration gradient. These transport processes, which consume a large portion of cellular energy, must be constantly regulated. Many structurally distinct families of channels, carriers, and pumps have been characterized in considerable detail during the past decades and defects in the function of some of these proteins have been linked to a growing list of human diseases. The dynamic regulation of the transport proteins present at the cell surface is vital for both normal cellular function and for the successful adaptation to changing environments. The composition of proteins present at the cell surface is controlled on both the transcriptional and post-translational level. Post-translational regulation involves highly conserved mechanisms of phosphorylation-and ubiquitylation-dependent signal transduction routes used to modify the cohort of receptors and transport proteins present under any given circumstances. In this review, we will summarize what is currently known about one facet of this regulatory process: the endocytic regulation of alkali metal transport proteins. The physiological relevance, major contributors, parallels and missing pieces of the puzzle in mammals, yeast and plants will be discussed.

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Inhibition of Tumor Growth and Metastasis by Depletion of Vesicular Sorting Protein Hrs: Its Regulatory Role on E-Cadherin and β-Catenin

Cited by 67 publications

References 50 publications

Early to Intermediate Steps of Tumor Embolic Formation Involve Specific Proteolytic Processing of E-Cadherin Regulated by Rab7

Early to Intermediate Steps of Tumor Embolic Formation Involve Specific Proteolytic Processing of E-Cadherin Regulated by Rab7

Differential expression of microRNAs in human parathyroid carcinomas compared with normal parathyroid tissue

Endocytic regulation of alkali metal transport proteins in mammals, yeast and plants

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